Metropolitan Hospital Center

This guideline has been approved by the AASLD and represents the position of the association. These recommendations provide a data-supported approach to the management of primary biliary cirrhosis (PBC). They are based on the following: (1) formal review and analysis of the recently published world literature on the topic (Medline search); (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines2; and (4) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the quality of evidence supporting recommendations, the Practice Guideline Committee of the AASLD requires a Class (reflecting benefit versus risk) and Level (assessing strength or certainty) of Evidence to be assigned and reported with each recommendation (Table 1, adapted from the American College of Cardiology and the American Heart Association Practice Guidelines3). AASLD, American Association for the Study of Liver Diseases; AIH, autoimmune hepatitis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; IAIH-G, International Autoimmune Hepatitis Group score; Ig, immunoglobulin; PBC, primary biliary cirrhosis; PDC-E2, pyruvate dehydrogenase complex; UDCA, ursodeoxycholic acid. PBC is often considered a model autoimmune disease because of its hallmark serologic signature, the antimitochondrial antibody (AMA) and specific bile duct pathology.4, 5 The etiology of PBC is thought to be due to a combination of genetic predisposition and environmental triggers.6 Although the genetic predisposition is clear, major histocompatibility complex associations are varied.7 Several large epidemiologic studies have been performed and have suggested an association with urinary tract infections, reproductive hormone replacement, nail polish, past cigarette smoking, and toxic waste sites, as well as xenobiotics in an animal model of PBC.8-10 One critical and unique feature of PBC is the high degree of specificity for involvement of the small intrahepatic bile ducts. Staining of small bile ducts with monoclonal antibodies against mitochondrial autoantigens demonstrates an intense staining at the apical surface of biliary epithelial cells.11, 12 The characteristic serologic hallmark of PBC is the AMA, a highly disease-specific autoantibody found in 90%-95% of patients and less than 1% of normal controls.13 The targets of the disease-specific antimitochondrial response are all members of a family of enzymes, the 2-oxo-acid dehydrogenase complexes and include pyruvate dehydrogenase complex (PDC-E2), branched chain 2-oxo-acid dehydrogenase complex, and 2-oxo-glutaric acid dehydrogenase complex. These enzymes catalyze the oxidative decarboxylation of keto acid substrates and are located in the inner mitochondrial membrane.14, 15 Fewer than 5% of patients with PBC are AMA-negative in one study.16 Both immunofluorescence, and now more commonly enzyme-linked immunosorbent assays, are used to test for AMA. There is a 100-fold to 150-fold increase of autoreactive CD4 PDC-E2–specific T cells in liver and regional lymph node compared to blood in patients with PBC, and a 10-fold to 15-fold increase in autoreactive CD8 PDC-E2–specific T cell infiltrates in liver compared to blood. These data strongly suggest that the antimitochondrial response is either directly related to pathology or intimately associated with the etiological insult.17, 18 PBC is a chronic cholestatic disease with a progressive course which may extend over many decades. The rate of progression varies greatly among individual patients. Over the past decades, there have been many changes in the diagnosis and management of PBC. More patients are being recognized with earlier stage disease and many of these patients respond well to medical therapy. In both Europe and North America the number of liver transplants for PBC is falling.19, 20 AMA may be detectable in serum when patients are symptom-free and liver tests are normal. Based on one small study, it is believed that many of these patients may eventually develop abnormal liver tests and symptoms. The median follow-up time from the first positive AMA test to persistently abnormal liver tests in this series was 6 years with a range between 1 and 19 years. However, none of the patients developed cirrhosis during the follow-up.21 It is estimated that 0.5% of the general population is AMA-positive, which means that fewer than 10% of patients with AMA will develop PBC.22 The proportion of asymptomatic patients (which has been variably defined) who will subsequently develop PBC-related symptoms has been investigated in several series from the United Kingdom, North America, and Sweden.23-28 All of these studies provide evidence of progressive disease in a substantial proportion of patients, with between 36% and 89% becoming symptomatic during average follow-up periods ranging from 4.5-17.8 years. In the two most recent studies,27, 28 the median time from diagnosis to the appearance of symptoms was found to be 2 and 4.2 years. Patients with early disease in the absence of ursodeoxycholic acid (UDCA) therapy have a shortened survival comparable to a healthy population regardless of symptoms.27, 28 The 10-year survival of asymptomatic patients in three contemporary series ranged from 50%-70%; whereas the median duration of survival for symptomatic patients ranged from 5-8 years from the onset of symptoms.27, 28 In an older study of 279 patients from the United States,24 the median survival of symptomatic patients was 7.5 years, much shorter than the median survival of 16 years for asymptomatic patients. This marked difference in survival has not been found in the study from Northeast England, a finding possibly explained by an excess of deaths unrelated to liver disease in asymptomatic patients who were on average a decade older.29 Histologic stages have been found to predict survival.30, 31 The rate of histologic progression has been assessed in three large groups of patients in the absence of a therapeutically effective agent.30, 32, 33 The median time to develop extensive fibrosis was 2 years. After 4 years, the probability of remaining in the early stage was 29% (confidence interval: 15%-52%), while cirrhosis was diagnosed in 50% of patients who initially had only interface hepatitis without fibrosis. Only a minority (20%) of patients who were precirrhotic showed histologic stability. Overall, the histologic stage progressed by one stage every 1.5 years. The development of liver failure (ascites, bleeding, hepatic encephalopathy, or hyperbilirubinemia [>6 mg/dL]) during a follow-up of 5 years has been estimated to be 15% in the large community-based study of 770 patients in Northeast England27 and 25% of the 236 patients enrolled in the European azathioprine trial.30 The rate of development of esophageal varices and its impact on survival were evaluated in a prospective study of 256 patients (28% of whom had cirrhosis) who were observed for a median time of 5.6 years.34 A total of 31% of patients developed esophageal varices. After the development of varices, the 3-year survival was 59%, whereas after a first bleeding episode, it was 46%. UDCA is currently the only drug approved for the treatment of patients with PBC. Several randomized trials, combined analyses, and long-term observational studies have shown that this agent not only improves biochemical indices but also delays histologic progression and improves survival without transplantation.32, 35-46 Accordingly, most patients are now treated with UDCA. In an early study, the rate of histologic progression to cirrhosis was significantly less in the UDCA group than in the control group (13% versus 49%).35 In a trial involving 192 patients, UDCA therapy significantly delayed histologic stage progression after a median follow-up of 3.4 years.39 In the French trial of UDCA, the risk of progression from stages I-II to stages III-IV was 7% ± 2% with UDCA and 34% ± 9% with placebo.32 Predictive factors for cirrhosis developing included serum bilirubin higher than 1 mg/dL, and moderate to severe lymphocytic piecemeal necrosis on the liver biopsy.47 