Joshua C Briscoe, MD

• Medical Instructor in the Department of Psychiatry and Behavioral Sciences
• Medical Instructor in the Department of Medicine

https://medicine.duke.edu/faculty/joshua-c-briscoe-md

Familial and environmental variables can also influence development of birth defects virus dmmd buy generic trimethoprim 960 mg on line. Thus antibiotics mastitis 960 mg trimethoprim buy visa, an important criterion for teratogenicity is that two or more high-quality epidemiological studies report similar findings antibiotics and birth control buy discount trimethoprim 960 mg. In fact antibiotics depression discount trimethoprim american express, the Teratology Society (2005) states that establishment of causation in teratology-related litigation requires human data antibiotics for dogs eye infection order trimethoprim 480 mg visa. Failure to employ these tenets and criteria has contributed to erroneous conclusions regarding the safety of some widely used drugs. This antiemetic was a combination of doxylamine and pyridoxine, with or without dicyclomine, and was safe and effective for nausea and vomiting in early pregnancy. More than 30 million women used this drug worldwide, and the 3-percent congenital anomaly rate among exposed fetuses was not different from the background rate (McKeigue, 1994). Despite considerable evidence that this combination of an antihistamine and a B-vitamin is not teratogenic, Bendectin was the target of numerous lawsuits, and the financial burden of defending these forced its withdrawal from the marketplace. Studies in Pregnant Women the study of medication safety-or teratogenicity-in pregnant women is fraught with complications. For example, thalidomide is harmless in several animal species but resulted in phocomelia in thousands of children born across Europe in the late 1950s and early 1960s. Instead, pregnant women are considered a special population and summarily excluded from medication trials. Last, drug concentration and thus embryo-fetal exposure are affected by pregnancy physiology. These include changes in volume of distribution, cardiac output, gastrointestinal absorption, hepatic metabolism, and renal clearance. In the absence of research trials, counseling is based on case reports or series, case-control studies, cohort studies, and pregnancy registry data. Case Reports and Series Many, if not most, major teratogens were first described by clinicians who observed a rare defect occurring after a rare exposure. Congenital rubella syndrome was identified in this way by Gregg (1941), an Australian ophthalmologist whose observations challenged the view that the uterine environment was impervious to noxious agents. Other teratogens identified through case series include thalidomide and alcohol (Jones, 1973; Lenz, 1962). Shepard (2002a) recommended that establishment of teratogenicity in this way requires proven exposure at a critical time in development and probably at least three such cases, each carefully delineated. Unfortunately, teratogens are less likely to be identified if the exposure is uncommon, if the defects are relatively nonspecific, or if abnormalities develop in only a small proportion of exposed fetuses. Case-Control Studies these studies begin with groups of affected infants (cases) and unaffected controls and are structured to allow retrospective assessment of prenatal exposure to particular substances. These permit investigators to evaluate associations and generate useful hypotheses. Namely, parents of an affected infant are often more likely to recall exposure than those whose child is not ill. Confounding by indication is another concern, that is, the indication for the medication may be the cause of the birth defect. And importantly, birth defect registries have statistical power to detect small differences that may not be clinically meaningful. Grimes and Schulz (2012) have cautioned that unless odds ratios in case-control studies are above three- to fourfold, the observed associations may not be correct. Clinical geneticists reviewed each potential case, and standardized telephone interviews were conducted with mothers whose pregnancies were affected or unaffected to obtain information regarding medication exposure and risk factors (Mitchell, 2011; Reefhuis, 2015). Live births, stillbirths, and terminated pregnancies were included and totaled approximately 32,000 cases and nearly 12,000 controls. First, interviews were conducted 6 weeks to 2 years following delivery, which raised the likelihood of recall bias. For example, 25 percent of women could not remember which antibiotic they had taken (Ailes, 2016). Another weakness was that only two thirds of women agreed to participate, and there were differences in ethnicity and socioeconomic status between cases and controls. In addition, medical records were not reviewed to verify dosage, and this precluded assessment of dose-response relationships. As a result, some of the associations observed were likely due to chance (Alwan, 2015). For example, the study of antibiotics and birth defects included 43 comparisons and identified four significant associations, but chance alone predicted that two associations would be identified (Ailes, 2016). Last, the low absolute risk of an abnormality complicates counseling and prenatal management. Cohort Studies these studies begin with cohorts of pregnant women who are exposed or unexposed to a particular medication. The percentage of infants or children affected with birth defects is examined in each cohort. Because individual birth defects are rare, cohort studies require a very large sample size. Medicaid datasets and private insurance claims databases are commonly used for cohort studies of teratogenicity in the United States (Ehrenstein, 2010). Inability to adjust for confounding variables-such as the indication for which the medication was needed-may be an important limitation of this study design. Pregnancy Registries Potentially harmful agents may be monitored by clinicians who prospectively enroll exposed pregnancies in a registry. Similar to case series, exposure registries are hampered by lack of a control group. The prevalence of an abnormality identified through a registry requires knowledge of the baseline prevalence of that anomaly in the population. Investigators typically use a birth defect registry to assess population prevalence. One example is the Metropolitan Atlanta Congenital Defects Program, which is an active surveillance program established in 1967 for fetuses and infants with birth defects. Individuals tend to underestimate the background risk for birth defects in the general population and exaggerate potential risks associated with medication exposure. In a recent population-based study of more than 270,000 births from Utah that included 5500 fetuses and infants with major birth defects, only 4 cases were attributed to medication exposure. And yet, Koren and colleagues (1989) reported that a fourth of women exposed to nonteratogenic drugs thought they had a 25-percent risk for fetal anomalies. Knowledgeable counseling may allay anxiety considerably and may even avert pregnancy termination. Several sources are available to assist providers with accurate and updated risk information. PubMed is a free tool from the National Center for Biomedical Information that aids rapid search of published research. They summarize human and animal studies of teratogenicity and fetotoxicity, address the quality of the available evidence, and provide magnitude of risk. Lactmed, a database from the National Library of Medicine, specifically deals with medication use by breastfeeding