VA Long Beach Healthcare System

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmatising, and can improve awareness and patient identification.

The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) initiated the hepatitis C virus (HCV) guidance project (hereafter HCV guidance) in 2013. The AASLD-IDSA HCV guidance website (www.HCVGuidelines.org) disseminates up-to-date, peer-reviewed, unbiased, evidence-based recommendations to aid clinicians making decisions regarding the testing, management, and treatment of HCV infection. Using a web-based system enables timely and nimble distribution of the HCV guidance, which is periodically updated in near real time as necessitated by emerging research data, recommendations from public health agencies, the availability of therapeutic agents, or other significant developments affecting the rapidly evolving hepatitis C arena. The value and utility of the online HCV guidance to the community of hepatitis C care providers throughout the world is evidence by the nearly 10 million pageviews by 1.5 million users originating from 228 countries and territories since the January 2014 launch of the website. A major update of the HCV guidance was released electronically in November 2019. This HCV guidance update summarizes and highlights key new or amended recommendations since the previous October 2018 print publication.1 The advent of safe, well-tolerated, and highly efficacious (>95% cure rate)2 direct-acting antiviral (DAA) therapy for HCV infection has ushered in an era in which elimination of hepatitis C is conceivable. In 2016, the World Health Organization (WHO) proposed a global health sector strategy to eliminate hepatitis C as a public health threat by 2030 and developed an action plan to facilitate this goal.3 In response to the WHO action plan, the National Academies of Science, Engineering, and Medicine (NASEM) developed a US strategy for the elimination of hepatitis C.4 Key elements of the elimination plan include improved detection of undiagnosed cases, increased linkage and access to care for newly diagnosed persons, and expanded treatment access. Many of the recommendations included in the latest update to the HCV guidance and highlighted herein align with and support the goals of the NASEM and WHO strategies to move from control to eventual elimination of hepatitis C. Topics addressed include universal and risk-based hepatitis C screening, simplified treatment algorithms for treatment-naive adults without cirrhosis or with compensated cirrhosis, hepatitis C management in the pediatric population, acute hepatitis C testing and management, and transplantation of organs from HCV-viremic donors into HCV-negative recipients. For detailed evidence reviews related to these topics and information addressing other aspects of HCV testing and management, see the online HCV guidance (www.HCVGuidelines.org). The HCV guidance was developed and is updated by a volunteer panel (representing the AASLD and the IDSA) of hepatology and infectious diseases clinicians with hepatitis C expertise using an evidence-based review of available data, including information presented at scientific conferences and published in peer-reviewed journals. Based on scientific evidence and expert opinion, recommendations are rated by the level of evidence (I, II, or III) and the strength of the recommendation (A, B, or C) using a system adapted from the American College of Cardiology and the American Heart Association.5, 6 See the original AASLD–IDSA hepatitis C guidance publication7 or the HCV guidance website for additional details about the processes and methods employed. All recommendations are reviewed and approved by the governing boards of the AASLD and the IDSA. The HCV guidance panel classifies therapeutic regimens as recommended, alternative, or not recommended based on patient factors (i.e., treatment-naive versus experienced, cirrhosis status, and comorbidities) and viral characteristics (i.e., genotype, subtype, resistance-associated substitutions). Recommended regimens are considered equivalent; alternative regimens are effective but, compared to recommended regimens, have potential disadvantages, limitations for use in certain patient populations, or less supporting data. The identification of risk factors associated with contracting HCV infection served as the basis for the risk-based hepatitis C screening recommendations issued by the US Centers for Disease Control and Prevention (CDC) in 1998.8 Although sensitive for the identification of persons with chronic HCV infection, risk-based screening failed to identify the majority of individuals with HCV infection due to both clinician and patient barriers.9-12 Analysis of the 2003-2010 National Health and Nutrition Examination Survey prevalence data demonstrated that approximately three fourths of individuals with chronic hepatitis C in the United States belonged to the 1945-1965 birth cohort.13 Based on these data, both the CDC and the US Preventive Services Task Force (USPSTF) recommended one-time hepatitis C screening of all individuals in this birth cohort (1945-1965) regardless of risk factors.14, 15 Since these recommendations were established in 2012, HCV epidemiology in the United States has changed. Hepatitis C infection incidence nearly quadrupled from 2010 to 2017, primarily driven by increased injection drug use related to the opioid epidemic.16-19 CDC viral hepatitis surveillance data indicate progressively increasing acute HCV infection incidence each year from 2009 through 2017. Most of these new HCV infections occurred in persons born after 1965, with those aged 20-39 years accounting for the majority of cases. This ongoing trend has spurred interest in expanding HCV screening among the general US population. Several modeling studies suggest the cost-effectiveness of such an approach.20-23 Accordingly, the AASLD–IDSA guidance HCV screening and follow-up recommendations have been updated and include recommended universal HCV screening for all adults aged 18 years or older followed by periodic testing for persons with ongoing risk behaviors and/or exposures. In light of the inadequacy of targeted HCV case finding using risk-based and birth cohort HCV screening,24, 25 investigators have modeled the cost-effectiveness of one-time universal HCV screening for adults aged ≥ 18 years. Independent studies using different modeling techniques demonstrate that one-time universal screening for adults aged ≥ 18 years is cost-effective (<$30,000/quality-adjusted life-years) compared with birth-cohort screening.20, 26 Additionally, the cost-effectiveness of nontargeted HCV screening has proven robust in a variety of venues including correctional,27 prenatal,28, 29 and primary care30 settings as well as substance use treatment centers.31, 32 Given the current epidemiology of HCV disease in the United States, the cost-effectiveness of universal HCV screening, the high efficacy of DAA therapy, and the myriad liver-related and other health benefits of virologic cure,33-38 the HCV guidance panel recommends universal, one-time, opt-out HCV screening of adults aged ≥ 18 years. Although neither the CDC nor the USPSTF currently recommend universal HCV screening in adults, the CDC initiated a peer review process to consider such a recommendation in July 2019. Similarly, in August 2019, the USPSTF published a draft recommendation for universal HCV screening among adults aged 18-79 years. The USPSTF draft universal hepatitis C screening recommendation differs from that of the AASLD–IDSA HCV guidance by setting an upper age limit of 79 years. The HCV guidance panel does not recommend an age limit for universal adult HCV screening due to the excellent quality of life of many octogenarians and the association between advanced age and more rapid HCV disease progression. The HCV guidance panel's new universal screening recommendation is intended to enhance HCV case finding among adults not included in the 1945-1965 birth cohort and aligns with the WHO and NASEM goals of eliminating HCV as a public health threat by 2030. This is particularly important for men and women aged 20-39 years due to the disproportionate overlapping impact of the opioid epidemic and associated injection drug use and the rising rate of incident HCV infections in this age group. Universal HCV screening also bypasses the inherent barriers in ascertaining an accurate risk factor assessment. One-time, risk-based HCV screening is recommended for persons younger than 18 years old with current or past behaviors, exposures, or conditions or circumstances associated with an increased risk of HCV infection (see Table 1). There is currently insufficient evidence to support universal HCV screening in the pediatric population. People with an ongoing risk factor(s) for HCV infection remain vulnerable for as long as the behavior, exposure, condition, or circumstance persists, thereby warranting periodic repeat HCV testing. There is a paucity of data addressing the optimal frequency of repeat testing, thereby leaving the periodicity to the clinician's discretion on a case-by-case basis with consideration of an individual's risk for HCV infection or reinfection. People who inject drugs (PWID) and men with HIV infection who have unprotected sex with men are exceptions to this guidance. Because of the high incidence and prevalence of HCV infection in these populations,39-47 at least annual HCV testing is recommended. Given that many PWID lack access to or eschew traditional health care–delivery systems, integration of HCV testing services into substance use treatment programs, needle/syringe service programs, and acute detoxification programs expands the opportunities to accomplish periodic HCV testing in this key population.48-50 HCV-antibody testing using a US Food and Drug Administration (FDA)–approved assay (laboratory-based or point-of-care) is recommended for initial HCV screening.51, 52 The sensitivity and specificity of the lone FDA-approved point-of-care test (OraQuick HCV Rapid Antibody Test; OraSure Technologies Inc., Bethlehem, PA) are similar to laboratory-based assays.53, 54 A positive HCV-antibody test indicates current (active) HCV infection (acute or chronic), a past resolved infection, or rarely a false-positive result.55 A test to detect HCV viremia is necessary to confirm active HCV infection (see Fig. 1). Ideally, a positive HCV-antibody test automatically reflexes to HCV-RNA testing. This approach requires a single blood collection and avoids a return visit for confirmatory testing, a major barrier in the continuum of care.56 Collection of dried blood spots is an option for sequential HCV-antibody and reflex HCV-RNA testing. Dried blood spot collection can be accomplished with a fingerstick rather than venepuncture, and transport does not require an intact cold chain, making this an advantageous testing option in rural areas and among people for whom phlebotomy is a testing barrier.57 An FDA-approved quantitative or qualitative HCV-RNA assay with a detection level of ≤25 IU/mL should be used. HCV-RNA testing is required to detect reinfection after previous spontaneous or treatment-related viral clearance because HCV-antibody positivity is expected (see Fig. 1). Immunocompromised persons and those with possible HCV exposure in the prior 6 months may be HCV antibody–negative due to delayed or failed seroconversion58 or being in the seroconversion window period,52 respectively. HCV-RNA testing is a consideration for these individuals, particularly for those with a known risk factor(s). Persons who have a reactive HCV-antibody test and a negative (not detected) HCV-RNA test should be informed that they do not have evidence of current HCV infection. Although additional testing is typically unnecessary, HCV-RNA testing can be repeated for persons with ongoing HCV infection risk or if there is a high index of suspicion for recent infection. If either the clinician or the patient wishes to determine whether a positive HCV-antibody test in the absence of HCV viremia represents a resolved HCV infection or a biologic false positive, repeat testing with a different HCV-antibody assay can be undertaken. A false positive typically does not occur with two different assays.51, 59 Quantitative HCV-RNA testing is recommended prior to initiating antiviral therapy to determine baseline viremia (viral load), which may affect treatment duration with ledipasvir/sofosbuvir therapy. With the advent of pangenotypic DAA regimens, HCV genotyping is no longer universally required prior to treatment initiation. Pretreatment genotyping is recommended for persons with a prior HCV treatment failure because DAA regimen selection and duration may differ by genotype. Pretreatment genotyping is not required for treatment-naive patients without cirrhosis if a pangenotypic regimen is used. Upon diagnosis of active HCV infection, patients require counseling and certain clinical