The effect of UDCA therapy on the development of esophageal varices was addressed in a prospective study of 180 patients who received UDCA versus placebo and were observed for up to 4 years.48 A total of 139 patients had no varices and 41 had varices at baseline. After 4 years, the risk of developing varices was 16% for the UDCA-treated patients and 58% for those receiving the placebo. However, UDCA did not reduce the low rate of bleeding. To overcome the lack of power of clinical trials in assessing the long-term effectiveness of therapy, a Markov model has been used to study the effect of UDCA on the natural history of PBC.46 The study included 262 patients who had received 13-15 mg/kg UDCA daily for a mean of 8 years (range 1-22 years), and their survival was substantially better than that predicted by the model. The overall survival rates without liver transplantation were 84% and 66% at 10 years and 20 years, respectively. The survival rate was better than the spontaneous survival rate as predicted by the updated Mayo model (relative risk: 0.5, P < 0.01). In early-stage patients, 6% were predicted to progress to liver transplantation or death after 10 years and 22% by 20 years. The survival rate of these patients was similar to that in the control population. In contrast, the probability of death or liver transplantation was significantly increased in patients treated in late stages of the disease (relative risk: 2.2, P < 0.05). Several clinical, biochemical, and histologic features have prognostic significance in PBC although bilirubin level is the best predictor of survival and is the most important component in all mathematical models of prognosis in PBC.49, 50 Some of these models have been useful in predicting survival in UDCA-treated patients as well (http://www.mayoclinic.org/gi-rst/mayomodel1.html). The diagnosis of PBC should be suspected in the setting of chronic cholestasis after exclusion of other causes of liver disease. The diagnosis is suspected based on cholestatic serum liver tests and largely confirmed with tests for AMA. A liver biopsy can be used to further substantiate the diagnosis if needed. Most patients with PBC have abnormal liver tests including elevations of alkaline phosphatase, mild elevations of aminotransferases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) activity, and increased levels of immunoglobulins (mainly immunoglobulin M [IgM]). Some patients with PBC may have high ALT or AST activities associated with hyperglobulinemia (increase in IgG). The changes in biochemical tests are related in part to the stage of the disease and to severity of histologic lesions.30, 51, 52 In patients without cirrhosis, the degree of elevation in alkaline phosphatase is strongly related to the severity of ductopenia and inflammation; the increase in aminotransferase activity and IgG levels reflects mainly the degree of periportal and lobular necrosis and inflammation; hyperbilirubinemia reflects the severity of ductopenia and biliary piecemeal necrosis. A rise in serum bilirubin, gamma globulins, and hyaluronic acid together with a fall in serum albumin and platelet count are the early indicators of the development of cirrhosis and portal hypertension.51, 52 As in other cholestatic diseases, serum cholesterol levels are often elevated.53 Individual serum bile acid levels can be elevated but are not routinely determined. AMA is found in nearly 95% of patients with PBC.5 Antinuclear antibody and anti–smooth muscle antibody are found in nearly half of patients with PBC.5 In approximately 5%-10% of the patients, AMA antibodies are absent or present only in low titer (≤ 1/80), when immunofluorescent techniques are used. The presence or absence of antibody, rather than the magnitude of antibody level, is most important. In some patients, antinuclear antibodies, particularly anti-GP210 and/or anti-SP100 are present and may correlate with prognosis54; in some other AMA-negative patients, antibodies against the major M2 components (PDC-E2, 2-oxo-glutaric acid dehydrogenase complex) are present using enzyme-linked immunosorbent assay or western blotting techniques. PBC is characterized by chronic, nonsuppurative cholangitis that mainly affects interlobular and septal bile ducts. When focal lesions show intense inflammatory changes and necrosis around bile ducts, the term "florid duct lesion" is often used. The inflammatory infiltrate consists essentially of lymphocytes and mononuclear cells in close contact with the basal membrane of cholangiocytes undergoing necrosis. The infiltrate consists of plasma cells, macrophages, polymorphonuclear cells (especially eosinophils), and in some cases epithelioid granulomas which are present more often in the early stage of disease.5 There are few (if any) arterial lesions. In contrast, portal venules are often compressed and occluded by the inflammatory reaction. Terminal hepatic venules are often retained in their central location with progression of fibrosis and sometimes even in cirrhosis. Bile duct paucity or ductopenia is usually defined in less than 50% of portal tracts containing ducts. The size of the liver biopsy specimen is important. The probability of observing cholangitis and bile duct destruction increases with the number of portal tracts because of the typical patchy distribution of the lesions. At least 10-15 portal tracts should be present, and multiple sections should be reviewed to adequately appreciate or rule out cholangitis and ductopenia. These would include periportal/periseptal copper deposition, periportal/periseptal feathery degeneration with or without Mallory-Denk bodies, and cholestatic rosettes. Actual bile stasis is not appreciated until decompensated liver disease has occurred. Histologic lesions are classically divided into four stages. Stage I is characterized by portal inflammation with or without florid bile duct lesions. In this stage, inflammation remains confined to the portal triads. Disease progression is characterized by the gradual increase of periportal lesions extending into the hepatic parenchyma referred to as interface hepatitis (stage II). Periportal regions become focally irregular, and the lesion is characterized by cellular necrosis or apoptosis, separation of hepatocytes by inflammatory cells, and macrophages. There are two main types of interface hepatitis. The first is lymphocytic piecemeal necrosis, the association of hepatocellular necrosis or apoptosis with lymphohistiocytic cells. This is similar to the lesion found in autoimmune hepatitis (AIH). Second is biliary piecemeal necrosis, which is marked by a striking ductular reaction, sometimes referred to as ductular proliferation, and accompanied by edema, neutrophil infiltration, periductular fibrosis, and necrotic hepatocytes, the latter associated with cholestasis. The French have shown that severity of interface hepatitis is highly predictive of development of extensive fibrosis.47, 55 Stage III is characterized by a distortion of the hepatic architecture with numerous fibrous septa. Cirrhosis with the existence of regenerative nodules defines stage IV. Nodular regenerative hyperplasia is a known complication of PBC and should be differentiated from cirrhosis. With the high disease specificity of a positive AMA test, the role of liver biopsy to diagnose PBC is questionable with alkaline phosphatase activity ≥ 1.5 times normal and AST values < 5 times normal.56 Liver biopsy may be recommended in AMA-negative patients and to exclude other concomitant diseases such as AIH and nonalcoholic steatohepatitis.46, 47, 55 Expert noninvasive imaging of the liver and biliary tree is mandatory in all patients with biochemical evidence of cholestasis. If the diagnosis is uncertain, then cholangiography may be necessary preferentially with noninvasive magnetic resonance imaging or endoscopically to exclude primary sclerosing cholangitis or other biliary tract diseases. Transient elastography (Fibroscan; Echosens, Paris, France) is a new noninvasive tool to evaluate the degree of liver fibrosis, which