women. Its entries on specific medications describe levels in breast milk and potential effects on the infant. Five categories- A, B, C, D, and X-were intended to summarize available evidence from human or animal studies of embryonic­fetal risk. These letters also conveyed benefits of the given medication balanced against its potential risks. Food and Drug Administration Letter Categories for Drugs and Medications (1979­2015)a Unfortunately, information regarding medication risk was very often incomplete and led to an overreliance on the definition of the letter category alone. However, a higher letter grade did not necessarily mean greater risk, and drugs in the same category often had very different risks. Very few medications-fewer than 1 percent-had demonstrated safety in human pregnancy (category A), and most had no safety data in human or animal studies (category C). Another difficulty was that the classification system did not address inadvertent exposure, a common reason for counseling. Ultimately, it is the responsibility of the clinician to interpret letter category information in the context of medication dosage and route, timing of exposure during pregnancy, other medications used, and underlying medical condition(s). To address these deficiencies, new labeling requirements were created and went into effect in 2015. Updates to older medications will be phased in over time (Food and Drug Administration, 2014). The format for providing information includes a summary of risks, clinical considerations, and available data. The pregnancy subsection has registry information, if available, as well as labor and delivery information. For each medication, a lactation subsection-formerly called "nursing mothers"-is included. There is also a section to address potential risks in females and males with reproductive potential. Presenting Risk Information In addition to potential embryonic and fetal risks from drug exposure, counseling should discuss the risks and/or genetic implications of the underlying condition for which the drug is given. For example, women given negative information-such as a 2-percent chance of a malformed newborn-are more likely to perceive an exaggerated risk than women given positive information-such as a 98-percent chance of an unaffected infant (Jasper, 2001). Instead of citing a higher odds ratio, it may be helpful to provide the absolute risk for a particular defect or the attributable risk, which is the difference between prevalence in exposed and unexposed individuals (Conover, 2011). The association between oral corticosteroid medications and cleft lip sounds far more concerning when presented as a tripling or 200-percent increase in risk than when described as an increase from 1 per 1000 to 3 per 1000 or as a 99. With a few notable exceptions, most commonly prescribed drugs and medications can be used with relative safety during pregnancy. Many drugs discussed in this chapter are low-risk teratogens, which are medications that produce defects in fewer than 10 per 1000 maternal exposures (Shepard, 2002a). Because risks conferred by low-risk teratogens are so close to the population background rate of fetal anomalies, they may not be a major factor in deciding whether to discontinue treatment for an important condition (Shepard, 2002b). Remember that all women have an approximate 3-percent chance of having a newborn with a birth defect. Although exposure to a confirmed teratogen may elevate this risk, the magnitude of the increase is usually only 1 or 2 percent or at most, doubled or tripled. Some untreated diseases pose a more serious threat to both mother and fetus than medication exposure risks. With few exceptions, in every clinical situation potentially requiring therapy with a known teratogen, alternative drugs can be given with relative safety. Realizing limitations in available evidence, pregnant women should be advised to take any medication only when it is clearly needed. In general, targeted sonography is indicated if there has been exposure to any major teratogen during the embryonic period. It is considered the leading cause of preventable developmental disabilities worldwide (Hoyme, 2016). In the United States, 8 percent of pregnant women report drinking alcohol and between 1 and 2 percent admit to binge drinking (Centers for Disease Control and Prevention, 2012). Lemoine (1968) and Jones (1973) and their coworkers are credited with describing the spectrum of alcohol-related fetal defects known as fetal alcohol syndrome (Table 12-4). For every child with the syndrome, many more are born with neurobehavioral deficits from alcohol exposure (American College of Obstetricians and Gynecologists, 2013). Fetal alcohol spectrum disorder is an umbrella term that includes five conditions attributed to prenatal alcohol damage: (1) fetal alcohol syndrome, (2) partial fetal alcohol syndrome, (3) alcohol-related birth defects, (4) alcohol-related neurodevelopmental disorder, and (5) neurobehavioral disorder associated with prenatal alcohol exposure (Williams, 2015). The birth prevalence of fetal alcohol syndrome is estimated to be as high as 1 percent in the United States (Centers for Disease Control, 2012; Guerri, 2009). But, studies of school children have identified fetal alcohol spectrum disorder in 2 to 5 percent (May, 2009, 2014). Criteria for Prenatal Alcohol Exposure, Fetal Alcohol Syndrome, and Alcohol-Related Birth Defects Criteria and Characteristics Fetal alcohol syndrome has specific criteria (see Table 12-4). Similar criteria have been established for the other conditions that make up fetal alcohol spectrum disorder (Hoyme, 2016). Note persistence of short palpebral fissures, epicanthal folds, flat midface, hypoplastic philtrum, and thin upper vermilion border. Natural history of fetal alcohol syndrome: a 10-year follow-up of eleven patients, Lancet. An association has further been reported between periconceptional alcohol use and omphalocele and gastroschisis (Richardson, 2011). There are no established sonographic criteria for prenatal diagnosis of fetal alcohol syndrome. That said, in some cases, major abnormalities or growth restriction may be suggestive (Paintner, 2012). Dose Effect Fetal vulnerability to alcohol is modified by genetic components, nutritional status, environmental factors, coexisting maternal disease, and maternal age (Abel, 1995). Binge drinking, however, is believed to pose particularly high risk for alcohol-related birth defects and has also been linked to a higher risk for stillbirth (Centers for Disease Control, 2012; Maier, 2001; Strandberg-Larsen, 2008). Antiepileptic Medications Traditionally, women with epilepsy requiring treatment with medication were informed that their risk for fetal malformations was increased. More recent data suggest that the risk may not be as great as once thought, particularly for newer agents. The most frequently reported anomalies are orofacial clefts, cardiac malformations, and neural-tube defects. Regarding other specific anticonvulsants, one recent metaanalysis identified higher malformation rates among exposed children compared with rates among children born to women with untreated epilepsy. Rates were twofold higher among children exposed to carbamazepine or phenytoin, threefold higher among those exposed to phenobarbital, and fourfold higher among those exposed to topiramate as monotherapy (Weston, 2016). The risk for fetal malformations is approximately doubled if multiple agents are required (Vajda, 2016). Facial features including upturned nose, mild midfacial hypoplasia, and long upper lip with thin vermilion border.

