VA Connecticut Healthcare System

In this paper, inspired by the plenary panel at the 2013 meeting of the International Society for Traumatic Stress Studies, Dr. Steven Southwick (chair) and multidisciplinary panelists Drs. George Bonanno, Ann Masten, Catherine Panter-Brick, and Rachel Yehuda tackle some of the most pressing current questions in the field of resilience research including: (1) how do we define resilience, (2) what are the most important determinants of resilience, (3) how are new technologies informing the science of resilience, and (4) what are the most effective ways to enhance resilience? These multidisciplinary experts provide insight into these difficult questions, and although each of the panelists had a slightly different definition of resilience, most of the proposed definitions included a concept of healthy, adaptive, or integrated positive functioning over the passage of time in the aftermath of adversity. The panelists agreed that resilience is a complex construct and it may be defined differently in the context of individuals, families, organizations, societies, and cultures. With regard to the determinants of resilience, there was a consensus that the empirical study of this construct needs to be approached from a multiple level of analysis perspective that includes genetic, epigenetic, developmental, demographic, cultural, economic, and social variables. The empirical study of determinates of resilience will inform efforts made at fostering resilience, with the recognition that resilience may be enhanced on numerous levels (e.g., individual, family, community, culture).

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

A set of criteria based upon biostatistical considerations for determining the interrater reliability of specific adaptive behavior items in a given setting was presented. The advantages and limitations of extant statistical assessment procedures were discussed. Also, a set of guidelines for differentiating type of adaptive behavior that are statistically reliable from those that are reliable in a clinical or practical sense was delineated. Data sets were presented throughout in order to illustrate the advantages of recommended statistical procedures over other available ones.