has been studied in patients with PBC,57 but it is not yet approved by the U.S. Food and Drug Administration. The diagnosis of PBC is generally based on the following criteria: (1) biochemical evidence of cholestasis with elevation of alkaline phosphatase activity; (2) presence of AMA; and (3) histopathologic evidence of nonsuppurative cholangitis and destruction of small or medium-sized bile ducts if a biopsy is performed. The differential diagnosis includes a cholestatic drug reaction, biliary obstruction, sarcoidosis, AIH and primary sclerosing cholangitis. The diagnosis of PBC can be established when two of the following three criteria are met: Biochemical evidence of cholestasis based mainly on alkaline phosphatase elevation. Presence of AMA. Histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts (Class I, Level B). Fatigue is the most common symptom in PBC and has been found in up to 78% of patients.56-62 Fatigue is nonspecific and occurs in many conditions other than PBC. Fatigue does not correlate with the severity, histologic stage, or duration of PBC. Severe fatigue may impair the quality of life in patients with PBC61, 62 and may be associated with decreased overall survival.63 Its etiology is unknown. Recently, an autonomic neuropathy has been described in association with fatigue in patients with PBC.64 Fatigue does not improve with treatment of depression, is often constant over time,65 is frequently associated with and may be a of which occurs in of patients with is a more specific symptom of PBC than fatigue and in of patients with PBC. It is now less common because patients with PBC are often asymptomatic at It can be or usually at while in and is often by contact with other or occurs in PBC, its severity may over However, it is to without treatment until a cirrhosis and liver The of in PBC is It is that the of including that to PBC, is at least in part by increased while other studies a role for components of and/or is and are associated symptoms. The is usually normal. and are and are found in the setting of portal is a late finding in patients with liver disease. to other liver diseases, portal most often late in the course of PBC, when patients have cirrhosis. However, in contrast to other liver diseases, portal may also develop in patients with precirrhotic PBC. These patients may from esophageal varices, varices, or portal normal or normal liver Nodular regenerative hyperplasia is associated with of the portal venules and may to portal in some of these Patients can for many years after without liver and hepatic may develop in patients with histologic PBC and cirrhosis. is the most often in and occurs in up to of The risk for in PBC compared to an and healthy population is It is usually not associated with specific and by The disease that was and often by multiple is now The of in PBC is Patients with PBC to have in which is and is low or is normal in patients with PBC for those with and may be elevated in The of in PBC is from that in other of cholesterol are elevated and such as may cholesterol levels were and in two studies of patients with PBC and levels ranged from in individual cholesterol is elevated compared to and patients with PBC are not at increased risk of death from Although patients with PBC may have decreased bile acid in increased risk of important of the and are is and serum levels of and are usually normal in most patients, including those with The occurs in patients who are liver transplantation who may also have and levels may be in and decreased activity, Patients with AMA-negative PBC to those who lack AMA but clinical liver and natural history are nearly to patients with typical PBC. all of these patients have antinuclear and/or anti–smooth muscle in and between the and AMA-negative is on the apical of biliary epithelial cells from with AMA-negative as well as PBC, that their is The diagnosis of AMA-negative PBC requires a liver biopsy that demonstrates the typical features of bile duct destruction in PBC. The diagnosis is more if granulomas are A recent large study has shown AMA-negative cases of PBC have less and more autoimmune diseases and levels are in AMA-negative than patients with A recent has published of patients treated for AMA-negative PBC, which only 52 patients. The authors no difference in biochemical response to UDCA was observed when patients with and AMA-negative PBC were There is no formal of the between PBC and features of PBC usually to AIH in patients who have a diagnosis of PBC and not to patients with AIH who have AMA. reported to are of size to with degree of a diagnosis of PBC with AIH is from PBC. observational data that response to therapy with UDCA for is no from that observed in patients with PBC A may also to patients with PBC followed by AIH as described recently in a less AIH followed by PBC has been There are two that have been used to evaluate patients with PBC for evidence of Both of these are are by without the of long-term follow-up The first is the International Autoimmune Hepatitis Group the of which was in two diagnosed with This was subsequently and it is this that has been used in several recent studies to this was for AIH and positive for AIH are when there is an absence of factors unrelated to a diagnosis of PBC, hepatitis and In for AMA and/or features of biliary disease would be assigned by A has been used to the presence of a by for the presence of two of the three following (1) ALT activity 5 times of (2) IgG ≥ 2 times of normal and/or positive anti–smooth muscle and (3) liver biopsy with moderate or severe periportal or There have been several with PBC who have been a diagnosis of PBC and have then been evaluated for of using one of these two However, it is if the biochemical, and data were at the time as the liver factors such as drug or concomitant diseases may and possibly all of these studies have reported in patients with patients with who were followed for a mean of years were compared with patients with This study a in of of portal or for liver in patients with PBC and a or However, an estimated 50% of patients in either group had received treatment with UDCA and some in both groups had received a of other UDCA with or without therapy has been but no in therapy for these patients There are no data which best to patients thought to have There are of patients with PBC who respond to UDCA therapy yet subsequently present with clinical features of These patients may no have AMA and liver more typical of AIH which to therapy. Patients with PBC may have florid duct lesions and all have evidence of bile duct usually with cholestatic A review of cases of PBC followed for the term that have features of PBC and AIH and develop an AIH on their These authors to cases of AIH who then developed PBC. More patients from more than patients with PBC were described who developed AIH after years of There are few data on the of detectable serum AMA in patients who have typical features of These data may be from histologic review of patients with AIH, in whom small bile duct pathology was on a of In this none of the patients who positive for AMA had bile duct changes on of liver There are of patients with AIH who but on long-term these patients not develop there is a for better long-term analysis the natural history of both PBC and The effect of therapy on the and its components will to be and only then will the clinical significance of these features become UDCA in a of 13-15 is the only therapy for PBC approved by the U.S. Food and Drug Administration. The drug is and generally in two divided A number of studies have shown the benefit of UDCA in this Individual studies have evidence of liver Some studies with follow-up have also shown from data to increase which has of the of Some have these these include studies of duration and those that have used is now known to be an of UDCA is used and has the to a in for liver transplantation for this The drug is used for patients with stage of PBC as as their liver are A liver biopsy in not for the diagnosis for PBC in many