The principles of the surgery remain the same in all types of interrupted aortic arch antibiotics for uti and ear infection purchase trimethoprim pills in toronto. Surgical intervention typically includes aortic arch reconstruction as well as correcting any associated intracardiac lesions infection leg pain cheap 960 mg trimethoprim overnight delivery. Dissection of the ascending aorta and associated branches and the main pulmonary artery is carried out while avoiding hemodynamic compromise antibiotic vaginal itching generic trimethoprim 480 mg otc. The arterial cannula is inserted into a graft sutured to the innominate artery and bicaval venous cannulation is utilized infection treatment generic trimethoprim 960 mg. When the core temperature reaches 18 C bacterial gastroenteritis trimethoprim 480 mg free shipping, circulatory arrest or low flow cerebral perfusion is established. The descending aorta is well mobilized and is brought up to the level of left innominate artery. A tension-free anastomosis is performed between the ascending and descending aorta. The timing of surgery is preferably within the first week of life before the fall in pulmonary resistance. Without surgical correction, approximately 40% of patients will die within first month of life and 90% during infancy. Patients with severe truncal valve regurgitation and severe congestive cardiac failure are better served with surgical intervention within 24­48 hours. The Fio2 should be kept at 17­21% and relative hypercarbia (PaCo245­50%) maintained in order to keep the pulmonary resistance high. A heart rate of 120­140 beats per minute and diastolic blood pressure above 25 mmHg is preferred to avoid coronary ischemia from diastolic runoff. The aorta is cross-clamped as distally as possible to provide access to the pulmonary artery ostia. After cardiac arrest, the aorta is opened taking care to avoid the truncal valve, coronary origins, and pulmonary ostia. In patients with type 1 Collett and Edwards, in which origin of the truncus is well away from the left main coronary artery, the pulmonary arteries with a small rim of truncal wall are mobilized. A right ventriculotomy is made in the infundibulum avoiding the coronary arteries ans well as the truncal valve. The subarterial ventricular septal defect is closed with a large bovine pericardial patch. The risk of heart block is small because the subarterial ventricular septal defect is separated from conduction system by the septal band. After ventricular septal defect closure, the truncal valve is assessed and repaired if neccesary. The subarterial ventricular septal defect is well visualized through a right ventriculotomy. The distal anastomosis of the allograft is performed at the level of confluence of the pulmonary arteries. The proximal posterior aspect of the allograft is then approximated to the superior portion of the right infundibulotomy directly. A bovine pericardial patch is used anteriorly to augment the allograft to right ventricle connection. Note the completed proximal anastomosis between the homograft and pulmonary arteries. However, the surgery can be carried out in the cardiac operating room in the stable neonate. Transferring a preterm baby with mechanical ventilation and inotropic support requires a great team effort and necessitates particular attention to the inspired oxygen (Fio2) and body temperature. The patient is positioned with the left side of the chest up with left arm supported above the level of the head to elevate the scapula. The chest is entered through third intercostal space and the left lung is retracted. The mediastinal pleura over the descending aorta is divided after cauterizing the overlying left superior intercostal vein. After the aortic arch, left subclavian artery and descending aorta are identified, careful dissection of the ductus is carried out. At the same time, the femoral arterial line or pulse oximetry are observed to confirm that the descending aorta remains patent. Care should be taken to not apply the clip too close to the aorta to avoid creating an aortic coarctation. The majority of these patients have related severe congenital heart diseases and debilitating cardiomyopathies, which usually present during first year of life [2]. There has been a progressive increase in the rates of heart transplant, especially in infants, but the limited availability of donor hearts for children prolongs the waiting period [3], resulting in increased rates of death while waiting [4]. More than 80% of these patients are post cardiotomy for complex congenital heart disease and cardiomyopathies or myocarditis, most of which develop in the first year of life [7]. Cannulation Techniques and Circuit Designs Cannulation site is dependent on clinical situation. Serial echocardiograms to evaluate volume status, right heart function, and left ventricle unloading should be carried out. The protocols for management of anticoagulation differ from institution to institution; however, the general strategies for management of bleeding and thrombosis complications are shown in Box 67. The simplification of the circuit with fewer connectors and the use of a manifold shunt line are strategies for minimizing clot formation in the circuit. These children should be supported with parenteral or enteral nutrition as soon as feasible. However, serious adverse events, including infection, stroke, and bleeding, occurred in a majority of study participants. Since then, as is evident in this update, the five participating contractors have made outstanding technical advancements toward the ultimate goal of providing safe and effective devices for circulatory support in infants, neonates, and young children with advanced severe heart disease. Life-threatening intrathoracic complications during treatment with extracorporeal membrane oxygenation. The technique of heart transplantation was developed in the laboratory and the first human-to-human heart transplant was performed in December 3, 1967 on an adult by Dr. Several days later, on December 6, 1967, the first heart transplant in North America was performed on an 18-day-old infant with a fatal heart defect from an anencephalic baby by Dr. Early attempts at transplantation were limited by the diagnosis and medical management of rejection. Heart transplantation was brought into the modern era by the development of endomyocardial biopsy which allowed accurate diagnosis of rejection, and by the development of the immunosuppressant cyclosporine. Leonard Bailey and the team at Loma Linda made world headlines in 1984 by transplanting a baboon heart into baby Fae. He obtained prolonged survival and is still alive 25 years post transplant with the original heart graft [1]. Infant transplantation subsequently grew dramatically during the late 1980s and early 1990s, but reached a plateau in the mid 1990s. This plateau is likely related to limited number of donors and to improved surgerical results for single ventricle palliation. Evolution in the care of neonates with congenital heart disease has resulted in a progressive change in the indications for infant heart transplantation. The majority of infant transplants were initially performed for congenital heart disease (75%). Because of improvements in surgical outcomes for complex neonatal heart surgeries and development of alternative therapies, the number infant heart transplants for cardiomyopathy now equal those for congenital heart disease. Post-Transplant Survival While the initial risks of infant