This guidance provides a data-supported approach to risk stratification, diagnosis, and management of patients with cirrhosis and portal hypertension (PH). A guidance document is different from a guideline. Guidelines are developed by a multidisciplinary panel of experts who rate the quality (level) of the evidence and the strength of each recommendation using the Grading of Recommendations Assessment, Development, and Evaluation system. A guidance document is developed by a panel of experts in the topic, and guidance statements, not recommendations, are put forward to help clinicians understand and implement the most recent evidence. This guidance focuses on PH, varices, and variceal hemorrhage (VH), and statements are based on the following: (1) review of the recent literature using PubMed, giving more weight to large, well-designed, prospective trials and well-performed meta-analyses; (2) several consensus conferences among experts; and (3) the authors' years of experience caring for patients with cirrhosis and varices. Management of ascites and encephalopathy is addressed in other documents. When little or no data exist from well-designed, prospective trials, emphasis is given to results from large series and reports from recognized experts. In this case, clinical studies needed to clarify that management are specified in a section on future research. Practice guidelines for the diagnosis and treatment of gastroesophageal VH were published in 2007, endorsed by the American Association for the Study of Liver Diseases (AASLD), American College of Gastroenterology, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy (ASGE).1 Since then, a number of randomized, controlled trials (RCTs) have advanced our approach to managing VH. Additionally, four international consensus conferences were held since then, where experts in the field evaluated the changes in pathophysiology, diagnosis, and management of varices and VH. These include two AASLD/European Association for the Study of the Liver single-topic conferences in 2007 (many of the recommendations from this conference were incorporated into the aforementioned guidelines)2 and in 2013, and two Baveno consensus conferences in 20103 and in 2015.4 In this updated practice guidance, recommendations derived from these consensus conferences were also incorporated, particularly those from the latest Baveno conference that took place in Baveno, Italy, in April 2015. Perhaps the most relevant change in these recommendations has been the recognition of the different stages of cirrhosis,5 so that recommendations are now focused on risk stratification and individualizing care for PH. Intended for use by health care providers, this guidance identifies preferred approaches to the diagnostic, therapeutic, and preventive aspects of care of patients with PH. As with other guidance documents, it is not intended to replace clinical judgment, but rather to provide general guidance applicable to the majority of patients. They are intended to be flexible, in contrast to formal treatment recommendations or standards of care, which are inflexible policies designed to be followed in every case. Clinical considerations may justify a course of action that differs from this guidance. Cirrhosis is a chronic condition with a high mortality. It constitutes the fifth-leading cause of adult deaths and ranks eighth in economic cost among the major illnesses.6 Cirrhosis is a heterogeneous disease that cannot be studied or managed as a single entity and is classified in two main prognostic stages: compensated and decompensated cirrhosis.5, 7 This classification depends on the presence or absence of clinically evident decompensating events (specifically ascites, VH, and encephalopathy [HE]), with a median survival in the compensated stage that exceeds 12 years, whereas it is only 1.8 years in patients who develop decompensation.8 The Child-Turcotte-Pugh (CTP) classification has been used to stratify patients with cirrhosis. Patients with cirrhosis belonging to the CTP-A class are compensated, whereas those in the CTP-B/C class are mostly decompensated. PH is the initial and main consequence of cirrhosis and is responsible for the majority of its complications. In fact, it has been shown that portal pressure (PP), determined by the hepatic venous pressure gradient (HVPG), is better than liver biopsy in predicting development of complications of cirrhosis in patients with chronic liver disease (CLD) without cirrhosis on liver biopsy.9 Therefore, a new entity denominated compensated advanced chronic liver disease (cACLD) has been proposed, emphasizing that PH may occur before a formal anatomical diagnosis of cirrhosis is established.4 This entity would encompass patients with cirrhosis and those with advanced liver fibrosis with PH (HVPG > 5 mm Hg). For ease of understanding, in the rest of this guidance, the entity of cACLD will be referred to as compensated cirrhosis (CC), both terms being interchangeable and acceptable by consensus.4 The stage of CC is asymptomatic, and it is the longest stage. Pathophysiological mechanisms are evolving at this stage, and therefore several substages are being recognized. Based on PP, patients with CC can be divided into those with mild PH (HVPG > 5 but < 10 mm Hg) and those with clinically significant portal hypertension (CSPH), defined by an HVPG ≥10 mm Hg. CSPH is associated with an increased risk of developing varices,10 overt clinical decompensation (ascites, VH, and HE),11 postsurgical decompensation,12 and hepatocellular carcinoma (HCC).13 This substaging is not only prognostically important, but, as mentioned below, the mechanisms maintaining PH at these substages are different, and therefore their therapeutic approach will be different. CSPH is present in approximately 50%-60% of patients with CC without gastroesophageal varices (GEV).10 Patients with GEV have, by definition, CSPH, because patients with GEV have an HVPG of at least 10 mm Hg.14, 15 Prognosis is worse in patients with CC with GEV compared to those without GEV.16, 17 Therefore, among patients with CSPH, two substages are recognized based on the absence or presence of GEV. It is important to recognize that although PH and its direct consequences (varices) form the bases of staging in CC, liver insufficiency, even at this stage, plays an important role, given that serum albumin and the Model for End-Stage Liver Disease (MELD) score are also independent predictors of decompensation.11 VH constitutes a decompensating event, but its mortality differs whether it presents as an isolated complication of cirrhosis (20% 5-year mortality) or whether it presents in association with other complications (over 80% 5-year mortality).8 Whereas in the past, emphasis had been placed on managing the direct complications of PH, varices, and VH, it is now clear that these complications cannot be considered in an isolated manner. Rather, they should be considered in the context of advances in the staging of cirrhosis and in the context of other complications of cirrhosis that may occur concomitant or subsequent to development of varices and VH.4 Stages of PH in cirrhosis are depicted in Fig. 1, and goals of therapy at each stage are shown in Table 1. Stages and substages of cirrhosis. The two main stages are the compensated and decompensated stages. The latter is characterized by the presence of clinically overt complications: ascites, VH, or HE. The compensated stage is the longest stage, and it is asymptomatic. There are at least two main substages of compensated cirrhosis with different prognostic and predominant pathophysiological mechanisms: patients with mild PH and those with CSPH. Patients in the latter stage are at risk of developing decompensation, particularly those who have GEV. The decompensated stage is much shorter and can rapidly progress to a stage of further decompensation in which renal failure (HRS) and liver failure (encephalopathy and jaundice) develop, leading to a high mortality. GEV are present in approximately 50% of patients with cirrhosis, but this depends on the clinical stage. In patients with CC, GEV are present in 30%-40%, whereas they can be present in up to 85% of patients with decompensated cirrhosis.18, 19 In patients with CC, varices develop at a rate of 7%-8% per year,10 and progression from small to large varices occurs at a rate of 10%-12% per year, with decompensated cirrhosis being an independent predictor of progression.20 VH occurs at a rate of around 10%-15% per year and depends on the severity of liver disease, size of varices, and presence of red wale marks (areas of thinning of the variceal wall).21, 22 Six-week mortality, which is now recognized as the primary endpoint to assess the impact of therapies for acute VH,4 ranges between 15% and 25%.23-25 Other factors associated with poor outcomes in patients with VH are the presence of bacterial infections and an HVPG >20 mm Hg, which is mostly observed in patients belonging to the CTP-C class.26, 27 If untreated, recurrent VH occurs in 60% of patients, usually within 1-2 years of index hemorrhage.28 Obesity and alcohol use are associated conditions of prognostic relevance in patients with cirrhosis, independent of etiology. Obesity has been shown to predict worsening of liver fibrosis, cirrhosis decompensation, and lack of regression of cirrhosis in patients with viral cirrhosis,29-31 whereas even moderate alcohol intake can lead to worsening PP and has been shown to worsen prognosis of hepatitis C virus (HCV)- and nonalcoholic steatohepatitis (NASH)-related cirrhosis.32, 33 Therefore, although beyond the scope of this guidance, weight loss and alcohol abstinence are important considerations in patients with cirrhosis. PP increases initially as a consequence of an increased intrahepatic resistance to portal flow attributed to structural mechanisms (e.g., fibrous tissue, vascular distortion from regenerative nodules, and microthrombi; Fig. 2). This "structural" component, which explains around 70% of the increased intrahepatic resistance, could be targeted by treating the etiology of cirrhosis, the use of antifibrotic agents, and even anticoagulants.34 However, at least one third of the increased intrahepatic resistance is attributed to an increased intrahepatic vascular tone, which, in turn, is attributed to endothelial dysfunction resulting mostly from reduced nitric oxide (NO) bioavailability.35 This "functional" component is amenable to vasodilators (such as nitrates, alpha-adrenergic antagonists, and angiotensin-2 blockers).36 These drugs should not be used alone, given that they also cause systemic vasodilatation, decrease arterial blood pressure, and may worsen sodium retention. A conceptually more appealing approach to ameliorate the functional component is to use drugs that will reduce PP by improving endothelial dysfunction, such as statins.37 An added advantage of these drugs is that, by causing intrahepatic vasodilatation, they may improve hepatic blood flow and liver function. Statins in particular also have antifibrotic properties.34 Pathogenesis of PH and sites of action of currently recommended therapies to reduce PP or obliterate varices. In cirrhosis, PP increases initially as a consequence of an increased intrahepatic resistance to portal flow attributed to structural mechanisms (e.g., fibrous tissue, regenerative nodules) and an increased intrahepatic vascular tone (functional component). One of the initial consequences of PH is the formation of portosystemic collaterals. Concomitant or even preceding development of collaterals, splanchnic vasodilatation occurs, leading to increased flow into the gut and into the portal venous system. Vasodilation leads to activation of neurohumoral and vasoconstrictive systems, sodium and water retention, increased blood volume, and increased cardiac output; that is, a hyperdynamic circulatory state that further increases portal venous inflow and PP. Additionally, activated vasoconstrictive systems to further contribute to intrahepatic vasoconstriction. Treatment of etiology, by ameliorating fibrosis/inflammation, target the mechanical component of the increased intrahepatic resistance. Vasodilators (like the α-adrenergic blocking effect of carvedilol) target its functional component (this is the site of action of statins). NSBBs (β2-adrenergic blocking effect), SMT, and VP act by causing splanchnic vasoconstriction, thereby