interventions prior to initiation of antiviral therapy. Prevention of further liver damage is crucial. To that end, counseling patients to abstain from alcohol takes priority because of associations between excess alcohol use and incident or progressive fibrosis and the development of HCC.60-69 There is no known safe level of alcohol use for patients with chronic hepatitis C. All patients with chronic hepatitis C, especially those with advanced fibrosis or cirrhosis, should be advised to abstain from alcohol use.70-72 Persons suffering from alcohol use disorder require treatment for this condition; consider referring these individuals to an addiction specialist. Ongoing alcohol use, however, is not a contraindication to antiviral therapy. Data indicate that ongoing alcohol use does not affect therapeutic outcomes with DAA regimens among treatment-adherent patients.73 From a public health perspective, educating persons with HCV infection about how to avoid transmitting the virus to others (Table 2) serves as an essential primary prevention measure to curb and eventually eliminate the hepatitis C epidemic. Exposure to infected blood is the primary mode of HCV transmission. Epidemics of acute HCV due to sexual transmission in men with HIV infection who have sex with men have also been described.74-77 Persons should be counseled to stop using illicit drugs and enter substance abuse treatment. Those who continue to inject drugs should be counseled to: Assessing liver disease severity is an essential component of the workup for all persons with newly diagnosed chronic hepatitis C as this factor influences initial and follow-up evaluation. This assessment (i.e., presence or absence of cirrhosis) can usually be accomplished with noninvasive tests (Table 3). Liver biopsy is rarely required but is a consideration if other causes of liver disease are suspected. Persons with known or suspected cirrhosis are at increased risk for complications of advanced liver disease and require frequent follow-up. They should also avoid hepatotoxic drugs, such as excessive acetaminophen (>2 g/day) and certain herbal supplements. Nephrotoxic drugs (e.g., nonsteroidal anti-inflammatory drugs) should also be avoided. Ongoing imaging surveillance for HCC and gastroesophageal varices is recommended for patients with cirrhosis.78-80 Cirrhosis with portal hypertension portends a greater likelihood of developing future hepatic complications in untreated patients.81, 82 Transient elastography provides point-of-care information regarding liver stiffness and can reliably distinguish patients with a high versus low likelihood of cirrhosis.83-85 Screening for HBV with an FDA-approved hepatitis B surface antigen (HBsAg) assay and HIV with an FDA-approved HIV-antigen/antibody test is recommended because these coinfections are associated with a poorer HCV prognosis.86-90 Persons who test positive for HBsAg require additional monitoring during HCV treatment due to HBV reactivation risk.91 Anti-HBV therapy is another consideration for these patients. For persons who test negative for HBsAg but positive for hepatitis B core antibodies (with or without hepatitis B surface antibodies) have resolved HBV infection, and no further workup or additional monitoring is needed.92 Primary prevention measures for persons without coinfection include counseling about how to avoid contracting HIV and HBV and immunization against HBV and hepatitis A virus (HAV) as needed. The CDC also recommends pneumococcal vaccination for all persons with chronic liver disease.93 Chronic HCV infection is an important infectious cause of death in the United States and a major contributor to morbidity and mortality from viral hepatitis globally. The availability of safe, effective, well-tolerated therapy substantially facilitates the goal of expanding HCV treatment as recommended in the HCV elimination strategies of the WHO3 and the NASEM.4 Overall, DAA regimens successfully cure HCV infection in > 95% of treated persons.2 Moreover, the development of coformulated, pangenotypic regimens that require relatively short treatment durations has greatly simplified HCV antiviral therapy administration. Despite these remarkable therapeutic improvements, in 2015, only 7.4% of persons with diagnosed HCV had begun antiviral treatment.94 Although more recent limited data indicate increased DAA access and uptake, this has been uneven geographically and across different patient populations.95-97 Thus, only a minority of persons with HCV infection obtain the many health benefits of successful treatment. From a public health perspective, successful HCV treatment also supports primary prevention by decreasing the population of persons capable of transmitting the virus, thereby reducing the incidence of HCV infection. Eradicating hepatitis C infection results in numerous health benefits, including reduced rates of all-cause mortality, cirrhosis, hepatic decompensation, and HCC.33, 37, 98-110 Successful treatment also confers improvement in extrahepatic manifestations of HCV disease, including cryoglobulinemic vasculitis111-116 and HCV-related non-Hodgkin lymphoma and other lymphoproliferative disorders,117-125 as well as improved productivity and quality of life.34, 35, 126-131 Given these and other benefits associated with virologic cure, the HCV guidance panel strongly recommends antiviral treatment for all adults with acute or chronic HCV infection (except those with a short life expectancy that cannot be remediated). Importantly, this recommendation includes persons with ongoing substance use (alcohol or drugs). Several studies demonstrate that treatment-committed individuals in this disproportionately affected population achieve sustained virologic response (SVR) rates with DAA therapy comparable to those without known, current substance use.73, 132-139 The universal treatment recommendation represents a principal tenet of the HCV guidance along with newly recommended universal hepatitis C screening of adults. The HCV guidance panel urges health care providers caring for adults to encourage hepatitis C screening and treatment (if positive) because DAA therapy is safe and cures HCV infection in most people.2 One approach to improving access to curative HCV treatment is expanding the number of health care providers administering antiviral therapy. Data demonstrate that HCV treatment can be effectively provided by a broad range of health care professionals with differing expertise—including specialists, primary care physicians, nurse practitioners, clinical pharmacy specialists, physician assistants, and registered nurses—without compromising treatment efficacy or safety.95, 140 Consequently, the HCV guidance panel developed simplified HCV treatment algorithms for treatment-naive adults (without cirrhosis or with compensated cirrhosis), which align with the NASEM plan to eliminate HCV as a US public health burden by 2030. These simplified treatment algorithms are designed to be used by any health care provider knowledgeable about HCV disease and treatment, including those without extensive experience who have timely access to a specialist. The simplified treatment algorithms provide concise, clear guidance on pretreatment assessment, on-treatment monitoring, assessment of response, and posttreatment management (see Figs. 2 and 3). The simplified HCV treatment algorithm for adults without cirrhosis (see Fig. 2) applies to persons aged ≥ 18 years who have not been previously treated for their infection and do not have evidence of cirrhosis as defined by the noninvasive parameters in the HCV guidance. of cirrhosis includes a > or any of the from a previously elastography cirrhosis (e.g., stiffness > noninvasive tests that (e.g., Liver clinical evidence of cirrhosis (e.g., liver and/or on and/or prior liver biopsy This simplified treatment algorithm is not recommended for persons with HIV and/or HBV infection, prior liver disease (i.e., rate and/or current because they require more See the online HCV guidance for management and treatment recommendations for these patients. The pretreatment should include an assessment for cirrhosis, and patient regarding treatment and the of and transmission Recommended pretreatment testing is to confirm chronic HCV infection and liver disease, HBV and/or HIV disease, and prior to treatment initiation. of HCV infection with DAA therapy can hepatic and thereby affect the and efficacy of data indicate an association between DAA therapy and reduced particularly among people with should be informed of the potential for during and after DAA therapy. monitoring during and after DAA treatment is of may be needed. data also indicate an association between DAA therapy and a significant in should be informed of the potential for a in their monitoring for is recommended during and after DAA may be needed. For on-treatment monitoring is not required a patient treatment-related or there are Several robust clinical have demonstrated the and high curative efficacy of and among treatment-naive persons without cirrhosis regardless of HCV genotype. These have been in cohort studies for both and Based on these data, of or of is recommended for adults for the simplified treatment To treatment response, HCV-RNA and hepatic testing is recommended or more after DAA treatment. HCV represents and virologic In the absence of cirrhosis, persons who require no follow-up. For those with ongoing HCV risk counseling is recommended as well as HCV-RNA testing or an in hepatic HCV viremia after of represents either reinfection or a (i.e., of the HCV With treatment are to those for initial treatment. If is suspected or cannot be such patients should be by clinicians with expertise in HCV treatment Persons who but have hepatic require for other causes of liver for whom treatment can be successfully see the online HCV guidance for management and antiviral regimen recommendations for If is delayed or not assessment for liver disease months is recommended, as in Fig. all regardless of to avoid excess alcohol to liver The simplified HCV treatment algorithm for adults with compensated cirrhosis (see Fig. applies to persons aged ≥ 18 years who have not been previously treated for their infection and have evidence of compensated cirrhosis (i.e., but not cirrhosis (i.e., B or evidence of cirrhosis the parameters in the previous and are in Fig. of the is recommended to compensated versus A ≥ or any of these patients for the simplified treatment Recommended pretreatment assessment also includes clinical for and hepatic and imaging of the liver the prior 6 months to for HCC and any of these clinical or imaging are to use of the simplified treatment See the online HCV guidance for treatment and management of persons with circumstances and conditions that a patient for use of the simplified treatment algorithm those in the previous and are in Fig. Similarly, assessment for potential and pretreatment and counseling are the as for treatment-naive patients without cirrhosis (see Fig. 3). Pretreatment assessment of patients with compensated cirrhosis for use of the simplified treatment algorithm includes blood a hepatic and months of initiating antiviral therapy. Quantitative and HBsAg tests are recommended any time prior to initiating DAA therapy. pretreatment testing is recommended if therapy is because of the for baseline testing in persons with cirrhosis and infection. Because hepatic rarely during HCV DAA treatment, clinicians may for on-treatment blood tests to detect liver who experience hepatic parameters and/or or other new liver-related or should see a liver specialist. monitoring of blood and are recommended for persons on or with as (see previous for a more detailed clinical have demonstrated the and high curative efficacy of and among treatment-naive adults with compensated cirrhosis, regardless of HCV genotype. These have been in cohort studies for both and Based on these data, recommended regimens for adults for the simplified treatment algorithm are of for patients with or of for those with or Pretreatment testing is recommended for persons with because only those without a baseline are for a of with and a baseline should be treated with or an alternative regimen (see the online HCV HCV-RNA and testing are recommended or more after of DAA therapy to treatment HCV represents and virologic surveillance for HCC (with or without 6 months after treatment is recommended for patients with cirrhosis, regardless of surveillance for varices is recommended, with AASLD guidance on portal in all patients to abstain from alcohol use to the risk of liver disease progression. counseling is recommended for persons with ongoing HCV risk HCV-RNA testing or an in hepatic is also recommended for these HCV viremia after of represents either reinfection or a With the treatment are to those for initial treatment. If is suspected or cannot be such patients should be by clinicians with expertise in HCV