transplantation are higher than older age transplants (likely because of operative risk), the longitudinal survival is better. The Loma Linda experience indicates that neonatal transplants have a graft survival advantage relative to other infants, with a 59% graft survival rate at 25 years post neonatal heart transplant [1]. Post- transplant survival for infants is affected by the underlying diagnosis, with congenital heart disease having an increased risk of mortality compared to those post-transplant for cardiomyopathy. Stratifying survival by era indicates that more recent transplantation provides better initial survival. This is likely related to improvements in perioperative care and to a lower operative mortality rate, which will result in better longitudinal survival. Maintenance immunosuppression is weaned aggressively in infants to mono or dual therapy with a calcineurin inhibitor (cyclosporine or tacrolimus) with or without mycophenolate or azathioprine. It is thought to be a manifestation of chronic rejection and is related to cytomegalovirus infection. Quality of Life the majority of patients post infant heart transplant (>85%) have no activity limitations and have an excellent functional status post-transplant. Immunosuppression All heart transplant patients require immunosuppression to prevent rejection and this is based on classic (adult) triple-drug therapy. These protocols include the use of steroids, antiproliferative agents (azathioprine, mycophenolate), and calcineurin inhibitors (tacrolimus and cyclosporine), and are evolving with the introduction of new medications. There is an growing recognition that neonates likely require less aggressive immunosuppression than older heart transplant patients [3]. A common strategy utilizes induction therapy with Waitlist Mortality Infant heart transplant waitlist mortality has been reported to be as high as 20­25%, providing the highest mortality for any solid organ waitlist [5]. Recent advances, including recognition that infant transplants can be performed across blood type [3] and advances in mechanical support (such as the Berlin Heart) have 454 Neonatal Cardiac Transplantation improved the effective donor pool and may decrease waitlist mortality. The Loma Linda data also suggest that graft ischemic time can be safely extended above 4 hours for infant donors [6, 8] which allows for longer travel times and, potentially, extends donor availability and utilization. Transplantation would likely provide equivalent or better intermediate survival, good functional capacity, good quality of life, and likely long-term graft survival [9]. Infant heart transplant is performed via a median sternotomy and cardiopulmonary bypass. Hypothermia can facilitate both myocardial protection and operative exposure by allowing lower flow rates (and pulmonary venous return), and allow for circulatory arrest to complete arch reconstruction. Remote aortic cannulation via placement of a tube graft to the innominate artery allows for selective cerebral perfusion if arch reconstruction is required. Biatrial reconstruction, as described by Lower and Shumway, is generally performed [10, 11], although a bicaval technique can be utilized if the cava are large enough to avoid the potential risks of caval stenosis. If required, the arch is reconstructed utilizing the donor aortic graft to augment the arch. Benefits the favorable long-term outcome following neonatal heart transplantation has led some to believe that infants have a relatively naïve immune system that makes the neonatal period an ideal time to perform heart transplantation [3]. This unique time can present a window of opportunity for optimal transplant decision-making relative to other operative strategies. Analysis of the original Loma Linda series for infant heart transplantation suggests a survival after listing for transplant of 68% at 1 year and 61% at 5 years [4]. It has been associated with excellent long-term survival and quality of life relative to older patients and other treatment alternatives. Long-term outcome following neonatal and infant heart transplantation suggests that neonates have a relatively naïve immune system that may provide for an optimal timing for heart transplantation. Goal-directed medical care based on objective indices of cardiovascular well-being has a proven track record of improving outcomes. Anticipatory care based on evidence and institutional experience has resulted in prevention rather than management of adverse events. Clinical pathways are an excellent tool to ensure that an individual patient remains on track for an excellent recovery. The focus today is not only on preventing postoperative mortality in the neonatal period, but also on favorably impacting the overall well-being of the baby and reducing complications that would impact the life of the child. Optimum outcomes after newborn heart surgery require a comprehensive multidisciplinary team of specialists (Box 69. There has been debate over which type of intensive care unit these babies should be placed for postoperative recovery: a neonatal intensive care unit, a pediatric intensive care unit, or a pediatric cardiac intensive care unit. The best cardiovascular results begin with appropriate evaluation and stabilization of the preoperative patient. Diagnostic evaluation of most neonates can be completed non-invasively at the bedside. Occasionally, additional information such as cardiac catheterization or magnetic resonance imaging studies are required. Stabilization of the critically ill newborn includes restoration of perfusion and oxygen delivery to vital organs, including the brain. Babies presenting in extremis should be allowed to recover from the presenting condition if possible and show signs of end-organ recovery before surgery. There are exceptions to this general rule and those patients should undergo surgery without delay. For other neonates, once there is evidence that adequate end-organ function has improved, there is no need to delay surgery. General Principles 457 Postoperative management begins with a comprehensive handover of the baby from the anesthesia and transport team to the critical care team. Standardized preprinted forms are highly recommended for recovering babies after complex procedures. A description of the operation is essential along with details of expected and unexpected findings. Perfusion records should provide data on duration of cardiopulmonary bypass, circulatory arrest, and aortic cross-clamp times. In the postoperative care of the newborn cardiac patient, the goal is to optimize the relationship between oxygen delivery and oxygen consumption through increasing oxygen delivery, decreasing oxygen consumption, or both. Critically ill patients who can achieve a normal level of oxygen delivery have been shown to have lower mortality, better end organ function, and shorter length of hospital stay. Unfortunately, measuring oxygen delivery or consumption in the postoperative neonate is difficult and not routinely performed clinically. The mixed venous oxygen saturation actually defines this relationship, but will not give the clinician any data regarding the primary aberration. When the A-V O2 difference is increased, clinical expertise is needed to decide whether oxygen delivery is diminished or oxygen consumption is increased. For certain patients, such as a baby recovering after the Norwood palliation, oxygen consumption can be pathologically elevated, even in the sedated and intubated neonate.