reducing portal venous inflow. NSBBs also act by decreasing cardiac output (β1-adrenergic blocking effect). The TIPS connects the hypertensive portal vein with a normotensive hepatic vein, thereby bypassing the site of increased resistance. Varices can be obliterated either endoscopically (EVL or cyanoacrylate injection) or by an endovascular approach (BRTO). One of the initial consequences of PH is the formation of portosystemic collaterals, the most important being those that develop through the coronary and/or short gastric veins and constitute GEV. Although formation of collaterals had been assumed to be the result of dilatation of preexisting vascular channels, research studies have implicated a process of neoangiogenesis.38 Concomitant or even preceding the development of collaterals, splanchnic vasodilatation occurs, leading to increased flow into the gut and into the portal venous system. Therefore, even when portal flow is entirely diverted through collaterals, PH persists.39 Increased splanchnic NO production is the main factor that leads to vasodilatation and increased splanchnic blood flow. Hyperglucagonemia and neoangiogenesis further contribute to the increased splanchnic blood flow that maintains the portal hypertensive state.38 Vasodilation occurs not only in the splanchnic, but also in the systemic circulation (manifested clinically as arterial hypotension), leading to activation of neurohumoral and vasoconstrictive systems, sodium and water retention, increased blood volume, and increased cardiac output, that is, a hyperdynamic circulatory state that further increases portal venous inflow and PP. Additionally, norepinephrine, angiotensin-2, and antidiuretic hormone (activated neurohumoral and vasoconstrictive systems) further contribute to intrahepatic vasoconstriction. Drugs that act by causing splanchnic vasoconstriction, such as non-selective beta-blockers (NSBBs; propranolol, nadolol, and carvedilol), vasopressin (VP), and its analogue, terlipressin, and somatostatin (SMT) and its analogues (octreotide, vapreotide) are known to reduce PP and constitute the current mainstay in the treatment of varices and VH. Given that these drugs act by decreasing flow to the splanchnic circulation and liver, an improvement in liver function would not be expected. β-1 adrenergic blockade decreases portal flow through a decrease in cardiac output, and β-2 blockade decreases portal flow through splanchnic vasoconstriction by unopposed α-adrenergic activity. Therefore, it is essential that beta-blockers used in the treatment of PH be nonselective. Importantly, the effect of NSBBs in decreasing flow is more related to their β-2 blocking effect rather than to their β-1 effect40 and explains the lack of correlation between decreases in PP and decreases in heart rate.41 Carvedilol, an NSBB with anti-α1 adrenergic (vasodilator) activity, acts as an NSBB decreasing portal flow, but also acts as a vasodilator (intrahepatic circulation). HVPG response is greater with carvedilol than with propranolol or nadolol, but, given its vasodilatory properties, carvedilol is associated with a greater decrease in mean arterial pressure (MAP).42 It has been recently shown that patients with mild PH (HVPG > 5 but < 10 mm Hg) have a normal cardiac index (i.e., they have not yet developed the hyperdynamic circulatory state), whereas those with CSPH, especially if varices are present, have already developed a hyperdynamic state. Accordingly, response to NSBB in patients with mild PH is suboptimal compared to that of those with CSPH,43 indicating that there is no role for NSBB in the setting of mild PH. Endoscopic variceal ligation (EVL) is a local therapy that consists of placing rubber bands around esophageal varices (EV) in repeated sessions until they become obliterated. Because it is a local therapy that has no effect on PH, recurrence of varices is the rule, and patients require indefinite endoscopic monitoring. Local therapies for management of gastric (mostly cardiofundal) varices consist of the (1) transendoscopic obturation by injection of cyanoacrylate glue into the varices or (2) transvenous obliteration by instillment of sclerosants and/or liquid embolic agents into a gastro-/splenorenal collateral through the left renal vein aided by balloon occlusion, that is, balloon occluded retrograde transvenous obliteration (BRTO).44 In patients with decompensated cirrhosis, placement of the transjugular intrahepatic portosystemic shunt (TIPS) by interventional radiological techniques that consist of connecting the hypertensive portal vein with a normotensive hepatic vein by a coated stent causes a significant decrease, and even normalization, of PP. Therefore, in patients with functional TIPS stents, there is no need for other therapies for PH (e.g., NSBB, EVL). PH is defined as a portal pressure gradient (the difference in pressure between the portal vein and the hepatic veins) greater than 5 mm Hg. The best method to assess PP is through the catheterization of the hepatic vein with determination, through a balloon catheter, of the HVPG, which is the difference between the wedged (or occluded) hepatic venous pressure and the free hepatic venous pressure.45 Normal HVPG is 3-5 mm Hg. It should be underlined that the wedged (occluded) pressure (and, consequently, the HVPG) is a measure of sinusoidal pressure and does not provide useful data in prehepatic or presinusoidal PH (Table 2). An HVPG over 5 mm Hg identifies patients with cACLD/CC secondary to conditions associated with sinusoidal hypertension (Table 2). As mentioned above, PH is further defined as mild PH (HVPG > 5 but < 10 mm Hg) and as CSPH (HVPG ≥ 10 mm Hg). Above this threshold of 10 mm Hg, all the complications of PH are more likely to appear (varices, clinical decompensation). In patients with GEV (who, by definition, have CSPH), an HVPG > 12 mm Hg identifies bleeding risk, mostly because there is clear evidence that shows that reducing the HVPG to levels of 12 mm Hg or below is associated with protection from variceal hemorrhage (VH).28 An HVPG > 16 mm Hg indicates a higher risk of death.46 As mentioned previously, an HVPG ≥20 mm Hg predicts failure to control bleeding, early rebleeding, and death during acute VH,27, 47 and in patients with cirrhosis awaiting liver transplantation, each 1-mm-Hg increase in HVPG predicts a 3% increase in the risk of death in a median follow-up of 19 months.48 Despite the crucial role of HVPG in the determination of CSPH and other outcomes, HVPG measurements require specific expertise, are invasive, relatively expensive, and not available in all centers. Therefore, HVPG measurements are not considered standard of care for every patient with cirrhosis, particularly because noninvasive or surrogate indicators are increasingly utilized at most centers. In a step-wise diagnostic approach, specific signs of PH should be first looked for on physical examination. They include spider nevi or visible abdominal portosystemic collaterals. The absence of physical signs cannot be used to rule out CSPH. Among laboratory data, a low platelet count is the most common laboratory sign of PH; it correlates slightly with HVPG and with the presence of GEV. However, taken alone, it is not to either or CSPH or GEV. the other the of platelet count with other noninvasive the noninvasive diagnosis of provides and evidence of associated with cirrhosis and PH. The presence of circulation on or vein, and left and short gastric veins) or the of a of flow within the portal is specific for and is to CSPH. other signs of PH have been such as dilatation of portal vein and the of portal vein (or their as index of the portal Although taken is a but sign of PH, the size of the should be when with platelet count and liver it provides data on the presence of The to assess liver a physical of liver by the of liver fibrosis has a major in this by has for patients with and without CSPH, with a mean the of in a recent on studies and can be currently considered the of the noninvasive diagnosis of PH. However, most of the data have been in patients with viral cirrhosis and cirrhosis. other and data in patients who have require further studies have shown that the best to CSPH is with a diagnostic over In a prospective HVPG ≥10 mm Hg and were in predicting In a large an size count > specific in in CSPH with a of Importantly, these have to be considered in the context of clinical In this a recent prospective a based on measurements in the context of the presence of and/or a platelet count and the of patients with CC in CSPH would be more by has been recently as a more related to PH, with In fact, > better than and to HVPG in predicting first clinical decompensation in one However, cannot be by without a and cannot be if the is not Therefore, measurements by cannot be recommended in clinical direct of the liver and is but and results with higher and in the of CSPH. is an that provides data on and of much of the liver and compared to Although has been shown to be in the staging of liver data its diagnostic in the diagnosis of CSPH are with one that determined by of clinical decompensation in patients with studies are needed in this the presence and size of varices and presence of red wale marks an and that is not free of studies have looked for noninvasive of the presence of varices varices, those so as to the need for The of in predicting the presence of GEV is between and and the use of to GEV is not However, are to rule out varices in patients with In with platelet count identifies patients at low risk of These data have been mostly from patients with viral cirrhosis. in patients with cirrhosis, liver disease, and in those with cirrhosis response are consensus among and review of the it that patients with CC with by and a platelet count were to have varices and could be in studies have these and that of can be In patients with cirrhosis secondary to hepatitis an size count < in out this can be to patients with cirrhosis attributed to other to be Because measurements of are more with of this is a in and out varices and to other in data in and American patients are Patients without evidence of CSPH should be to of the if data on this specific are data from published that and platelet count could be The of new portosystemic collaterals during follow-up has been shown to be associated with variceal formation and as is Therefore, when for evidence of worsening PH should be Patients without varices on constitute an of given that their has not yet been particularly with the of therapies that the that if liver is (e.g., in and lack of in and/or of disease are present (e.g., should be repeated at in the absence of are considered Although there are no data to if several of are for varices. In patients with small varices on who are not for primary is It has been that if the liver is (e.g., in and lack of in and/or of disease are present (e.g., should be repeated at in the absence of are considered Because development of decompensation could worsening of PH and liver dysfunction with a higher of cirrhosis, patients with no or small varices on should have a when and if decompensation in HVPG, or during have been shown to be of In patients with a of VH, a decrease in HVPG to than 12 mm Hg or a decrease greater than from the risk of recurrent ascites, and In patients with CC, in HVPG from have been associated with a in development of varices,10 first VH, and studies that the need for HVPG to assess response to therapy can be by the acute response to propranolol during a single but this further there have been no (e.g., that with changes in As mentioned above, therapy of varices and VH should be to the different clinical stages of cirrhosis and PH that are shown in Table 1. The of therapy for patients at an early stage is to the development of stages. Varices and VH should be managed in the context of the presence (or of other complications of (e.g., ascites, and therefore the or of the patient with should be considered in the of the different In the compensated the is to that is, the is not only to varices or VH, but also to the other complications of cirrhosis. In to specific therapies that will be below, in the compensated every should be taken to the and to associated such as and liver given that these in can decrease portal pressure and reduce the risk of This stage is defined by an HVPG but < 10 mm Hg. Patients in this stage not have varices or