BACKGROUND: Coronary revascularization guided by fractional flow reserve (FFR) is associated with better patient outcomes after the procedure than revascularization guided by angiography alone. It is unknown whether the instantaneous wave-free ratio (iFR), an alternative measure that does not require the administration of adenosine, will offer benefits similar to those of FFR. METHODS: We randomly assigned 2492 patients with coronary artery disease, in a 1:1 ratio, to undergo either iFR-guided or FFR-guided coronary revascularization. The primary end point was the 1-year risk of major adverse cardiac events, which were a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization. The trial was designed to show the noninferiority of iFR to FFR, with a margin of 3.4 percentage points for the difference in risk. RESULTS: At 1 year, the primary end point had occurred in 78 of 1148 patients (6.8%) in the iFR group and in 83 of 1182 patients (7.0%) in the FFR group (difference in risk, -0.2 percentage points; 95% confidence interval [CI], -2.3 to 1.8; P<0.001 for noninferiority; hazard ratio, 0.95; 95% CI, 0.68 to 1.33; P=0.78). The risk of each component of the primary end point and of death from cardiovascular or noncardiovascular causes did not differ significantly between the groups. The number of patients who had adverse procedural symptoms and clinical signs was significantly lower in the iFR group than in the FFR group (39 patients [3.1%] vs. 385 patients [30.8%], P<0.001), and the median procedural time was significantly shorter (40.5 minutes vs. 45.0 minutes, P=0.001). CONCLUSIONS: Coronary revascularization guided by iFR was noninferior to revascularization guided by FFR with respect to the risk of major adverse cardiac events at 1 year. The rate of adverse procedural signs and symptoms was lower and the procedural time was shorter with iFR than with FFR. (Funded by Philips Volcano; DEFINE-FLAIR ClinicalTrials.gov number, NCT02053038 .).