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It is caused by pressure disequilibrium across the tympanic membrane when the Eustachian tube fails to ventilate the ear antibiotics discovery order 960 mg trimethoprim amex. This usually happens in case of excessive increase in middle ear pressure beyond a certain point when the Eustachian tube is normal and also in a sudden increase in volume of the middle ear space when the tube is malfunctioning antibiotic resistance vets discount trimethoprim uk. Rapid ascent or descent infection without antibiotics order trimethoprim 480 mg free shipping, nasal infections antibiotics dogs order genuine trimethoprim on line, polyps infection 2 walkthrough order trimethoprim master card, or allergy may precipitate barotraumas. Infants and young children also suffer more from barotrauma because of the shorter, wider, straighter, and immature auditory tube in comparison with adults. Normally the Eustachian or auditory tube passively allows air to escape from the middle ear cleft 4. This is necessary when the external or atmospheric pressure falls, and consequently the middle ear volume rises while pressure falls. The increased volume of air in the middle ear cavity would cause passive opening of the auditory tube. If the nasopharyngeal end of the tube is malfunctioning either due to edema or compression from adenoids or nasopharyngeal masses, the tube fails to open passively. The middle ear pressure continues to fall, and a vacuum is created in the middle ear cleft, causing capillaries to rupture and bleed and resulting in effusion or hemotympanum. The patient experiences pain, fullness or ear block, and hearing impairment until the time the insult passes, and the fluid contents are slowly resorbed. Long-term sequelae could be fibrosis, ankylosis, tympanosclerosis, or cholesterol granuloma, all resulting in conductive deafness. When the atmospheric pressure rises, as happens during the descent phase of a flight or deep sea dive, the middle ear is compressed, and the volume in the middle ear cleft falls, while the pressure rises. This would normally prevent the nasopharyngeal end of the tube from opening passively, and now active muscular action at this end causes the tube to open widely and equalize the middle ear pressure. Active muscular action is brought about and augmented by yawning, swallowing, sucking, and the Toynbee, Muller, and Valsalva maneuvers. All these may be difficult to perform in the event of an upper respiratory tract infection or external compression by adenoids or other masses. The continued rise in pressure leads to capillary hemorrhages and sometimes perforation of the eardrum, resulting in pain and conductive hearing loss. The facial canal is narrowest at its labyrinthine portion where the facial nerve enters the internal acoustic meatus. These two latter problems add to the propensity of the facial nerve to undergo ischemic injury in this portion. The facial nerve then turns backward sharply behind the processus cochleariformis, forming the first genu and continuing as the horizontal or tympanic segment 58 4 Trauma to Ear until it turns downward at the level of the pyramidal eminence, forming the second genu and continuing as the vertical/longitudinal or mastoid segment, to finally escape from the skull base through the stylomastoid foramen. It then enters the parotid gland to divide into the five terminal branches-temporal, zygomatic, buccal, mandibular, and cervical-at the posterior border of the parotid gland in a formation known as the pes anserinus or the foot of a duck. The facial nerve nucleus at the pons receives the majority of its innervation from the opposite cerebral cortex, with only the portion for the temporal branch receiving ipsilateral innervations as well. Thus it is that supranuclear lesions spare the upper part of the contralateral but affected side, whereas infranuclear or lower motor neuron lesions cause a complete paralysis of the same side of the face. This, together with the deep petrosal nerve derived from the branches of the cervical sympathetic plexus, forms the nerve of the pterygoid canal, otherwise known as the Vidian nerve. It supplies the secretomotor glands of the lacrimal and nasal regions and may be affected in transverse fractures of the temporal bone where the nerve gets sheared at its point of exit from the first genu. Just after the second genu, the facial nerve gives off its nerve to the stapedius which controls the stapedial reflex and then the chorda tympani nerve which is responsible for the perception of taste in the anterior two thirds of the ipsilateral tongue. Both these branches may be injured in transverse fractures of the temporal bone with or without involvement of the otic capsule. The mastoid and subsequent portions of the facial nerve carry motor innervations to the muscles of the face, and injury in these regions could occur from both temporal bone fractures and penetrating injuries of the upper neck region. The most common manifestation of facial nerve injury is paralysis, and this has been classified by Seddon into three types-neuropraxia, axonotmesis, neurotmesis-and by Sunderland into five types: neuropraxia, axonotmesis, neurotmesis, partial transection (perineural disruption), and complete transection (epineural disruption). The classification system of House and Brackmann is slightly different and is composed of six grades that take into account the muscle groups involved, the functional impairment, and also the nature of return of spontaneous facial nerve activity. The practical aspect of this second classification system is that grade 4 and higher means incomplete eye closure with maximal effort and therefore demands utmost attention to care of the affected eye. Grade 3 paralyses may also necessitate some form of eye care as complete closure takes place only with maximal effort. Grades 5 and 6 of the House-Brackmann classification describe the effects of faulty regeneration of the nerve and the presence of abnormal features such as synkinesia and mass movements. Facial nerve injury poses three principal problems-eye and corneal exposure with the risk of blindness, inability to express smile and other emotions, and asymmetry of the face at rest leading to a socially frightening and unacceptable appearance. The symptoms produced would be dry eye with epiphora, alteration in taste, hyperacusis and intolerance to sound, as well as weakness of the facial musculature on the affected side. A third category, caused by human or animal bites, usually involves the extracranial portion of the cranial nerve and may additionally cause injuries over the face and parotid gland. The facial nerve can also be affected in barotraumas of the ear and result in facial nerve paralysis. This usually occurs when there are natural dehiscences of the facial nerve canal or when the facial canal has been involved in temporal bone trauma. Transmission of pressure waves may then lead to concussion, edema, or inflammation of the exposed facial nerve and cause a facial nerve paresis or palsy depending on the extent of the underlying defect and superimposed injury. This kind of facial weakness is usually temporary and responds to conservative measures. Surgical exploration may be needed when medical or conservative measures fail and would follow the same protocol as that for facial nerve injury seen in temporal bone trauma. Indeed, popular anecdotes abound as to the proficiency of the otologist who causes a facial nerve paralysis, and that one has not done a good mastoidectomy if one has not injured the facial nerve in the process! In the current era, however, such humor may well be considered to be in extremely bad taste, what with exacting standards for resident training, sophisticated imaging techniques, and the use of intraoperative facial nerve monitoring. Any trauma, including iatrogenic facial nerve trauma, is most commonly encountered in the tympanic segment because of the considerably high incidence of facial nerve canal dehiscence involving this portion, in roughly 50% of the general population. Causes of facial palsy of immediate onset following temporal bone fracture include nerve transection or laceration, bony spicules and fragments of the facial canal impinging on the nerve, and hematoma(s) compressing the nerve sheath exposed by the injury or in cases of congenital dehiscence. It has five parts, namely the squamous, petrous, mastoid, tympanic, and zygomatic, which articulates with the zygoma or cheek bone. The zygomatic process of the temporal bone divides the lateral surface of the skull into the temporal part above and the infratemporal fossa below, which also forms the roof of the glenoid fossa of the temporomandibular joint. Temporal bone fractures