This guideline has been approved by the American Association for the Study of Liver Diseases and the American College of Gastroenterology and represents the position of both associations. These recommendations provide a data-supported approach to the management of patients with varices and variceal hemorrhage. They are based on the following: (1) formal review and analysis of the recently published world literature on the topic (Medline search); (2) several consensus conferences among experts; (3) the American College of Physicians' Manual for Assessing Health Practices and Designing Practice Guidelines1; (4) guideline policies, including the American Association for the Study of Liver Diseases' Policy Statement on Development and Use of Practice Guidelines and the American Gastroenterological Association's Policy Statement on the Use of Medical Practice Guidelines2; and (5) the authors' years of experience caring for patients with cirrhosis and varices. Intended for use by healthcare providers, these recommendations suggest preferred approaches to the diagnostic, therapeutic, and preventive aspects of care. As with other practice guidelines, this guideline is not intended to replace clinical judgment but rather to provide general guidelines applicable to the majority of patients. They are intended to be flexible, in contrast to standards of care, which are inflexible policies designed 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 Guidelines 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, 4). When little or no data exist from well-designed prospective trials, emphasis is given to results from large series and reports from recognized experts. Further controlled clinical studies are needed to clarify aspects of this statement, and revision may be necessary as new data appear. Clinical considerations may justify a course of action that differs from these recommendations. These recommendations are fully endorsed by the American Association for the Study of Liver Diseases and the American College of Gastroenterology. Portal hypertension is a progressive complication of cirrhosis. Therefore, the management of the patient with cirrhosis and portal hypertensive gastrointestinal bleeding depends on the phase of portal hypertension at which the patient is situated, from the patient with cirrhosis and portal hypertension who has not yet developed varices to the patient with acute variceal hemorrhage for whom the objective is to control the active episode and prevent rebleeding. Practice guidelines for the diagnosis and treatment of gastroesophageal variceal hemorrhage, endorsed by the American Association for the Study of Liver Diseases (AASLD), American College of Gastroenterology (ACG), American Gastroenterological Association (AGA), and American Society of Gastrointestinal Endoscopy (ASGE), were published in 1997.5 Since then, a number of randomized controlled trials have advanced our approach to managing variceal hemorrhage. Three international consensus conferences have been held (Baveno III in 2000, Baveno IV in 2005, and an AASLD/EASL single topic conference in 2007) in which experts in the field have evaluated the changes that have occurred in our understanding of the pathophysiology and management of gastroesophageal hemorrhage.6, 7 In this updated practice guideline we have reviewed the randomized controlled trials and meta-analyses published in the last decade and have incorporated recommendations made by consensus. Cirrhosis, the end stage of any chronic liver disease, can lead to portal hypertension. Portal pressure increases initially as a consequence of an increased resistance to flow mostly due to an architectural distortion of the liver secondary to fibrous tissue and regenerative nodules. In addition to this structural resistance to blood flow, there is an active intrahepatic vasoconstriction that accounts for 20%-30% of the increased intrahepatic resistance,8 and that is mostly due to a decrease in the endogenous production of nitric oxide.9, 10 Portal hypertension leads to the formation of porto-systemic collaterals. However, portal hypertension persists despite the development of these collaterals for 2 reasons: (1) an increase in portal venous inflow that results from splanchnic arteriolar vasodilatation occurring concomitant with the formation of collaterals11; and (2) insufficient portal decompression through collaterals as these have a higher resistance than that of the normal liver.12 Therefore, an increased portal pressure gradient results from both an increase in resistance to portal flow (intrahepatic and collateral) and an increase in portal blood inflow. The preferred, albeit indirect, method for assessing portal pressure is the wedged hepatic venous pressure (WHVP) measurement, which is obtained by placing a catheter in the hepatic vein and wedging it into a small branch or, better still, by inflating a balloon and occluding a larger branch of the hepatic vein. The WHVP has been shown to correlate very closely with portal pressure both in alcoholic and non-alcoholic cirrhosis.13 The WHVP is always corrected for increases in intraabdominal pressure (e.g., ascites) by subtracting the free hepatic vein pressure (FHVP) or the intraabdominal inferior vena cava which as The pressure is the hepatic venous pressure gradient which is with the use of a balloon with a is very and Since it is a of the be in intrahepatic of portal as but be normal in of portal as portal vein The normal is The and changes in that have for the development of the of variceal the development of of portal and are in the of both and are to to and of liver to the use of are the of and to guidelines that and as as varices are the relevant porto-systemic collaterals results in variceal hemorrhage, the complication of cirrhosis. and variceal hemorrhage are the of cirrhosis that from portal hypertension. with cirrhosis and gastroesophageal varices have an of at varices are in of patients with cirrhosis. with the of liver (Table of patients have are in of with cirrhosis may varices and variceal hemorrhage in the course of the in the of has been shown that of patients with and have varices at a of and the for development of varices in with cirrhosis who have no varices at the of is an with small varices large varices at a of cirrhosis alcoholic and of as on the variceal at the of are the with the from small to large hemorrhage at a of and the of hemorrhage is the of with the of hemorrhage occurring in patients with large of hemorrhage are cirrhosis and the of bleeding from varices in to of and despite in the last it is with a of at at with an of variceal have been as at a higher for bleeding the of or to control bleeding and a higher to with in of mostly years of the is the that variceal is of the of variceal an a large a small not of the of variceal is the pressure the which is to the Therefore, a in lead to a decrease in variceal the of variceal hemorrhage not the is to has been shown that the of with in than from to or at from not have a of variceal but have a of and varices are than varices and are in of patients with portal hypertension with a reported of bleeding of in 2 with a higher bleeding for for variceal hemorrhage the of varices as and class and of variceal as or on the of a varices are based on with varices as as in the varices are an of varices and are into 2 The are which the They are of varices and be 2 varices the and to be and more varices in the of varices and are into 2 are in the and to be and and 2 are in the or the The of varices requires the of vein The in the diagnosis of varices is In a consensus it that the be as as in 2 and by or by with a of with large varices than When varices are in or in by a small varices as the varices as than of the and large varices as more than of the recommendations for varices are the as for large this is were in As shown prevent bleeding in more than of patients with or large varices. Therefore, it is that patients with cirrhosis for varices at the of Since the of varices is the majority of not have varices or have varices that not in to the of varices by studies have evaluated of varices in patients with as the portal vein and However, the of is and large prospective studies of are is the of assessing for the of have for patients with or for patients with and for patients with of these a that not prevent the development of varices and are with variceal as an prospective studies these is the The of in patients with no or small varices depends on be the diagnosis of cirrhosis is In patients with cirrhosis who have no varices on the be in In who have small the be in In the of be at is and requires can be in patients with cirrhosis who are on for other (e.g., hypertension. In on a for other to a be that may replace is studies that is a and to to be may a in for varices larger studies the method for variceal The diagnosis of variceal hemorrhage is made of the following: active bleeding from a a a a or varices with no other of for the diagnosis of and varices is the diagnosis of cirrhosis is made varices be as small or large with the varices are The or of or on varices be for the management of varices for the management of hemorrhage and on portal venous portal and portal pressure are in of splanchnic and and and by splanchnic vasoconstriction and portal venous inflow. by intrahepatic However, (e.g., have a and the decrease in portal pressure to be more to a decrease in rather than a decrease in The of a and a has a portal as or variceal are that have no on portal flow or intrahepatic or by the of increased portal pressure by the of increased large to a benefit of in the of varices in patients with cirrhosis who portal hypertension at but not yet developed The that patients who a in of from a development of and that a larger of patients on this in to on larger number of patients with or were in the to the occurred in patients in the and in patients in the These results not the use of in the of consensus have that be every years in these and in the of In patients with cirrhosis who not have be to prevent development In patients who have cirrhosis and no varices on the it be in years there is evidence of hepatic be at that and of trials in the of variceal hemorrhage the results of trials that patients with small In this the of variceal hemorrhage 2 and it with 2 this not studies have the of in the of small with In the the of patients with large varices larger in the to the However, the patients with no and small varices and a of the patients were to large but that patients with small varices with a to large varices at than patients who were randomized to at with no in The of variceal bleeding in patients who treatment with varices were small at with patients who large varices were at However, this benefit to the patients in a of given that large varices developed and patients were with the of bleeding very to other a higher of patients on to be from the of to patients on with be in patients with small varices who are at a for that with advanced liver and the of on patients with small varices can to prevent variceal benefit has not been In who not to consensus have that be every 2 and in the of In patients with cirrhosis and small varices that have not but have for increased of hemorrhage or of on be for the of variceal hemorrhage In patients with cirrhosis and small varices that have not and have no for increased of can be benefit has not been In patients with small varices that have not and who are not be in 2 years there is evidence of hepatic be at that and In patients with small varices who a is not of trials that patients versus treatment or in the of variceal hemorrhage that the of variceal bleeding in patients with or varices is by in in and that bleeding episode is for every 10 patients with is in the with the control and this has recently been shown to be a and that were the of portal pressure by more by splanchnic vasoconstriction portal blood are and are for of variceal hemorrhage. decrease in the of hemorrhage and from or from decrease the of variceal hemorrhage. In the majority of the published the of to decrease the from However, is not and a in not correlate with in the of is to is at a of a is is at a of a a randomized that the of bleeding treatment with is be of patients from trials have to the use of as of