PURPOSE: The objective of this study was to investigate the clinical outcome and radiographic findings after arthroscopic superior capsule reconstruction (ASCR) for symptomatic irreparable rotator cuff tears. METHODS: From 2007 to 2009, 24 shoulders in 23 consecutive patients (mean, 65.1 years) with irreparable rotator cuff tears (11 large, 13 massive) underwent ASCR using fascia lata. We used suture anchors to attach the graft medially to the glenoid superior tubercle and laterally to the greater tuberosity. We added side-to-side sutures between the graft and infraspinatus tendon and between the graft and residual anterior supraspinatus/subscapularis tendon to improve force coupling. Physical examination, radiography, and magnetic resonance imaging (MRI) were performed before surgery; at 3, 6, and 12 months after surgery; and yearly thereafter. Average follow-up was 34.1 months (24 to 51 months) after surgery. RESULTS: Mean active elevation increased significantly from 84° to 148° (P < .001) and external rotation increased from 26° to 40° (P < .01). Acromiohumeral distance (AHD) increased from 4.6 ± 2.2 mm preoperatively to 8.7 ± 2.6 mm postoperatively (P < .0001). There were no cases of progression of osteoarthritis or rotator cuff muscle atrophy. Twenty patients (83.3%) had no graft tear or tendon retear during follow-up (24 to 51 months). The American Shoulder and Elbow Surgeons (ASES) score improved from 23.5 to 92.9 points (P < .0001). CONCLUSIONS: ASCR restored superior glenohumeral stability and function of the shoulder joint with irreparable rotator cuff tears. Our results suggest that this reconstruction technique is a reliable and useful alternative treatment for irreparable rotator cuff tears. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favor of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panelists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms "nonalcoholic" and "fatty" were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease. There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction-associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction-associated steatotic liver disease, who consume greater amounts of alcohol per week (140-350 g/wk and 210-420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and nonstigmatising, and can improve awareness and patient identification.