are a kind of skull base fractures, which occur as result of transmission of forces across the suture lines and foramina of the skull base. Temporal bone fractures are the result of complex trauma to the head and facial skeleton and thus accompany head injuries and facial fractures, more commonly the former. Though the petrous part of the temporal bone is one of the strongest bones in the body, it is vulnerable to fracture along lines of weakness owing to the shearing forces distributed along the base of the skull. Thus the temporal bone may break at any of its parts-squamous, mastoid, petrous, tympanic ring, or zygomatic process, or even at the styloid process. Along with bone, soft tissue injury also occurs, and neural and vascular elements are also affected. Temporal bone fractures have traditionally been divided into two broad categories-longitudinal and transverse. Longitudinal fractures are more common and comprise about 80% of fractures, and the rest are transverse fractures. A longitudinal fracture is so called because it occurs along the long axis of the temporal bone-from the external auditory meatus to the apex of the petrous part-and usually traverses the middle ear cleft and auditory tube. It is caused by a lateral impact upon the skull due to direct physical assault with a blunt object, falls to the side, and motor vehicle accidents with a lateral shearing force. It tends to cause more soft tissue than bony injury, and thus external ear abrasions, contusions, or lacerations may be seen. The external auditory canal and the contiguous tympanic membrane may be lacerated or avulsed, and perforations may be seen. Hemotympanum or the presence of blood behind an intact tympanic membrane is common due to bleeding into the middle ear cleft. Pain, bleeding from ear or nose (through the auditory tube), deformity, and conductive hearing loss are seen. Permanent conductive loss occurs due to incudostapedial joint subluxation or disarticulation, dislocation of the incus, stapes arch fractures, malleus fracture, and finally fixation of the incus or head of the malleus as the outer attic wall is pushed medially or laterally by compressive forces. Although these latter varieties form a severe type of conductive hearing loss, it is not truly permanent in nature as surgical correction may be undertaken if the cochlear reserve is good. A fracture line passing through the Eustachian tube may result in refractory otitis media with effusion due to damage to the Eustachian cushion and would have to be treated with myringotomy and insertion of a ventilation tube. A transverse fracture refers to the occurrence of the fracture line through the broad aspect of the petrous temporal, thus cutting across it transversely instead of along it longitudinally. The most common site is across the otic capsule-either just in front of it (medial) or behind it (lateral). Thus, it has a high predilection for causing injury to the inner ear and facial nerve. Therefore, even though transverse fractures comprise about 20% of temporal bone fractures, nearly 50% of this type of fracture can cause facial nerve paralysis. Irreversible hearing loss due to damage to the cochlea, or occurrence of a perilymphatic fistula, intractable vertigo, and 4. A transverse fracture follows a linear path from the foramen magnum to the foramen spinosum across the foramen lacerum, also traversing and affecting on its way the jugular foramen, hypoglossal foramen, and internal auditory meatus. A longitudinal fracture is roughly perpendicular to this, that is, it extends across the squamous part of the temporal bone to the foramen spinosum, passing on its way the posterior superior part of the external auditory canal, upper portion of the middle ear, and the carotid canal. The relative incidences of longitudinal and transverse fractures mentioned above, though the most often cited, are not constant and vary rather widely across the published literature on this topic. This is a more practical classification, and features of both transverse and longitudinal fractures are seen. Temporal bone fractures in children may have a similar presentation as in adults but with less morbidity as the pneumatization of the mastoid air cells lends a good amount of elasticity and shockabsorbing capacity to the temporal bone and the involved structures. Ear canal lacerations if circumferential need to be gently packed with a steroid antibiotic ointment to minimize chances of stenosis, whereas isolated areas of injury may be left to heal on their own without packing, taking care only to maintain aseptic conditions, or prophylactic antibiotics orally if required. Presence of a hemotympanum does not always mean active intervention, aspiration, or drainage, but a strict vigil must be maintained to promptly detect and treat ossicular chain damage or fibrosis. Blast trauma is due to the transmission of a very strong pressure wave across all the components of the ear-external, middle, and inner. It may be due to an excessively loud noise or an explosive force as is seen in bomb blasts, gunshot, and other ballistic wounds. While loud noise spares the external ear and tends to damage the more delicate middle and inner ear structures, explosions could damage all the three components as they also carry physical particles such as shrapnel and gunpowder and also chemicals or toxins. External ear lacerations, perichondritis, eardrum perforations, ossicular damage, and inner ear barotrauma can also occur. In addition, the spiral lamina of the cochlea may be disrupted leading to various degrees of hearing loss which is usually permanent. They may be pierced into the tissue or attached with a press-style clamp or have a combination of both. Piercing methods may not always be aseptic in nature, and infections are very common and in some cases may lead to serious problems such as perichondritis. Ear manipulation with buds and other solid objects such as hairpins and safety pins is very common and can cause direct trauma to the skin of the ear canal and may even perforate the tympanic membrane if forcibly introduced deeper into the ear, such as when another person pushes or brushes against the user. Medication abuse or routine use of potentially ototoxic eardrops may be considered a form of trauma-both self-induced and iatrogenic. Medication abuse with antibiotic eardrops may lead to fungal infections of the ear canal, while ototoxic medications may cause hearing impairment. External ear trauma has been classified by Weerda [1] into the following four types: 1. Minor abrasion-this type, as the definition suggests, involves minimal intervention in the form of an antibiotic cream for superficial abrasion and primary suturing of the wound with topical or oral antibiotic cover. Minor avulsion-where only a part of the pinna has been avulsed but has a pedicle about 5 mm in size with a feeding vessel, primary suturing may be done with fine nonabsorbable monofilament material, taking care to approximate the edges carefully. Major avulsion-if the pinna is avulsed and a large piece up to several millimeters in size is lost or devitalized, the missing part may be sacrificed and primary suturing is still possible. In some areas of the pinna, some distortion of normal anatomy may be acceptable, as over the lobule or rim. The pinna may look 64 4 Trauma to Ear slightly smaller in size as compared to the unaffected side but structurally similar and hence cosmetically all right. Primary repair and direct reattachment of an avulsed auricle as a composite graft can be done if the size of the amputated part is smaller than 15 mm in diameter [2]. Even if the amputated segment has suffered an ischemia time of the usual 4­6 h, it does not affect the chances of graft uptake or failure of a directly replanted composite graft, especially if a microsurgical replantation has been carried out [3]. Another method of primary repair is by repositioning the cartilage and covering it with local skin flaps such as a platysma or temporoparietal fascia flap [4]. Complete avulsion-when there is complete loss of the pinna, or a wound size larger than one and a half centimeter, bringing the skin edges together may not be possible. A soft tissue flap harvested from the same site, or a free flap from another region, may then be necessary. For example, blunt soft tissue impact may cause enough shearing forces to tear the auricle apart including both the skin and the underlying cartilage. This could be seen in direct impact as in assault or contact sport, motor vehicle accidents with exposure of the side of head, blast trauma with shattering of soft tissue, and penetrating injury with gunshot or sharp weapons. Loss of cartilage from the pinna results in severe scarring and distortion of anatomy.