and The to in cirrhosis are and of of these with or treatment in of patients. in which have reported of than have not been variceal has been to in several randomized trials in patients with varices varices with or meta-analyses of these trials have been the trials and with with and the studies with with that is with a small but of variceal hemorrhage in The results are the fully published trials or trials are the has a of the are more and bleeding from in 10 patients 2 and in This last complication is to given the use of that the use of for In the of of the 10 patients on of 2 of the more studies in these meta-analyses to be the number of patients and a of analysis a higher number of treatment or a in the to the The of this is in that that bleeding were not and that in the have the In the 2 randomized and a more not in the have shown that is to or to in the variceal hemorrhage. review of the a consensus of experts that both and are in variceal hemorrhage and the be based on patient and and not for The of a and has a portal and be more than in variceal In a with a of hemorrhage in the with These results were of in However, 2 more larger trials were to these and a number of were in the Therefore, the use of a of a and be for there is of The of a and has been shown to portal pressure by and splanchnic blood has been recently in a The results suggest that the addition of not increase the of in the of variceal hemorrhage. The of of a and in the of variceal hemorrhage recently evaluated in a randomized but not in patients with and cirrhosis who were no in the of bleeding or and varices more in the were more in the the of in the be shown in to be as as in variceal However, of patients in this higher in patients than a may lead to a higher in these patients by the of the as shown in trials other as and In in a patients with varices and or to were randomized to or to there a and of variceal hemorrhage in the with no in were more in patients These results were in randomized of patients with Therefore, not be in patients with cirrhosis. trials have shown very in variceal hemorrhage, blood from the liver is by more and higher These results can be to the intrahepatic is the as that of of blood from the Therefore, or not be in the of variceal hemorrhage. trials have studies studies no and to be it the higher in the than in the not be for the of variceal hemorrhage. In patients with varices that have not but have a of hemorrhage or variceal on or may be for the of variceal hemorrhage In patients with varices that have not and are not at the of hemorrhage patients and no are preferred and be in patients with or or to a patient is on a it be to the is a patient is with it be every with the and every to for variceal or in with or not be in the of variceal hemorrhage is evidence that treatment for acute variceal hemorrhage, including general and have in an both in the and with acute variceal hemorrhage be to an for and including assessing the and venous be but with with the of and a of This recommendation is based on studies that that of blood leads to increases in portal pressure to higher than and to more and with be in addition to variceal hemorrhage, this can or the of or at other that of blood can or more may be for to in patients with concomitant hepatic The of and can be in patients with of in patients with gastrointestinal hemorrhage to a of analysis of a of and patients that of the of patients with to control variceal studies are needed this can be in patients with and variceal patients with bleeding have a of and other that are with of variceal hemorrhage and a patients with liver are at an increased of this is in with more liver and The use of in patients with cirrhosis and hemorrhage with or has been shown not to decrease the of but to increase This is to a decrease in the of in patients with variceal hemorrhage who Therefore, be practice in patients with cirrhosis and acute variceal The is at a of for 7 The the of a is the at of in the the of However, with of as be When is not can be In a in patients with advanced cirrhosis and hemorrhage, IV more than in mostly due to The of in the not and this have to the has the of applicable and of as as a diagnosis of variceal hemorrhage is to of trials and treatment or a with with that be treatment of variceal not be in the acute as decrease blood pressure and a increase in with is the splanchnic blood flow to splanchnic to a decrease in portal venous inflow and to a decrease in portal The clinical of is by which are to including and and and are by the addition of of are higher than with or it can be at the for a of to the development of is at a IV of that can be increased to a of always be by IV at a of which can be increased to a of to a blood pressure a of that has a and is in acute variceal hemorrhage and has been with a but is not yet in the is at an of 2 IV every and can be to IV every hemorrhage is and as and splanchnic vasoconstriction at it has been that this is due to an of the of studies suggest that has a The of and as and is that are and can be for or is in the and it has been mostly as an IV of followed by a of Use of of a IV followed by of is given as a IV followed by of However, results of meta-analyses of trials of are and a more of trials of in general a The may not be is has been with and a more to However, as shown to be as an to be the diagnosis of variceal hemorrhage is be as as (e.g., and be the variceal of hemorrhage is the a of 10 randomized controlled trials including patients an benefit of in the control of bleeding to of with a of In of the studies in the that increased both and it for the of the in the to by Therefore, by is the preferred of for acute variceal is in patients in whom is not of and is the approach in the treatment of acute variceal hemorrhage. The use of with to the which the of is the of trials to or the control of bleeding and in or variceal bleeding be controlled or in of patients. of has been shown to be of treatment or has clinical as for patients who to to or has reported control of bleeding and a with the of of of bleeding in patients a This approach has not been by other and is not a small has that of is with a in in patients as with an with acute variceal These results in a larger number of patients followed for a can be The of both and are on is very in bleeding with control of hemorrhage in of However, use is with as and of the with as as Therefore, it be to patients with bleeding for whom a more (e.g., is of is balloon is hemorrhage in a patient with cirrhosis is an that requires with and blood to a of 7 be in any patient with cirrhosis and hemorrhage or patients in whom is not is the In patients with advanced cirrhosis may be in with a of or and be as as variceal hemorrhage is and for diagnosis is be to the diagnosis and to variceal hemorrhage, with or is in patients in whom hemorrhage from varices be controlled or in whom bleeding despite and be as a in patients with bleeding for whom a more (e.g., or is The literature on the management of variceal hemorrhage is not as as that for variceal hemorrhage. there are controlled clinical trials, can be on guidelines for the management of varices. varices an of varices the of the Therefore, the approach to management be the as for varices the other there are very data the management of bleeding from are secondary to vein in which of to or variceal with tissue as or is more for acute variceal with better control of hemorrhage as as of large randomized variceal with versus in patients with acute variceal hemorrhage that control of active bleeding in both but that a of years occurred in the with an of In an an approved for in the has been as for and from Therefore, the use of these is preferred in the of varices. However, in the of these or the is with this of be studies the of for bleeding from varices with bleeding control of it been that bleeding from varices more to control with than bleeding from a prospective in patients with versus variceal bleeding and with control of hemorrhage in but patient in each The to for variceal hemorrhage is than for variceal hemorrhage and can be is not or a single of In patients who from variceal tissue as is preferred, is an be in patients in whom hemorrhage from varices be controlled or in whom bleeding despite and who an episode of acute variceal hemorrhage have a very of and The in is years of the hemorrhage, with a of is that patients who have from an episode of variceal hemorrhage and have no evidence of hemorrhage for at be on to prevent to from the who to control the acute episode not preventive these patients be to a are a or a or of variceal to patients with have a higher of However, there are better and the of a and has a portal and be more than has a the of and in patients with variceal This a benefit of but it not from randomized clinical trials that the in patients with is than that obtained with Therefore, the of in the of variceal is the of a and a However, this has to and is in clinical practice that patients end is the method of for variceal it has been shown to be to from randomized clinical trials a in patients with of are at to variceal which requires 2 to is every to to for variceal and for of in of but are The complication is and at the of each are the and may In a small randomized of IV followed by every for the number of at 10 the in both were in the not bleeding occurred in the These results the use of in patients with versus has been in randomized studies a benefit of a benefit of and a no treatment despite a in of These the of patient to be at in the of variceal with of is the approach to variceal and prevent variceal randomized trials the of versus in these 2 trials were and for to and for These results the use of to prevent a consensus conference or as in The a is in patients who variceal hemorrhage or on or a The of variceal is obtained in patients who are that patients in whom or leads to a in to or a from In patients who are it not be to use As the be to the to prevent variceal in the of this of the including the to the studies have the a of the and there is evidence that the of the in is with is very in rebleeding. However, it increases the of hepatic and has no on meta-analyses of trials that to as is with more and there is no in a than in it with and more in class with than Therefore, not be as a but as a for patients who have large of versus of and in patients with or cirrhosis who with a higher of in the both have the is on and to the and the trials have been The of that have been shown to have a and of may increase the for However, given results with it is that a not for secondary no be in the secondary of variceal hemorrhage. of trials which patients versus in the of variceal that the of variceal is by there were no in are and with and the number of needed to is than with suggest that is followed by a higher of variceal in with the no in variceal the of with in variceal has been 7 and a more no in or number of to variceal and a higher of in the Therefore, not be with with cirrhosis who an episode of active variceal hemorrhage to prevent of variceal hemorrhage of is the for secondary of variceal hemorrhage The be to the be every with the and every to for variceal be in patients who are or who experience variceal hemorrhage despite and In the is can be in patients who are be to a for that of varices of in the diagnosis of varices and variceal hemorrhage of in to with a on for varices and variceal hemorrhage In the decade the practice guidelines were a number of have our management of variceal hemorrhage. have been as a and have no in the of the development of varices but are the in the of variceal hemorrhage in patients with varices. variceal has been as an to for the of variceal hemorrhage. The of and variceal is the preferred approach to the management of acute variceal hemorrhage. is of as treatment of the acute bleeding and have been for the of variceal hemorrhage. of or are the the management of patients with varices may with the of that the intrahepatic more for and of liver This guideline in with the Practice Guidelines Committee of the American Association for the Study of Liver Diseases and the Practice Committee of the American College of Gastroenterology. These review of the of the AASLD Practice Guidelines Committee and of the Practice Committee and