BACKGROUND: Iron overload and hemochromatosis are common, treatable conditions. HFE genotypes, levels of serum ferritin, transferrin saturation values, and self-reported medical history were studied in a multiethnic primary care population. METHODS: Participants were recruited from primary care practices and blood-drawing laboratories. Blood samples were tested for transferrin saturation, serum ferritin, and C282Y and H63D mutations of the HFE gene. Before genetic screening, participants were asked whether they had a history of medical conditions related to iron overload. RESULTS: Of the 99,711 participants, 299 were homozygous for the C282Y mutation. The estimated prevalence of C282Y homozygotes was higher in non-Hispanic whites (0.44 percent) than in Native Americans (0.11 percent), Hispanics (0.027 percent), blacks (0.014 percent), Pacific Islanders (0.012 percent), or Asians (0.000039 percent). Among participants who were homozygous for the C282Y mutation but in whom iron overload had not been diagnosed (227 participants), serum ferritin levels were greater than 300 mug per liter in 78 of 89 men (88 percent) and greater than 200 microg per liter in 79 of 138 women (57 percent). Pacific Islanders and Asians had the highest geometric mean levels of serum ferritin and mean transferrin saturation despite having the lowest prevalence of C282Y homozygotes. There were 364 participants in whom iron overload had not been diagnosed (29 C282Y homozygotes) who had a serum ferritin level greater than 1000 microg per liter. Among men, C282Y homozygotes and compound heterozygotes were more likely to report a history of liver disease than were participants without HFE mutations. CONCLUSIONS: The C282Y mutation is most common in whites, and most C282Y homozygotes have elevations in serum ferritin levels and transferrin saturation. The C282Y mutation does not account for high mean serum ferritin levels and transferrin saturation values in nonwhites.

BACKGROUND: Cardiorenal syndrome (CRS) encompasses conditions in which cardiac and renal disorders co-exist and are pathophysiologically related. The newest classification of CRS into seven etiologically and clinically distinct types for direct patient management purposes includes hemodynamic, uremic, vascular, neurohumoral, anemia- and/or iron metabolism-related, mineral metabolism-related and protein-energy wasting-related CRS. This classification also emphasizes the pathophysiologic pathways. The leading CRS category remains hemodynamic CRS, which is the most commonly encountered type in patient care settings and in which acute or chronic heart failure leads to renal impairment. SUMMARY: This review focuses on selected therapeutic strategies for the clinical management of hemodynamic CRS. This is often characterized by an exceptionally high ratio of serum urea to creatinine concentrations. Loop diuretics, positive inotropic agents including dopamine and dobutamine, vasopressin antagonists including vasopressin receptor antagonists such as tolvaptan, nesiritide and angiotensin-neprilysin inhibitors are among the pharmacologic agents used. Additional therapies include ultrafiltration (UF) via hemofiltration or dialysis. The beneficial versus unfavorable effects of these therapies on cardiac decongestion versus renal blood flow may act in opposite directions. Some of the most interesting options for the outpatient setting that deserve revisiting include portable continuous dobutamine infusion, peritoneal dialysis and outpatient UF via hemodialysis or hemofiltration. KEY MESSAGES: The new clinically oriented CRS classification system is helpful in identifying therapeutic targets and offers a systematic approach to an optimal management algorithm with better understanding of etiologies. Most interventions including UF have not shown a favorable impact on outcomes. Outpatient portable dobutamine infusion is underutilized and not well studied. Revisiting traditional and novel strategies for outpatient management of CRS warrants clinical trials.

BACKGROUND: There have been many clinical reports of patch graft surgery for irreparable rotator cuff tears. However, the retear rate of the patch graft is relatively high because of the lack of superior stability, causing subacromial abrasions. PURPOSE: To compare superior stability among 3 types of patch grafting for simulated irreparable rotator cuff tears. STUDY DESIGN: Controlled laboratory study. METHODS: Eight cadaveric shoulders were tested in a custom shoulder testing system. Superior translation of the humerus, subacromial contact pressure, and glenohumeral joint force were quantified in the following 5 conditions: (1) when the rotator cuff was intact, (2) after cutting the supraspinatus tendon, (3) after the patch graft to reconstruct the supraspinatus tendon, (4) after the patch graft to reconstruct the superior capsule, and (5) after the patch graft to reconstruct both the supraspinatus tendon and superior capsule. While the graft was sutured to the torn tendon in condition 3, the graft was attached to the superior glenoid in condition 4. RESULTS: Compared with values for intact rotator cuffs, cutting the supraspinatus tendon significantly increased superior translation (P < .05), significantly increased subacromial contact pressure (P < .05), and significantly decreased glenohumeral compression force (P < .05). Superior translation was restored partially after the supraspinatus tendon patch graft and restored fully after the superior capsule patch graft and after both patch grafts. All patch grafts fully restored the subacromial contact pressure (P < .05) but did not alter the glenohumeral joint force. CONCLUSION: When patch graft surgery is chosen for irreparable rotator cuff tears, the graft should be attached medially to the superior glenoid and laterally to the greater tuberosity to restore superior stability of the humeral head. CLINICAL RELEVANCE: The superior capsule patch graft completely restored superior stability of the glenohumeral joint, while patch grafting to the supraspinatus tendon partially restored superior translation.