2Assistant Clinical Professor of Psychiatry, New York Medical College, New York, N. Y.; Assistant Attending Psychiatrist, Flower and Fifth Avenue Hospitals and Metropolitan Hospitals; Associate supervising Psychiatrist and Lecturer in Psychosomatic Medicine, Postgraduate Center for Psychotherapy, New York, N. Y. 3Clinical Psychologist; Medical Student, New York Medical College, Flower and Fifth Avenue Hospitals, New York, N. Y.

OBJECTIVE: To develop an evidence-based guideline for the pharmacologic and nonpharmacologic treatment of psoriatic arthritis (PsA), as a collaboration between the American College of Rheumatology (ACR) and the National Psoriasis Foundation (NPF). METHODS: We identified critical outcomes in PsA and clinically relevant PICO (population/intervention/comparator/outcomes) questions. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available pharmacologic and nonpharmacologic therapies for PsA. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of the evidence. A voting panel, including rheumatologists, dermatologists, other health professionals, and patients, achieved consensus on the direction and the strength of the recommendations. RESULTS: The guideline covers the management of active PsA in patients who are treatment-naive and those who continue to have active PsA despite treatment, and addresses the use of oral small molecules, tumor necrosis factor inhibitors, interleukin-12/23 inhibitors (IL-12/23i), IL-17 inhibitors, CTLA4-Ig (abatacept), and a JAK inhibitor (tofacitinib). We also developed recommendations for psoriatic spondylitis, predominant enthesitis, and treatment in the presence of concomitant inflammatory bowel disease, diabetes, or serious infections. We formulated recommendations for a treat-to-target strategy, vaccinations, and nonpharmacologic therapies. Six percent of the recommendations were strong and 94% conditional, indicating the importance of active discussion between the health care provider and the patient to choose the optimal treatment. CONCLUSION: The 2018 ACR/NPF PsA guideline serves as a tool for health care providers and patients in the selection of appropriate therapy in common clinical scenarios. Best treatment decisions consider each individual patient situation. The guideline is not meant to be proscriptive and should not be used to limit treatment options for patients with PsA.

The clinical and pathologic features of cutaneous metastasis were studied in 724 patients, with histopathologic confirmation of both the primary tumors and the secondary lesions in the skin. Cutaneous metastatic lesions from carcinoma of the lung and kidney were usually found in men, were often recognized before the primary tumor, and appeared in almost every area of the skin surface. Metastasis from carcinoma of the breast to the skin occurred almost exclusively in women, tended to be localized to the anterior chest wall, and was usually found after the primary tumor. Most cutaneous lesions metastasizing from squamous cell carcinoma of the oral cavity were found on the face or neck of men in whom there was previous histologic documentation of the primary tumor.

OBJECTIVE: To develop an evidence-based guideline for the pharmacologic and nonpharmacologic treatment of psoriatic arthritis (PsA), as a collaboration between the American College of Rheumatology (ACR) and the National Psoriasis Foundation (NPF). METHODS: We identified critical outcomes in PsA and clinically relevant PICO (population/intervention/comparator/outcomes) questions. A Literature Review Team performed a systematic literature review to summarize evidence supporting the benefits and harms of available pharmacologic and nonpharmacologic therapies for PsA. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of the evidence. A voting panel, including rheumatologists, dermatologists, other health professionals, and patients, achieved consensus on the direction and the strength of the recommendations. RESULTS: The guideline covers the management of active PsA in patients who are treatment-naive and those who continue to have active PsA despite treatment, and addresses the use of oral small molecules, tumor necrosis factor inhibitors, interleukin-12/23 inhibitors (IL-12/23i), IL-17 inhibitors, CTLA4-Ig (abatacept), and a JAK inhibitor (tofacitinib). We also developed recommendations for psoriatic spondylitis, predominant enthesitis, and treatment in the presence of concomitant inflammatory bowel disease, diabetes, or serious infections. We formulated recommendations for a treat-to-target strategy, vaccinations, and nonpharmacologic therapies. Six percent of the recommendations were strong and 94% conditional, indicating the importance of active discussion between the health care provider and the patient to choose the optimal treatment. CONCLUSION: The 2018 ACR/NPF PsA guideline serves as a tool for health care providers and patients in the selection of appropriate therapy in common clinical scenarios. Best treatment decisions consider each individual patient situation. The guideline is not meant to be proscriptive and should not be used to limit treatment options for patients with PsA.