Interleukin (IL)-13 is a pleiotropic cytokine produced in large quantities by activated CD4(+) Th2 lymphocytes. To define further its potential in vivo effector functions, the Clara cell 10-kDa protein promoter was used to express IL-13 selectively in the lung, and the phenotype of the resulting transgenic mice was characterized. In contrast to transgene-negative littermates, the lungs of transgene-positive mice contained an inflammatory response around small and large airways and in the surrounding parenchyma. It was mononuclear in nature and contained significant numbers of eosinophils and enlarged and occasionally multinucleated macrophages. Airway epithelial cell hypertrophy, mucus cell metaplasia, the hyperproduction of neutral and acidic mucus, the deposition of Charcot-Leyden-like crystals, and subepithelial airway fibrosis were also prominently noted. Eotaxin protein and mRNA were also present in large quantities in the lungs of the transgene-positive, but not the transgene-negative, mice. IL-4, IL-5, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein-5 were not similarly detected. Physiological evaluations revealed significant increases in baseline airways resistance and airways hyperresponsiveness (AHR) to methacholine in transgene-positive animals. Thus, the targeted pulmonary expression of IL-13 causes a mononuclear and eosinophilic inflammatory response, mucus cell metaplasia, the deposition of Charcot-Leyden-like crystals, airway fibrosis, eotaxin production, airways obstruction, and nonspecific AHR. IL-13 may play an important role in the pathogenesis of similar responses in asthma or other Th2-polarized tissue responses.