Graves' disease (GD) is a very common autoimmune disorder of the thyroid in which stimulatory antibodies bind to the thyrotropin receptor and activate glandular function, resulting in hyperthyroidism. In addition, some patients with GD develop localized manifestations including ophthalmopathy (GO) and dermopathy. Since the cloning of the receptor cDNA, significant progress has been made in understanding the structure-function relationship of the receptor, which has been discussed in a number of earlier reviews. In this paper, we have focused our discussion on studies related to the molecular mechanisms of the disease pathogenesis and the development of animal models for GD. It has become apparent that multiple factors contribute to the etiology of GD, including host genetic as well as environmental factors. Studies in experimental animals indicate that GD is a slowly progressing disease that involves activation and recruitment of thyrotropin receptor-specific T and B cells. This activation eventually results in the production of stimulatory antibodies that can cause hyperthyroidism. Similarly, significant new insights have been gained in our understanding of GO that occurs in a subset of patients with GD. As in GD, both environmental and genetic factors play important roles in the development of GO. Although a number of putative ocular autoantigens have been identified, their role in the pathogenesis of GO awaits confirmation. Extensive analyses of orbital tissues obtained from patients with GO have provided a clearer understanding of the roles of T and B cells, cytokines and chemokines, and various ocular tissues including ocular muscles and fibroblasts. Equally impressive is the progress made in understanding why connective tissues of the orbit and the skin in GO are singled out for activation and undergo extensive remodeling. Results to date indicate that fibroblasts can act as sentinel cells and initiate lymphocyte recruitment and tissue remodeling. Moreover, these fibroblasts can be readily activated by Ig in the sera of patients with GD, suggesting a central role for them in the pathogenesis. Collectively, recent studies have led to a better understanding of the pathogenesis of GD and GO and have opened up potential new avenues for developing novel treatments for GD and GO.

BACKGROUND: Reestablishment of the native footprint during rotator cuff repair has been suggested as an important criterion for optimizing healing potential and fixation strength. HYPOTHESIS: A double-row rotator cuff footprint repair will demonstrate superior biomechanical properties compared with a single-row repair. STUDY DESIGN: Controlled laboratory study. METHODS: In 9 matched pairs of fresh-frozen cadaveric shoulders, the supraspinatus tendon from 1 shoulder was repaired with a double-row suture anchor technique: 2 medial anchors with horizontal mattress sutures and 2 lateral anchors with simple sutures. The tendon from the contralateral shoulder was repaired using a single lateral row of 2 anchors with simple sutures. Each specimen underwent cyclic loading from 10 to 180 N for 200 cycles, followed by tensile testing to failure. Gap formation and strain over the footprint area were measured using a video digitizing system; stiffness and failure load were determined from testing machine data. RESULTS: Gap formation for the double-row repair was significantly smaller (P < .05) when compared with the single-row repair for the first cycle (1.67 +/- 0.75 mm vs 3.10 +/- 1.67 mm, respectively) and the last cycle (3.58 +/- 2.59 mm vs 7.64 +/- 3.74 mm, respectively). The initial strain over the footprint area for the double-row repair was nearly one third (P < .05) the strain of the single-row repair. Adding a medial row of anchors increased the stiffness of the repair by 46% and the ultimate failure load by 48% (P < .05). CONCLUSION: Footprint reconstruction of the rotator cuff using a double-row repair improved initial strength and stiffness and decreased gap formation and strain over the footprint when compared with a single-row repair. CLINICAL RELEVANCE: To achieve maximal initial fixation strength and minimal gap formation for rotator cuff repair, reconstructing the footprint attachment with 2 rows of suture anchors should be considered.

UNLABELLED: Retrospective studies suggest that subjects with chronic hepatitis C and advanced fibrosis who achieve a sustained virological response (SVR) have a lower risk of hepatic decompensation and hepatocellular carcinoma (HCC). In this prospective analysis, we compared the rate of death from any cause or liver transplantation, and of liver-related morbidity and mortality, after antiviral therapy among patients who achieved SVR, virologic nonresponders (NR), and those with initial viral clearance but subsequent breakthrough or relapse (BT/R) in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) Trial. Laboratory and/or clinical outcome data were available for 140 of the 180 patients who achieved SVR. Patients with nonresponse (NR; n = 309) or who experienced breakthrough or relapse (BT/R; n = 77) were evaluated every 3 months for 3.5 years and then every 6 months thereafter. Outcomes included death, liver-related death, liver transplantation, decompensated liver disease, and HCC. Median follow-up for the SVR, BT/R, and NR groups of patients was 86, 85, and 79 months, respectively. At 7.5 years, the adjusted cumulative rate of death/liver transplantation and of liver-related morbidity/mortality in the SVR group (2.2% and 2.7%, respectively) was significantly lower than that of the NR group (21.3% and 27.2%, P < 0.001 for both) but not the BT/R group (4.4% and 8.7%). The adjusted hazard ratio (HR) for time to death/liver transplantation (HR = 0.17, 95% confidence interval [CI] = 0.06-0.46) or development of liver-related morbidity/mortality (HR = 0.15, 95% CI = 0.06-0.38) or HCC (HR = 0.19, 95% CI = 0.04-0.80) was significant for SVR compared to NR. Laboratory tests related to liver disease severity improved following SVR. CONCLUSION: Patients with advanced chronic hepatitis C who achieved SVR had a marked reduction in death/liver transplantation, and in liver-related morbidity/mortality, although they remain at risk for HCC.

BACKGROUND: In patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain. METHODS: We conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90 microg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. The primary end point was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points. RESULTS: We randomly assigned the patients to receive peginterferon (517 patients) or no therapy (533 patients) for 3.5 years. The level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly (P<0.001) with treatment, but there was no significant difference between the groups in the rate of any primary outcome (34.1% in the treatment group and 33.8% in the control group; hazard ratio, 1.01; 95% confidence interval, 0.81 to 1.27; P=0.90). The percentage of patients with at least one serious adverse event was 38.6% in the treatment group and 31.8% in the control group (P=0.07). CONCLUSIONS: Long-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin. (ClinicalTrials.gov number, NCT00006164.)