OBJECTIVE: This guideline provides evidence-based recommendations on managing hoarseness (dysphonia), defined as a disorder characterized by altered vocal quality, pitch, loudness, or vocal effort that impairs communication or reduces voice-related quality of life (QOL). Hoarseness affects nearly one-third of the population at some point in their lives. This guideline applies to all age groups evaluated in a setting where hoarseness would be identified or managed. It is intended for all clinicians who are likely to diagnose and manage patients with hoarseness. PURPOSE: The primary purpose of this guideline is to improve diagnostic accuracy for hoarseness (dysphonia), reduce inappropriate antibiotic use, reduce inappropriate steroid use, reduce inappropriate use of anti-reflux medications, reduce inappropriate use of radiographic imaging, and promote appropriate use of laryngoscopy, voice therapy, and surgery. In creating this guideline the American Academy of Otolaryngology-Head and Neck Surgery Foundation selected a panel representing the fields of neurology, speech-language pathology, professional voice teaching, family medicine, pulmonology, geriatric medicine, nursing, internal medicine, otolaryngology-head and neck surgery, pediatrics, and consumers. RESULTS: The panel made strong recommendations that 1) the clinician should not routinely prescribe antibiotics to treat hoarseness and 2) the clinician should advocate voice therapy for patients diagnosed with hoarseness that reduces voice-related QOL. The panel made recommendations that 1) the clinician should diagnose hoarseness (dysphonia) in a patient with altered voice quality, pitch, loudness, or vocal effort that impairs communication or reduces voice-related QOL; 2) the clinician should assess the patient with hoarseness by history and/or physical examination for factors that modify management, such as one or more of the following: recent surgical procedures involving the neck or affecting the recurrent laryngeal nerve, recent endotracheal intubation, radiation treatment to the neck, a history of tobacco abuse, and occupation as a singer or vocal performer; 3) the clinician should visualize the patient's larynx, or refer the patient to a clinician who can visualize the larynx, when hoarseness fails to resolve by a maximum of three months after onset, or irrespective of duration if a serious underlying cause is suspected; 4) the clinician should not obtain computed tomography or magnetic resonance imaging of the patient with a primary complaint of hoarseness prior to visualizing the larynx; 5) the clinician should not prescribe anti-reflux medications for patients with hoarseness without signs or symptoms of gastroesophageal reflux disease; 6) the clinician should not routinely prescribe oral corticosteroids to treat hoarseness; 7) the clinician should visualize the larynx before prescribing voice therapy and document/communicate the results to the speech-language pathologist; and 8) the clinician should prescribe, or refer the patient to a clinician who can prescribe, botulinum toxin injections for the treatment of hoarseness caused by adductor spasmodic dysphonia. The panel offered as options that 1) the clinician may perform laryngoscopy at any time in a patient with hoarseness, or may refer the patient to a clinician who can visualize the larynx; 2) the clinician may prescribe anti-reflux medication for patients with hoarseness and signs of chronic laryngitis; and 3) the clinician may educate/counsel patients with hoarseness about control/preventive measures. DISCLAIMER: This clinical practice guideline is not intended as a sole source of guidance in managing hoarseness (dysphonia). Rather, it is designed to assist clinicians by providing an evidence-based framework for decision-making strategies. The guideline is not intended to replace clinical judgment or establish a protocol for all individuals with this condition, and may not provide the only appropriate approach to diagnosing and managing this problem.

THE quantitative estimation of urinary 17-ketosteroids has been proven of value as an aid to the clinical diagnosis of disease. Its more widespread use has been hampered by the actual and assumed difficulties inherent in the chemical methods employed. In 1947, there was proposed a simple and rapid method (1), some disadvantages of which became apparent following its use in thousands of determinations. For instance, the extraction with ether is a dangerous hazard. Adequate control throughout the various manipulative steps is difficult, since mechanical equipment cannot be readily adapted to separatory funnels. The funnels are clumsy to handle and the breakage rate is high. When large numbers of determinations have to be made, a special laboratory is a prerequisite. In view of the solubility of ether in water and water in ether, a correction factor must be used for the final aliquot. Unless special precautions are taken to reduce evaporation, considerable error may result. Over and above these problems, there still remains the controversial point concerning the proper way to correct for interfering pigments commonly present in urine.