The canalicular period of lung development antibiotic resistance gene database buy cheap trimethoprim 960 mg online, during which the bronchi and bronchioles enlarge and alveolar ducts develop infection nursing care plan 480 mg trimethoprim with visa, is nearly completed virus locked computer purchase 960 mg trimethoprim with mastercard. Despite this headphones bacteria 700 times trimethoprim 960 mg buy without a prescription, a fetus born at this time will attempt to breathe virus united states buy generic trimethoprim, but many will die because the terminal sacs, required for gas exchange, have not yet formed. The overall survival rate at 24 weeks is barely above 50 percent, and only approximately 30 percent survive without severe morbidity (Rysavy, 2015). Nociceptors are present over all the body, and the neural pain system is developed (Kadic, 2012). The otherwise normal neonate born at this age has a 90-percent chance of survival without physical or neurological impairment. In contrast, by 36 weeks, the fetal crown-rump length averages about 32 cm, and the weight approximates 2800 g (Duryea, 2014). Because of subcutaneous fat deposition, the body has become more rotund, and the previous wrinkled facies is now fuller. The average crownrump length measures about 36 cm, and the average weight approximates 3500 g. Hence, folic acid supplementation to prevent neural-tube defects must be in place before this point to be efficacious (Chap. The lumen becomes the ventricular system of the brain and the central canal of the spinal cord. During the sixth week, the cranial end of the neural tube forms three primary vesicles. In the seventh week, five secondary vesicles develop: the telencephalon-future cerebral hemispheres; diencephalon-thalami; mesencephalon-midbrain; metencephalon -pons and cerebellum; and myelencephalon-medulla. The end of the embryonic period signifies completion of primary and secondary neuralization. As expected, disorders in this cerebral development phase profoundly worsen function (Volpe, 2008). This process is characterized by movement of millions of neuronal cells from their ventricular and subventricular zones to areas of the brain in which they reside for life. Upregulation of gene expression for neuronal migration has been described (Iruretagoyena, 2014). Noninvasive methods to study fetal neurodevelopment have also been reported (Goetzl, 2016). During the second half of gestation, organizational events proceed with gyral formation and proliferation, differentiation, and migration of cellular elements. Thus, it is possible to identify fetal age from its external appearance (Volpe, 2008). Neuronal proliferation and migration proceed along with gyral growth and maturation. Myelination of the ventral roots of the cerebrospinal nerves and brainstem begins at approximately 6 months, but most myelination progresses after birth. This lack of myelin and incomplete skull ossification permit fetal brain structure to be seen sonographically throughout gestation. Spinal Cord Whereas the superior two thirds of the neural tube give rise to the brain, the inferior third forms the spinal cord. In the embryo, the spinal cord extends along the entire vertebral column length, but after that it lags behind vertebral growth. Ossification of the entire sacrum is visible sonographically by approximately 21 weeks (Chap. By 24 weeks, the spinal cord extends to S1, at birth to L3, and in the adult to L1. Spinal cord myelination begins at midgestation and continues through the first year of life. Synaptic function is sufficiently developed by the eighth week to demonstrate flexion of the neck and trunk (Temiras, 1968). During the third trimester, integration of nervous and muscular function proceeds rapidly. At its earliest stages of formation, the fetal heart undergoes molecular programming, and more than a hundred genes and molecular factors are integral to its morphogenesis. To summarize, the straight cardiac tube is formed by the 23rd day during an intricate morphogenetic sequence, during which each segment arises at a unique time. The tube then undergoes looping, and the chambers then fuse and form septa (Manner, 2009). Fetal Circulation this unique circulation is substantially different from that of the adult and functions until birth, when it changes dramatically. For example, because fetal blood does not need to enter the pulmonary vasculature to be oxygenated, most of the right ventricular output bypasses the lungs. In addition, the fetal heart chambers work in parallel, not in series, which effectively supplies the brain and heart with more highly oxygenated blood than the rest of the body. Oxygen and nutrient materials required for fetal growth and maturation are delivered from the placenta by the single umbilical vein. The ductus venosus is the major branch of the umbilical vein and traverses the liver to enter the inferior vena cava directly. Because it does not supply oxygen to the intervening tissues, it carries well-oxygenated blood directly to the heart. In contrast, the portal sinus carries blood to the hepatic veins primarily on the left side of the liver, and oxygen is extracted. The relatively deoxygenated blood from the liver then flows back into the inferior vena cava, which also receives more deoxygenated blood returning from the lower body. Blood flowing to the fetal heart from the inferior vena cava, therefore, consists of an admixture of arterial-like blood that passes directly through the ductus venosus and less well-oxygenated blood that returns from most of the veins below the level of the diaphragm. The oxygen content of blood delivered to the heart from the inferior vena cava is thus lower than that leaving the placenta. The degree of blood oxygenation in various vessels differs appreciably from that in the postnatal state. Well-oxygenated blood enters the left ventricle, which supplies the heart and brain, and less oxygenated blood enters the right ventricle, which supplies the rest of the body. These two separate circulations are maintained by the right atrial structure, which effectively directs entering blood to either the left atrium or the right ventricle, depending on its oxygen content. This separation of blood according to its oxygen content is aided by the pattern of blood flow in the inferior vena cava. The well-oxygenated blood tends to course along the medial aspect of the inferior vena cava and the less oxygenated blood flows along the lateral vessel wall. Once this blood enters the right atrium, the configuration of the upper interatrial septum-the crista dividens- preferentially shunts the well-oxygenated blood from the medial side of the inferior vena cava and the ductus venosus through the foramen ovale into the left heart and then to the heart and brain (Dawes, 1962). After these tissues have extracted needed oxygen, the resulting less oxygenated blood returns to the right atrium through the superior vena cava. The less oxygenated blood coursing along the lateral