INTRODUCTION: A meta-analysis was performed using individual patient data from the five most recent randomised controlled trials (RCTs) which evaluated corticosteroids in severe alcoholic hepatitis (Maddrey discriminant function (DF) ≥ 32 or encephalopathy). This approach overcomes limitations associated with the use of literature data and improves the relevance of the study and estimates of effect size. AIMS: To compare 28-day survival between corticosteroid- and non-corticosteroid-treated patients and to analyse the response to treatment using the Lille model. METHODS: Individual patient data were obtained from five RCTs comparing corticosteroid treatment with placebo (n=3), enteral nutrition (n=1) or an antioxidant cocktail (n=1). RESULTS: 221 patients allocated to corticosteroid treatment and 197 allocated to non-corticosteroid treatment were analysed. The two groups were similar at baseline. 28-day survival was higher in corticosteroid-treated patients than in non-corticosteroid-treated patients (79.97±2.8% vs 65.7±3.4%, p=0.0005). In multivariate analysis, corticosteroids (p=0.005), DF (p=0.006), leucocytes (p=0.004), Lille score (p<0.00001) and encephalopathy (p=0.003) were independently predictive of 28-day survival. A subgroup analysis was performed according to the percentile distribution of the Lille score. Patients were classified as complete responders (Lille score ≤ 0.16; ≤ 35th percentile), partial responders (Lille score 0.16-0.56; 35th-70th percentile) and null responders (Lille ≥ 0.56; ≥ 70th percentile). 28-day survival was strongly associated with these groupings (91.1±2.7% vs 79.4±3.8% vs 53.3±5.1%, p<0.0001). Corticosteroids had a significant effect on 28-day survival in complete responders (HR 0.18, p=0.006) and in partial responders (HR 0.38, p=0.04) but not in null responders. CONCLUSION: Analysis of individual data from five RCTs showed that corticosteroids significantly improve 28-day survival in patients with severe alcoholic hepatitis. The survival benefit is mainly observed in patients classified as responders by the Lille model.

BACKGROUND: The combination of daclatasvir, a hepatitis C virus (HCV) NS5A inhibitor, and the NS5B inhibitor sofosbuvir has shown efficacy in patients with HCV monoinfection. Data are lacking on the efficacy and safety of this combination in patients coinfected with human immunodeficiency virus type 1 (HIV-1). METHODS: This was an open-label study involving 151 patients who had not received HCV treatment and 52 previously treated patients, all of whom were coinfected with HIV-1. Previously untreated patients were randomly assigned in a 2:1 ratio to receive either 12 weeks or 8 weeks of daclatasvir at a standard dose of 60 mg daily (with dose adjustment for concomitant antiretroviral medications) plus 400 mg of sofosbuvir daily. Previously treated patients were assigned to undergo 12 weeks of therapy at the same doses. The primary end point was a sustained virologic response at week 12 after the end of therapy among previously untreated patients with HCV genotype 1 who were treated for 12 weeks. RESULTS: Patients had HCV genotypes 1 through 4 (83% with genotype 1), and 14% had compensated cirrhosis; 98% were receiving antiretroviral therapy. Among patients with genotype 1, a sustained virologic response was reported in 96.4% (95% confidence interval [CI], 89.8 to 99.2) who were treated for 12 weeks and in 75.6% (95% CI, 59.7 to 87.6) who were treated for 8 weeks among previously untreated patients and in 97.7% (95% CI, 88.0 to 99.9) who were treated for 12 weeks among previously treated patients. Rates of sustained virologic response across all genotypes were 97.0% (95% CI, 91.6 to 99.4), 76.0% (95% CI, 61.8 to 86.9), and 98.1% (95% CI, 89.7 to 100), respectively. The most common adverse events were fatigue, nausea, and headache. There were no study-drug discontinuations because of adverse events. HIV-1 suppression was not compromised. CONCLUSIONS: Among previously untreated HIV-HCV coinfected patients receiving daclatasvir plus sofosbuvir for HCV infection, the rate of sustained virologic response across all genotypes was 97.0% after 12 weeks of treatment and 76.0% after 8 weeks. (Funded by Bristol-Myers Squibb; ALLY-2 ClinicalTrials.gov number, NCT02032888.).

Fixed rotation of either the femur or tibia has a significant influence on the patellofemoral joint contact areas and pressures. This is due to the anatomic asymmetry in the knee with respect to all planes, as well as the laterally directed force vector that naturally exists in bipedal lower-limb biomechanics. Specifically, femoral rotation results in an increase in patellofemoral contact pressures on the contralateral facets of the patella, and tibial rotation results in an increase in patellofemoral contact pressures on the ipsilateral facets of the patella. This difference can be elucidated when one considers that rotation of the femur is biomechanically different than rotation of the tibia. For both tibial and femoral rotations, the patella's distal attachment to the tibial tubercle influences the direction of patellar movement. The biomechanical evidence reviewed in this manuscript suggests that the determining factor in patellofemoral pathology is the derangement of normal joint mechanics. However, despite considerable experimental data supporting this position, there also are theories that suggest otherwise. This illustrates a very important point in patellofemoral joint pathology, where no one factor may be the sole defining etiology. Instead, the patellofemoral joint is one of the most complex diarthrodial joints in the body and there are a number of etiologic factors that can lead to pathology. This should be considered for developing repair and rehabilitation strategies.

Vascular injury of esophageal and gastrointestinal mucosa caused by injurious and ulcerogenic factors leads to the cessation of blood flow, ischemia, and hypoxia and tissue necrosis in form of erosions or ulcers. The re-establishment of blood vessels through the process of angiogenesis--formation of new blood vessels--is critical for healing of tissue injury because is essential for delivery of oxygen and nutrients to the healing site. Hypoxia increases expression of hypoxia inducible factor (HIF-1), which serves as hypoxia sensor and activates compensatory and adaptive mechanisms. However, the molecular mechanisms and the role of HIF-1α in hypoxia-driven cellular and molecular events of angiogenesis in gastrointestinal injury healing have not been fully explored. The review discusses the novel molecular mechanisms of angiogenesis in gastric and esophageal mucosa with focus on HIF1α and VEGF interactions during healing of gastric mucosal injury and esophageal ulcers. HIF-1α is upregulated by gastric mucosal injury and esophageal ulcers; this upregulation correlates with VEGF gene activation and initiation of angiogenesis. The non-steroidal anti-inflammatory drugs (NSAIDs) interfere with hypoxia-induced HIF-1α accumulation, VEGF gene activation and angiogenesis through upregulation of von Hippel- Lindau (VHL) tumor suppressor, which activates degradation of HIF-1α protein. HIF-1α is a transcription factor that under hypoxic conditions, accumulates in endothelial cells and can bind to VEGF gene promoter and induce VEGF gene expression. In order to activate the VEGF gene, HIF-1α must be transported to the nucleus. Recent evidence implicates importins as key mechanism in this process.