PREFACE: The leadership of Women in Neurosurgery (WINS) has been asked by the Board of Directors of the American Association of Neurological Surgeons (AANS) to compose a white paper on the recruitment and retention of female neurosurgical residents and practitioners. INTRODUCTION: Neurosurgery must attract the best and the brightest. Women now constitute a larger percentage of medical school classes than men, representing approximately 60% of each graduating medical school class. Neurosurgery is facing a potential crisis in the US workforce pipeline, with the number of neurosurgeons in the US (per capita) decreasing. WOMEN IN THE NEUROSURGERY WORKFORCE: The number of women entering neurosurgery training programs and the number of board-certified female neurosurgeons is not increasing. Personal anecdotes demonstrating gender inequity abound among female neurosurgeons at every level of training and career development. Gender inequity exists in neurosurgery training programs, in the neurosurgery workplace, and within organized neurosurgery. OBSTACLES: The consistently low numbers of women in neurosurgery training programs and in the workplace results in a dearth of female role models for the mentoring of residents and junior faculty/practitioners. This lack of guidance contributes to perpetuation of barriers to women considering careers in neurosurgery, and to the lack of professional advancement experienced by women already in the field. There is ample evidence that mentors and role models play a critical role in the training and retention of women faculty within academic medicine. The absence of a critical mass of female neurosurgeons in academic medicine may serve as a deterrent to female medical students deciding whether or not to pursue careers in neurosurgery. There is limited exposure to neurosurgery during medical school. Medical students have concerns regarding gender inequities (acceptance into residency, salaries, promotion, and achieving leadership positions). Gender inequity in academic medicine is not unique to neurosurgery; nonetheless, promotion to full professor, to neurosurgery department chair, or to a national leadership position is exceedingly rare within neurosurgery. Bright, competent, committed female neurosurgeons exist in the workforce, yet they are not being promoted in numbers comparable to their male counterparts. No female neurosurgeon has ever been president of the AANS, Congress of Neurological Surgeons, or Society of Neurological Surgeons (SNS), or chair of the American Board of Neurological Surgery (ABNS). No female neurosurgeon has even been on the ABNS or the Neurological Surgery Residency Review Committee and, until this year, no more than 2 women have simultaneously been members of the SNS. Gender inequity serves as a barrier to the advancement of women within both academic and community-based neurosurgery. STRATEGIC APPROACH TO ADDRESS ISSUES IDENTIFIED: To overcome the issues identified above, the authors recommend that the AANS join WINS in implementing a strategic plan, as follows: 1) Characterize the barriers. 2) Identify and eliminate discriminatory practices in the recruitment of medical students, in the training of residents, and in the hiring and advancement of neurosurgeons. 3) Promote women into leadership positions within organized neurosurgery. 4) Foster the development of female neurosurgeon role models by the training and promotion of competent, enthusiastic, female trainees and surgeons.

Brain-stem auditory-evoked potentials were recorded in neurosurgical patients from surface electrodes applied to the VIIIth nerve, medulla, pons, midbrain and cortex; from depth electrodes in the thalamus; and from a movable electrode in the IVth, IIIrd, and lateral ventricles. The potentials recordable over the scalp within 10 ms after click stimulation are characterized by a slow positive wave (peaking at 5 to 6 ms) and a negative wave (8 to 10 ms) with 7 small positive wavelets superimposed upon them. The sources of these components have been identified by observing their increased amplitude in depth recordings, and by tracing the potentials from their intracranial maxima to the scalp. Wave I is generated within the most distal portion of the VIII nerve; Wave V in the midbrain (inferior colliculus); and Wave VI the medial geniculate body. Both low positive and negative components have their origins in the inferior colliculus. Intracranially-recorded brain-stem auditory-evoked potential showed very rapid changes in amplitude within the brain-stem but only slight changes in the more rostral regions, although their amplitude gradients varied in the different components. They also demonstrated minor but systematic shifts in latency with distance from the potential sources, reflecting a significant overlap of separate potentials. This effect must be taken into account in the interpretation of a 'concurrent' intracranial potential as the source of a far-field surface-recorded potential.

OBJECTIVES: To evaluate the efficacy and safety of new oral anticoagulants (NOACs) in elderly adults. DESIGN: Meta-analyses of randomized clinical trials (RCTs). SETTING: PubMed, Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched from January 1, 2001, through March 30, 2013. PARTICIPANTS: Elderly population (≥ 75) in RCTs comparing NOACs (rivaroxaban, apixaban, and dabigatran) with conventional therapy. MEASUREMENTS: Two authors reviewed the trials, and odds ratios (ORs) were calculated using a random effects model. RESULTS: Ten RCTs included 25,031 elderly participants. Risk of major or clinically relevant bleeding was not significantly different between NOACs and conventional therapy in elderly adults (OR = 1.02, 95% confidence interval = 0.73-1.43). Similar results were observed when comparing NOACs and pharmacologically active agents. In atrial fibrillation (AF) trials, NOACs were more effective than conventional therapy in prevention of stroke or systemic embolism in an elderly population with AF. In non-AF trials, NOACs also had a significantly lower risk of venous thromboembolism (VTE) or VTE-related death than conventional therapy in elderly adults. Analysis for individual NOACs showed that the NOAC was noninferior or more effective than conventional therapy for efficacy and safety outcomes. CONCLUSION: In participants of clinical trials aged 75 and older, NOACs did not cause excess bleeding and were associated with equal or greater efficacy than conventional therapy.

Cowden's diseases features facial trichilemmomas (a benign tumor of follicular epithelium), acral keratoses on the limbs, and oral mucosal papillomas and fibromas; it may also involve thyroid, gastrointestinal tract, ovaries, uterus, and breasts. Among 32 known cases of Cowden's disease, 21 are women, in 10 of whom breast cancer has already developed (bilateral in 4). The 11 women in whom breast cancer has not yet developed have fibroadenomas, fibrocystic disease, virginal hypertrophy of the breast, and malformations of nipples and areolae. Their median age is only 36 years. Two have mothers with breast cancer and in one both mother and maternal grandmother had breast cancer. Dermatologic lesions, including pathognomonic multiple facial trichilemmomas, precede the development of malignancy and can identify women with ahigh risk of developing breast cancer.