OBJECTIVE: Elevated levels of glucocorticoids in depression have been hypothesized to be associated with damage to the hippocampus, a brain area involved in learning and memory. The purpose of this study was to measure hippocampal volume in patients with depression. METHOD: Magnetic resonance imaging was used to measure the volume of the hippocampus in 16 patients with major depression in remission and 16 case-matched nondepressed comparison subjects. RESULTS: Patients with depression had a statistically significant 19% smaller left hippocampal volume than comparison subjects, without smaller volumes of comparison regions (amygdala, caudate, frontal lobe, and temporal lobe) or whole brain volume. The findings were significant after brain size, alcohol exposure, age, and education were controlled for. CONCLUSIONS: These findings are consistent with smaller left hippocampal volume in depression.

Singal, Amit G.; Llovet, Josep M.; Yarchoan, Mark; Mehta, Neil; Heimbach, Julie K.; Dawson, Laura A.; Jou, Janice H.; Kulik, Laura M.; Agopian, Vatche G.; Marrero, Jorge A.; Mendiratta-Lala, Mishal; Brown, Daniel B.; Rilling, William S.; Goyal, Lipika; Wei, Alice C.; Taddei, Tamar H. Author Information

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

BACKGROUND: The questions patients are asked about their preferences with regard to life-sustaining treatment usually focus on specific interventions, but the outcomes of treatment and their likelihood affect patients' preferences. METHODS: We administered a questionnaire about treatment preferences to 226 persons who were 60 years of age or older and who had a limited life expectancy due to cancer, congestive heart failure, or chronic obstructive pulmonary disease. The study participants were asked whether they would want to receive a given treatment, first when the outcome was known with certainty and then with different likelihoods of an adverse outcome. The outcome without treatment was specified as death from the underlying disease. RESULTS: The burden of treatment (i.e., the length of the hospital stay, extent of testing, and invasiveness of interventions), the outcome, and the likelihood of the outcome all influenced treatment preferences. For a low-burden treatment with the restoration of current health, 98.7 percent of participants said they would choose to receive the treatment (rather than not receive it and die), but 11.2 percent of these participants would not choose the treatment if it had a high burden. If the outcome was survival but with severe functional impairment or cognitive impairment, 74.4 percent and 88.8 percent of these participants, respectively, would not choose treatment. The number of participants who said they would choose treatment declined as the likelihood of an adverse outcome increased, with fewer participants choosing treatment when the possible outcome was functional or cognitive impairment than when it was death. Preferences did not differ according to the primary diagnosis. CONCLUSIONS: Advance care planning should take into account patients' attitudes toward the burden of treatment, the possible outcomes, and their likelihood. The likelihood of adverse functional and cognitive outcomes of treatment requires explicit consideration.

BACKGROUND: Combination antiretroviral therapy (ART) has significantly increased survival among HIV-positive adults in the United States (U.S.) and Canada, but gains in life expectancy for this region have not been well characterized. We aim to estimate temporal changes in life expectancy among HIV-positive adults on ART from 2000-2007 in the U.S. and Canada. METHODS: Participants were from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), aged ≥20 years and on ART. Mortality rates were calculated using participants' person-time from January 1, 2000 or ART initiation until death, loss to follow-up, or administrative censoring December 31, 2007. Life expectancy at age 20, defined as the average number of additional years that a person of a specific age will live, provided the current age-specific mortality rates remain constant, was estimated using abridged life tables. RESULTS: The crude mortality rate was 19.8/1,000 person-years, among 22,937 individuals contributing 82,022 person-years and 1,622 deaths. Life expectancy increased from 36.1 [standard error (SE) 0.5] to 51.4 [SE 0.5] years from 2000-2002 to 2006-2007. Men and women had comparable life expectancies in all periods except the last (2006-2007). Life expectancy was lower for individuals with a history of injection drug use, non-whites, and in patients with baseline CD4 counts <350 cells/mm(3). CONCLUSIONS: A 20-year-old HIV-positive adult on ART in the U.S. or Canada is expected to live into their early 70 s, a life expectancy approaching that of the general population. Differences by sex, race, HIV transmission risk group, and CD4 count remain.

Effective rehabilitative therapies are needed for patients with long-term deficits after stroke.In this multicenter, randomized, controlled trial involving 127 patients with moderate-to-severe upper-limb impairment 6 months or more after a stroke, we randomly assigned 49 patients to receive intensive robot-assisted therapy, 50 to receive intensive comparison therapy, and 28 to receive usual care. Therapy consisted of 36 1-hour sessions over a period of 12 weeks. The primary outcome was a change in motor function, as measured on the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke, at 12 weeks. Secondary outcomes were scores on the Wolf Motor Function Test and the Stroke Impact Scale. Secondary analyses assessed the treatment effect at 36 weeks.At 12 weeks, the mean Fugl-Meyer score for patients receiving robot-assisted therapy was better than that for patients receiving usual care (difference, 2.17 points; 95% confidence interval [CI], -0.23 to 4.58) and worse than that for patients receiving intensive comparison therapy (difference, -0.14 points; 95% CI, -2.94 to 2.65), but the differences were not significant. The results on the Stroke Impact Scale were significantly better for patients receiving robot-assisted therapy than for those receiving usual care (difference, 7.64 points; 95% CI, 2.03 to 13.24). No other treatment comparisons were significant at 12 weeks. Secondary analyses showed that at 36 weeks, robot-assisted therapy significantly improved the Fugl-Meyer score (difference, 2.88 points; 95% CI, 0.57 to 5.18) and the time on the Wolf Motor Function Test (difference, -8.10 seconds; 95% CI, -13.61 to -2.60) as compared with usual care but not with intensive therapy. No serious adverse events were reported.In patients with long-term upper-limb deficits after stroke, robot-assisted therapy did not significantly improve motor function at 12 weeks, as compared with usual care or intensive therapy. In secondary analyses, robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy. (ClinicalTrials.gov number, NCT00372411.)