wall of the inferior vena cava enters the right atrium and is deflected through the tricuspid valve to the right ventricle. The superior vena cava courses inferiorly and anteriorly as it enters the right atrium, ensuring that less well-oxygenated blood returning from the brain and upper body also will be shunted directly to the right ventricle. Similarly, the ostium of the coronary sinus lies just superior to the tricuspid valve so that less oxygenated blood from the heart also returns to the right ventricle. As a result of this blood flow pattern, blood in the right ventricle is 15 to 20 percent less saturated than blood in the left ventricle. Almost 90 percent of blood exiting the right ventricle is shunted through the ductus arteriosus to the descending aorta. High pulmonary vascular resistance and comparatively lower resistance in the ductus arteriosus and the umbilical­placental vasculature ensure that only about 8 percent of right ventricular output goes to the lungs (Fineman, 2014). Thus, one third of the blood passing through the ductus arteriosus is delivered to the body. The remaining right ventricular output returns to the placenta through the two hypogastric arteries. These two arteries course from the level of the bladder along the abdominal wall to the umbilical ring and into the cord as the umbilical arteries. In the placenta, this blood picks up oxygen and other nutrients and is recirculated through the umbilical vein. Circulatory Changes at Birth After birth, the umbilical vessels, ductus arteriosus, foramen ovale, and ductus venosus normally constrict or collapse. With the functional closure of the ductus arteriosus and the expansion of the lungs, blood leaving the right ventricle preferentially enters the pulmonary vasculature to become oxygenated before it returns to the left heart (Hillman, 2012). Virtually instantaneously, the ventricles, which had worked in parallel in fetal life, now effectively work in series. The more distal portions of the hypogastric arteries undergo atrophy and obliteration within 3 to 4 days after birth. These become the umbilical ligaments, whereas the intraabdominal remnants of the umbilical vein form the ligamentum teres. The ductus venosus constricts by 10 to 96 hours after birth and is anatomically closed by 2 to 3 weeks. Fetoplacental Blood Volume Although precise measurements of human fetoplacental blood volume are lacking, Usher and associates (1963) reported values in term normal newborns to average 78 mL/kg when immediate cord clamping was conducted. Gruenwald (1967) found the fetal blood volume contained in the placenta after prompt cord clamping to average 45 mL/kg of fetal weight. Thus, fetoplacental blood volume at term is approximately 125 mL/kg of fetal weight. This is important when assessing the magnitude of fetomaternal hemorrhage as discussed in Chapter 15 (p. Hemopoiesis In the early embryo, hemopoiesis is demonstrable first in the yolk sac, followed by the liver, and finally spleen and bone marrow. Both myeloid and erythroid cells are continually produced by progenitors that are from hematopoietic stem cells (Golub, 2013; Heinig, 2015). The first erythrocytes released into the fetal circulation are nucleated and macrocytic. The mean cell volume is at least 180 fL in the embryo and decreases to 105 to 115 fL at term. The erythrocytes of aneuploid fetuses generally do not undergo this maturation and maintain high mean cell volumes- 130 fL on average (Sipes, 1991). As fetal development progresses, more and more of the circulating erythrocytes are smaller and nonnucleated. With fetal growth, both the blood volume in the common fetoplacental circulation and hemoglobin concentration increase. The Society for Maternal-Fetal Medicine (2015) recommends a cutoff hematocrit value of 30 percent to define anemia. Reticulocytes are initially present at high levels, but decrease to 4 to 5 percent of the total at term. Fetal erythrocytes differ structurally and metabolically from those in the adult (Baron, 2012). Erythropoiesis is controlled primarily by fetal erythropoietin because maternal erythropoietin does not cross the placenta. Fetal hormone production is influenced by testosterone, estrogen, prostaglandins, thyroid hormone, and lipoproteins (Stockman, 1992). Although the exact production site is disputed, the fetal liver appears to be an important source until renal production begins. There is a close correlation between the erythropoietin concentration in amnionic fluid and that in umbilical venous blood obtained by cordocentesis. In contrast, platelet production reaches stable levels by midpregnancy, although there is some variation across gestation. The fetal and neonatal platelet count is subject to various agents as discussed in Chapter 15 (p. Genes for -type chains are on chromosome 11, and those for -type chains on 132chromosome 16. Each of these genes is turned on and then off during fetal life, until and genes, which direct the production of adult hemoglobin A, are permanently activated. The timing of production of each of these early hemoglobins corresponds to the site of hemoglobin production. Fetal blood is first produced in the yolk sac, where hemoglobins Gower 1, Gower 2, and Portland are made. When hemopoiesis finally moves to the bone marrow, adult-type hemoglobin A appears in fetal red blood cells and is present in progressively greater amounts as the fetus matures (Pataryas, 1972). If an -gene mutation or deletion occurs, no alternate -type chain can be substituted to form functional hemoglobin. In contrast, at least two versions of the chain- and -remain in production throughout fetal life and beyond. In the case of a -gene mutation or deletion, these two other versions of the chain often continue to be produced, resulting in hemoglobin A2 or hemoglobin F, which substitute for the abnormal or missing hemoglobin. Genes are turned off by methylation of their control region, which is discussed in Chapter 13 (p. For example, in newborns of diabetic women, hemoglobin F may persist due to hypomethylation of the gene (Perrine, 1988). With sickle cell anemia, the gene remains unmethylated, and large quantities of fetal hemoglobin continue to be produced. As discussed on page 140, there is a functional difference between hemoglobins A and F. At any given oxygen tension and at identical pH, fetal erythrocytes that contain mostly hemoglobin F bind more oxygen than do those that contain nearly all hemoglobin A. The amount of hemoglobin F in fetal erythrocytes begins to decrease in the last weeks of pregnancy. During the first 6 to 12 months of life, the hemoglobin F proportion continues to decline and eventually reaches the low levels found in adult erythrocytes. Coagulation Factors With the exception of fibrinogen, there are no embryonic forms of the various hemostatic proteins. The fetus starts producing normal, adult-type procoagulant, fibrinolytic, and anticoagulant proteins by 12 weeks.

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