Subacute sclerosing panencephalitis (SSPE) is a chronic encephalitis occurring after infection with measles virus. The prevalence of the disease varies depending on uptake of measles vaccination, with the virus disproportionally affecting regions with low vaccination rates. The physiopathology of the disease is not fully understood; however, there is evidence that it involves factors that favour humoral over cellular immune response against the virus. As a result, the virus is able to infect the neurons and to survive in a latent form for years. The clinical manifestations occur, on average, 6 years after measles virus infection. The onset of SSPE is insidious, and psychiatric manifestations are prominent. Subsequently, myoclonic seizures usually lead to a final stage of akinetic mutism. The diagnosis is clinical, supported by periodic complexes on electroencephalography, brain imaging suggestive of demyelination, and immunological evidence of measles infection. Management of the disease includes seizure control and avoidance of secondary complications associated with the progressive disability. Trials of treatment with interferon, ribavirin, and isoprinosine using different methodologies have reported beneficial results. However, the disease shows relentless progression; only 5% of individuals with SSPE undergo spontaneous remission, with the remaining 95% dying within 5 years of diagnosis.

During the 10-year period 1960 through 1969, 384 infants were born to 382 heroin addicted mothers. One hundred ninety (49.4%) of the infants were under 2,500 gm in weight. Seventy -seven (40%) of these were low weight for date infants. Two hundred fifty-nine (67.4%) of the total group of infants developed signs of withdrawal within the first 4 days of life. One hundred seventy-eight or 68.7% of these manifested signs severe enough to require treatment. Eighty-one infants had mild withdrawal signs which cleared without treatment. The 178 treated infants represented 46.3% of the entire group of heroin exposed infants. Our data indicated that there was a direct correlation between the length of maternal addiction and the occurrence of withdrawal signs in the infants; that with an increase of maternal intake of heroin, there was an increased incidence of neonatal withdrawal; and that the closer to delivery the last dose of heroin was taken, the higher and earlier was the occurrence of withdrawal signs in the neonate. Response to treatment with chlorpromazine was excellent. The incidence of congenital anomalies was no higher than in the general newbron population. Morphine and quinine could be demonstrated in the urine of the newborn infants within the first 24 hours of life. Fourteen infants (3.6%) died in the neonatal period; nine of these within the first 9 hours after birth. No evidence of Hyaline Membrane disease was found at autopsy in those that died in respiratory distress.

In patients who have locally advanced and inoperable head and neck cancer, the achievement of initial local control (complete response) of the disease with initial definitive treatment with radiotherapy (RT) with or without chemotherapy, is an important prognostic factor for overall survival. Cisplatin 100 mg/M2-intravenously (IV) with hydration and mannitol diuresis was given every 3 weeks for three doses concurrently with definitive radiotherapy (followed by salvage surgery [if possible] for persistent disease) was activated by the Radiation Therapy Oncology Group (RTOG) in 1981. One hundred thirty-four patients were initially registered and 124 were eligible and analyzed for this report. Eighty-two percent of the patients had Stage IV disease and greater than 50% of the primary sites were in oropharynx (39%), nasopharynx (22%), and oral cavity (18%). Eighty-seven percent of the patients are known to have finished the planned RT greater than 6450 cGy and 60% received three courses of cisplatin. Overall, 60% finished the planned combined treatment. Complete response to initial treatment occurred in 69% and an additional one patient (1%) was rendered disease-free after radical node dissection. Severe toxicities were as follows: leukopenia, 11%; anemia, 8%; nausea and vomiting, 6%; stomatitis, 31%; and renal, 6%. One toxic death occurred when a nephrotoxic antibiotic was administered at the same time. All patients were evaluated for total disease and survival regardless of compliance to the treatment or the cause of death. At 1 year, an estimated 51% of the patients had their disease totally controlled and an estimated 66% were alive. Incidence of initial complete response by various patient characteristics also were analyzed. The authors concluded that the combination of cisplatin and radiotherapy is an effective and safe treatment in patients with advanced head and neck cancer and needs to be tested against radiotherapy alone.

OBJECTIVE: To review recent secular trends in the prevalence of cerebral palsy in industrialized countries that have population-based cerebral palsy registries and to estimate such time-trends for the United States, where until recently such registries were absent. DATA SOURCES: Recent epidemiologic studies of cerebral palsy published in peer-reviewed journals in English, and US vital data bearing on the principal demographic determinants of cerebral palsy--birth rates, the birth weight distributions, birth weight-specific mortality risk, and cerebral palsy risk among survivors. RESULTS: Most epidemiologic studies from industrialized countries show a rise in the childhood prevalence of cerebral palsy in recent decades, largely because of the increasing contribution of children of low and very low birth weight to its prevalence. The only demographic determinant of cerebral palsy prevalence that is changing rapidly in the United States is survival of low birth weight and very low birth weight infants. Based on the magnitude of change in the survival of low and very low birth weight infants, it is estimated that childhood prevalence of cerebral palsy rose about 20% between 1960 and 1986 in the United States. CONCLUSION: An apparently unavoidable side effect of the increasing success of newborn intensive care is a moderate rise in the childhood prevalence of cerebral palsy.

The preanalytic phase is an important component of total laboratory quality. A wide range of variables that affect the result for a patient from whom a specimen of blood or body fluid has been collected, including the procedure for collection, handling, and processing before analysis, constitute the preanalytic phase. Physiologic variables, such as lifestyle, age, and sex, and conditions such as pregnancy and menstruation, are some of the preanalytic phase factors. Endogenous variables such as drugs or circulating antibodies might interact with a specific method to yield spurious analytic results. The preanalytic phase variables affect a wide range of laboratory disciplines.