We provide a single-cell atlas of idiopathic pulmonary fibrosis (IPF), a fatal interstitial lung disease, by profiling 312,928 cells from 32 IPF, 28 smoker and nonsmoker controls, and 18 chronic obstructive pulmonary disease (COPD) lungs. Among epithelial cells enriched in IPF, we identify a previously unidentified population of aberrant basaloid cells that coexpress basal epithelial, mesenchymal, senescence, and developmental markers and are located at the edge of myofibroblast foci in the IPF lung. Among vascular endothelial cells, we identify an ectopically expanded cell population transcriptomically identical to bronchial restricted vascular endothelial cells in IPF. We confirm the presence of both populations by immunohistochemistry and independent datasets. Among stromal cells, we identify IPF myofibroblasts and invasive fibroblasts with partially overlapping cells in control and COPD lungs. Last, we confirm previous findings of profibrotic macrophage populations in the IPF lung. Our comprehensive catalog reveals the complexity and diversity of aberrant cellular populations in IPF.

BACKGROUND: Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

This review discusses neurobiological and psychosocial factors associated with stress-induced depression and compares these factors with those believed to characterize stress resilience. Neurobiological factors that are discussed and contrasted include serotonin, the 5-HT1A receptor, polymorphisms of the 5-HT transporter gene, norepinephrine, alpha-2 adrenergic receptors, neuropeptide Y, polymorphisms of the alpha-2 adrenergic gene, dopamine, corticotropin-releasing hormone (CRH), dehydroepiandrosterone (DHEA), cortisol, and CRH receptors. These factors are described in the context of brain regions believed to be involved in stress, depression, and resilience to stress. Psychosocial factors associated with depression and/or stress resilience include positive emotions and optimism, humor, cognitive flexibility, cognitive explanatory style and reappraisal, acceptance, religion/spirituality, altruism, social support, role models, coping style, exercise, capacity to recover from negative events, and stress inoculation. The review concludes with potential psychological, social, spiritual, and neurobiological approaches to enhancing stress resilience, decreasing the likelihood of developing stress-induced depression/anxiety, and treating stress-induced psychopathology.

BACKGROUND: The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain. METHODS: We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group). RESULTS: In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001). CONCLUSIONS: The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.

OBJECTIVE: To describe the design and ongoing conduct of the Million Veteran Program (MVP), as an observational cohort study and mega-biobank in the Department of Veterans Affairs (VA) health care system. STUDY DESIGN AND SETTING: Data are being collected from participants using questionnaires, the VA electronic health record, and a blood sample for genomic and other testing. Several ongoing projects are linked to MVP, both as peer-reviewed research studies and as activities to help develop an infrastructure for future, broad-based research uses. RESULTS: Formal planning for MVP commenced in 2009; the protocol was approved in 2010, and enrollment began in 2011. As of August 3, 2015, and with a steady state of ≈50 recruiting sites nationwide, N = 397,104 veterans have been enrolled. Among N = 199,348 with currently available genotyping data, most participants (as expected) are male (92.0%) between the ages of 50 and 69 years (55.0%). On the basis of self-reported race, white (77.2%) and African American (13.5%) populations are well represented. CONCLUSIONS: By helping to promote the future integration of genetic testing in health care delivery, including clinical decision making, the MVP is designed to contribute to the development of precision medicine.

BACKGROUND: Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease. METHODS: In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction. RESULTS: By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003). CONCLUSIONS: In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

BACKGROUND: Nonselective beta-adrenergic blockers decrease portal pressure and prevent variceal hemorrhage. Their effectiveness in preventing varices is unknown. METHODS: We randomly assigned 213 patients with cirrhosis and portal hypertension (minimal hepatic venous pressure gradient [HVPG] of 6 mm Hg) to receive timolol, a nonselective beta-blocker (108 patients), or placebo (105 patients). The primary end point was the development of gastroesophageal varices or variceal hemorrhage. Endoscopy and HVPG measurements were repeated yearly. RESULTS: During a median follow-up of 54.9 months, the rate of the primary end point did not differ significantly between the timolol group and the placebo group (39 percent and 40 percent, respectively; P=0.89), nor were there significant differences in the rates of ascites, encephalopathy, liver transplantation, or death. Serious adverse events were more common among patients in the timolol group than among those in the placebo group (18 percent vs. 6 percent, P=0.006). Varices developed less frequently among patients with a baseline HVPG of less than 10 mm Hg and among those in whom the HVPG decreased by more than 10 percent at one year and more frequently among those in whom the HVPG increased by more than 10 percent at one year. CONCLUSIONS: Nonselective beta-blockers are ineffective in preventing varices in unselected patients with cirrhosis and portal hypertension and are associated with an increased number of adverse events. (ClinicalTrials.gov number, NCT00006398.)

The most common chronic condition experienced by adults is multimorbidity, the coexistence of multiple chronic diseases or conditions. In patients with coronary disease, for example, it is the sole condition in only 17% of cases.1 Almost 3 in 4 individuals aged 65 years and older have multiple chronic conditions, as do 1 in 4 adults younger than 65 years who receive health care.2 Adults with multiple chronic conditions are the major users of health care services at all adult ages, and account for more than two-thirds of health care spending.2 Despite the predominance of multiple chronic conditions, however, reimbursement remains linked to discrete International Classification of Diseases diagnostic codes, none of which are for multimorbidity or multiple chronic conditions. Specialists are responsible for a single disease among the patient’s many. Quality measurement largely ignores the unintended consequences of applying the multiple interventions necessary to adhere to every applicable measure. Uncertain benefit and potential harm of numerous simultaneous treatments, worsening of a single disease by treatment of a coexisting one, and treatment burden arising from following several disease guidelines are the well-documented challenges of clinical decision making for patients with multiple chronic conditions.3,4 To ensure safe and effective care for adults with multiple chronic conditions, particularly the millions of baby boomers entering their years of declining health and increasing health service use, health care must shift its current focus on managing innumerable individual diseases. To align with the clinical reality of multimorbidity, care should evolve from a disease orientation to a patient goal orientation, focused on maximizing the health goals of individual patients with unique sets of risks, conditions, and priorities. Patient goal–oriented health care involves ascertaining a patient’s health outcome priorities and goals, identifying the diseases and other modifiable factors impeding these goals, calculating and communicating the likely effect of alternative treatments on these goals, and guiding shared decision making informed by this information.4