BACKGROUND: -adrenoreceptor antagonist, has been effective in alleviating nightmares associated with post-traumatic stress disorder (PTSD) in military veterans. METHODS: We recruited veterans from 13 Department of Veterans Affairs medical centers who had chronic PTSD and reported frequent nightmares. Participants were randomly assigned to receive prazosin or placebo for 26 weeks; the drug or placebo was administered in escalating divided doses over the course of 5 weeks to a daily maximum of 20 mg in men and 12 mg in women. After week 10, participants continued to receive prazosin or placebo in a double-blind fashion for an additional 16 weeks. The three primary outcome measures were the change in score from baseline to 10 weeks on the Clinician-Administered PTSD Scale (CAPS) item B2 ("recurrent distressing dreams"; scores range from 0 to 8, with higher scores indicating more frequent and more distressing dreams); the change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index (PSQI; scores range from 0 to 21, with higher scores indicating worse sleep quality); and the Clinical Global Impression of Change (CGIC) score at 10 weeks (scores range from 1 to 7, with lower scores indicating greater improvement and a score of 4 indicating no change). RESULTS: A total of 304 participants underwent randomization; 152 were assigned to prazosin, and 152 to placebo. At 10 weeks, there were no significant differences between the prazosin group and the placebo group in the mean change from baseline in the CAPS item B2 score (between-group difference, 0.2; 95% confidence interval [CI], -0.3 to 0.8; P=0.38), in the mean change in PSQI score (between-group difference, 0.1; 95% CI, -0.9 to 1.1; P=0.80), or in the CGIC score (between-group difference, 0; 95% CI, -0.3 to 0.3; P=0.96). There were no significant differences in these measures at 26 weeks (a secondary outcome) or in other secondary outcomes. At 10 weeks, the mean difference between the prazosin group and the placebo group in the change from baseline in supine systolic blood pressure was a decrease of 6.7 mm Hg. The adverse event of new or worsening suicidal ideation occurred in 8% of the participants assigned to prazosin versus 15% of those assigned to placebo. CONCLUSIONS: In this trial involving military veterans who had chronic PTSD, prazosin did not alleviate distressing dreams or improve sleep quality. (Funded by the Department of Veterans Affairs Cooperative Studies Program; PACT ClinicalTrials.gov number, NCT00532493 .).

Although high-protein diets continue to be popular for weight loss and type 2 diabetes, evidence suggests that worsening renal function may occur in individuals with—and perhaps without—impaired kidney function. High dietary protein intake can cause intraglomerular hypertension, which may result in kidney hyperfiltration, glomerular injury, and proteinuria. It is possible that long-term high protein intake may lead to de novo CKD. The quality of dietary protein may also play a role in kidney health. Compared with protein from plant sources, animal protein has been associated with an increased risk of ESKD in several observational studies, including the Singapore Chinese Health Study. Potential mediators of kidney damage from animal protein include dietary acid load, phosphate content, gut microbiome dysbiosis, and resultant inflammation. In light of such findings, adopting current dietary approaches that include a high proportion of protein for weight reduction or glycemic control should be considered with care in those at high risk for kidney disease. Given the possibility of residual confounding within some observational studies and the conflicting evidence from previous trials, long-term studies including those with large sample sizes are warranted to better ascertain the effects of high protein intake on kidney health.

PURPOSE: To investigate the effects of graft length and thickness on shoulder biomechanics after superior capsule reconstruction. METHODS: Subacromial peak contact pressure and glenohumeral superior translation were measured at 0°, 30°, and 60° of glenohumeral abduction in 8 fresh-frozen cadaveric shoulders under 5 conditions: (1) intact shoulder; (2) irreparable supraspinatus tendon tear, (3) superior capsule reconstruction with a fascia lata allograft 4-mm thick and 15 mm longer than the distance from the superior glenoid to the lateral edge of the greater tuberosity, as determined during placement at 30° of glenohumeral abduction; (4) superior capsule reconstruction with a fascia lata allograft 8-mm thick and with the same 15 mm relative length determined at 10° of glenohumeral abduction, and (5) superior capsule reconstruction with a fascia lata allograft 8-mm thick and with the 15-mm relative length determined at 30° of glenohumeral abduction. To investigate the effect of graft thickness, we compared the data from conditions 1, 2, 3, and 5. To assess the effect of graft length, we compared conditions 1, 2, 4, and 5. RESULTS: With superior capsule reconstruction using a 4-mm graft, subacromial peak contact pressure (but not superior translation) was significantly lower than with irreparable supraspinatus tears (at 0° abduction: 259% decrease; P = .0002; at 30° abduction: 113% decrease; P = .01). The superior capsule reconstruction using an 8-mm graft significantly decreased both subacromial peak contact pressure (at 0° abduction: 246% decrease, P = .0002; at 30° abduction: 158% decrease; P = .0008; at 60° abduction: 57% decrease; P = .04) and superior translation (at 0° abduction: 135% decrease; P = .02; at 30° abduction; 130% decrease; P = .004). Graft length with placement at 10° glenohumeral abduction was 5 mm greater than that at 30° abduction. The 8-mm superior capsule reconstruction performed at 10° or 30° of glenohumeral abduction significantly decreased subacromial peak contact pressure (placement at 10° and 30°: 0° abduction, P = .0002 and .0002, respectively; 30° abduction, P = .0004 and .0005, respectively; 60° abduction, P = .04 and .04, respectively) and superior translation (placement at 10° and 30°; 0° abduction, P =.04 and .02, respectively; 30° abduction, P = .02 and .004, respectively) compared with irreparable supraspinatus tears. CONCLUSIONS: Superior capsule reconstruction normalized the superior stability of the shoulder joint when the graft was attached at 10° or 30° of glenohumeral abduction. An 8-mm-thick graft of fascia lata had greater stability than did a 4-mm-thick graft. CLINICAL RELEVANCE: Grafts 8-mm thick and attached at 15° to 45° of shoulder abduction (equal to 10° to 30° of glenohumeral abduction) biomechanically restore shoulder stability during superior capsule reconstruction using fascia lata.