BACKGROUND: We identified factors associated with pneumococcal colonization, high colonization density, and invasive pneumococcal pneumonia among patients hospitalized with acute lower respiratory tract infections (ALRTIs). METHODS: In 2010, 4025 cases were enrolled in surveillance in South Africa. A total of 969 of 4025 systematically selected nasopharyngeal-oropharyngeal specimens (24%) were tested for respiratory viruses and Streptococcus pneumoniae by real-time polymerase chain reaction. Of these, 749 (77%) had blood tested for S. pneumoniae. RESULTS: Pneumococcal colonization was detected in 55% of cases (534 of 969). On multivariable analysis that controlled for age and tuberculosis treatment, infection with influenza virus (adjusted odds ratio [OR], 2.2; 95% confidence interval [CI], 1.1-4.5), adenovirus (adjusted OR, 1.7; 95% CI, 1.1-2.7), rhinovirus (adjusted OR, 1.6; 95% CI, 1.1-2.3), and human immunodeficiency virus (HIV; adjusted OR, 1.6; 95% CI, 1.1-2.4) were associated with pneumococcal colonization. High colonization density was associated with respiratory virus coinfection (adjusted OR, 1.7; 95% CI, 1.1-2.6) and invasive pneumococcal pneumonia (adjusted OR, 2.3; 95% CI, 1.3-4.0), after adjustment for age and sex. Seven percent (52 of 749) had pneumococci detected in blood. On multivariable analysis among colonized cases, invasive pneumococcal pneumonia was associated with HIV (adjusted OR, 3.2; 95% CI, 1.4-7.5), influenza virus (adjusted OR, 8.2; 95% CI, 2.7-25.0), high colonization density (adjusted OR, 18.7; 95% CI, 2.3-155.1), and ≥5 days of hospitalization (adjusted OR, 3.7; 95% CI, 1.7-8.2). CONCLUSIONS: Respiratory virus infection was associated with elevated colonization density and, in turn, invasive pneumococcal pneumonia.

During the past 2 years we have studied eighty-nine biopsy specimens from nineteen patients with Cowden's syndrome. Among fifty-three facial lesions, twenty-nine were trichilemmomas. Twenty-three of the others were consistent with trichilemmoma, showed a non-specific benign verrucous acanthoma, or were not diagnostic; one was a blue naevus. All fourteen oral mucosal biopsy specimens were benign fibromas. Nineteen of twenty-two biopsy specimens from the hands and feet showed the pattern of benign keratosis. Multiple trichilemmomas were found in all patients with Cowden's syndrome, but at times several biopsy specimens were required before a diagnostic picture was uncovered. All patients with multiple facial trichilemmomas were found to have Cowden's syndrome. The combination of multiple facial trichilemmomas, oral fibromas, and benign acral keratoses enables one to diagnose Cowden's syndrome at a stage before serious internal complications develop.

IMPORTANCE: Randomized studies have shown a decreased risk of intracranial hemorrhage (ICH) with use of novel oral anticoagulants (NOACs). However, it is unclear whether the magnitude of benefit is similar for all NOACs currently available. OBJECTIVE: To perform a systematic review and meta-analysis to quantitatively assess the rates of ICH within the framework of both conventional and Bayesian statistics. DATA SOURCES: The MEDLINE, CENTRAL, CINAHL, and EBSCO databases, supplemented with conference abstracts, were searched up to December 1, 2012, with no language restriction. STUDY SELECTION: Randomized trials comparing NOACs vs a comparator and reporting on ICH events. DATA EXTRACTION AND SYNTHESIS: The NOACs were pooled to perform a comparison with all comparators and among themselves in both traditional frequentist and Bayesian random-effects models using vague priors and Markov chain Monte Carlo simulation with Gibbs sampling, calculating pooled odds ratios and associated 95% confidence intervals as well as numbers needed to treat and 95% credible intervals for the Bayesian analysis. MAIN OUTCOMES AND MEASURES: Intracranial hemorrhage events associated with NOACs in comparison with comparators, expressed as odds ratios. RESULTS: Six studies (1 administering dabigatran etexilate mesylate, 2 administering rivaroxaban, and 3 administering apixaban) enrolling a total of 57,491 patients were included for analysis. The NOACs significantly reduced the risk of ICH against all comparators (odds ratio = 0.49; 95% CI, 0.36-0.65). Each of the 3 drugs reduced the risk of ICH, with Bayesian indirect comparison analysis not revealing a significant credible difference between the specific medications. CONCLUSIONS AND RELEVANCE: Novel oral anticoagulants are uniformly associated with an overall reduced risk of ICH when used for stroke prevention in atrial fibrillation. Any of the currently available NOACs can be considered first line for patients at high risk for ICH.

BACKGROUND: The purpose of this study was to examine 1) the prevalence of psychiatric and substance use disorders in perinatally HIV-infected (HIV+) adolescents and 2) the association between HIV infection and these mental health outcomes by comparing HIV+ youths to HIV exposed but uninfected youths (HIV-) from similar communities. METHODS: Data for this paper come from the baseline interview of a longitudinal study of mental health outcomes in 9-16 year old perinatally HIV-exposed youths (61% HIV+) and their caregivers. Three hundred forty youths and their primary adult caregivers were recruited from four medical centers and participated in separate individual interviews. Youth psychiatric disorder was assessed using the caregiver and youth versions of The Diagnostic Interview Schedule for Children (DISC-IV). RESULTS: According to caregiver or youth report, a high percentage of HIV+ and HIV- youths met criteria for a non-substance use psychiatric disorder, with significantly higher rates among the HIV+ youths (61% vs. 49%, OR = 1.59; CI = 1.03,2.47; p < .05). The most prevalent diagnoses in both groups were anxiety disorders (46% for total sample) which included social phobia, separation anxiety, agoraphobia, generalized anxiety disorder, panic disorder, obsessive- compulsive disorder, and specific phobias. One quarter of the sample met criteria for a behavioral disorder (ADHD, conduct disorders, and oppositional defiant disorders), with ADHD being most prevalent. HIV+ youths had significantly higher rates of ADHD (OR = 2.45; CI = 1.20, 4.99, p < .05). Only 7% of youths met criteria for a mood disorder and 4% for a substance abuse disorder. Several caregiver variables (caregiver type and HIV status) were also associated with both child HIV status and mental health outcomes. CONCLUSIONS: Our data suggest that HIV+ youths are at high risk for mental health disorders. Further longitudinal research is necessary to understand the etiology, as well as potential protective factors, in order to inform efficacy-based interventions.