Ospedale di Parma

BACKGROUND: Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treatment to prevent thrombotic complications of acute coronary syndromes and percutaneous coronary intervention. METHODS: To compare prasugrel, a new thienopyridine, with clopidogrel, we randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. RESULTS: The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P=0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P=0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P=0.23) and fatal bleeding (0.4% vs. 0.1%; P=0.002). CONCLUSIONS: In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. (ClinicalTrials.gov number, NCT00097591 [ClinicalTrials.gov].)

BACKGROUND AND AIMS: Acute appendicitis (AA) is among the most common causes of acute abdominal pain. Diagnosis of AA is still challenging and some controversies on its management are still present among different settings and practice patterns worldwide. In July 2015, the World Society of Emergency Surgery (WSES) organized in Jerusalem the first consensus conference on the diagnosis and treatment of AA in adult patients with the intention of producing evidence-based guidelines. An updated consensus conference took place in Nijemegen in June 2019 and the guidelines have now been updated in order to provide evidence-based statements and recommendations in keeping with varying clinical practice: use of clinical scores and imaging in diagnosing AA, indications and timing for surgery, use of non-operative management and antibiotics, laparoscopy and surgical techniques, intra-operative scoring, and peri-operative antibiotic therapy. METHODS: This executive manuscript summarizes the WSES guidelines for the diagnosis and treatment of AA. Literature search has been updated up to 2019 and statements and recommendations have been developed according to the GRADE methodology. The statements were voted, eventually modified, and finally approved by the participants to the consensus conference and by the board of co-authors, using a Delphi methodology for voting whenever there was controversy on a statement or a recommendation. Several tables highlighting the research topics and questions, search syntaxes, and the statements and the WSES evidence-based recommendations are provided. Finally, two different practical clinical algorithms are provided in the form of a flow chart for both adults and pediatric (< 16 years old) patients. CONCLUSIONS: The 2020 WSES guidelines on AA aim to provide updated evidence-based statements and recommendations on each of the following topics: (1) diagnosis, (2) non-operative management for uncomplicated AA, (3) timing of appendectomy and in-hospital delay, (4) surgical treatment, (5) intra-operative grading of AA, (6) ,management of perforated AA with phlegmon or abscess, and (7) peri-operative antibiotic therapy.

BACKGROUND: The effect of decompressive craniectomy on clinical outcomes in patients with refractory traumatic intracranial hypertension remains unclear. METHODS: From 2004 through 2014, we randomly assigned 408 patients, 10 to 65 years of age, with traumatic brain injury and refractory elevated intracranial pressure (>25 mm Hg) to undergo decompressive craniectomy or receive ongoing medical care. The primary outcome was the rating on the Extended Glasgow Outcome Scale (GOS-E) (an 8-point scale, ranging from death to "upper good recovery" [no injury-related problems]) at 6 months. The primary-outcome measure was analyzed with an ordinal method based on the proportional-odds model. If the model was rejected, that would indicate a significant difference in the GOS-E distribution, and results would be reported descriptively. RESULTS: The GOS-E distribution differed between the two groups (P<0.001). The proportional-odds assumption was rejected, and therefore results are reported descriptively. At 6 months, the GOS-E distributions were as follows: death, 26.9% among 201 patients in the surgical group versus 48.9% among 188 patients in the medical group; vegetative state, 8.5% versus 2.1%; lower severe disability (dependent on others for care), 21.9% versus 14.4%; upper severe disability (independent at home), 15.4% versus 8.0%; moderate disability, 23.4% versus 19.7%; and good recovery, 4.0% versus 6.9%. At 12 months, the GOS-E distributions were as follows: death, 30.4% among 194 surgical patients versus 52.0% among 179 medical patients; vegetative state, 6.2% versus 1.7%; lower severe disability, 18.0% versus 14.0%; upper severe disability, 13.4% versus 3.9%; moderate disability, 22.2% versus 20.1%; and good recovery, 9.8% versus 8.4%. Surgical patients had fewer hours than medical patients with intracranial pressure above 25 mm Hg after randomization (median, 5.0 vs. 17.0 hours; P<0.001) but had a higher rate of adverse events (16.3% vs. 9.2%, P=0.03). CONCLUSIONS: At 6 months, decompressive craniectomy in patients with traumatic brain injury and refractory intracranial hypertension resulted in lower mortality and higher rates of vegetative state, lower severe disability, and upper severe disability than medical care. The rates of moderate disability and good recovery were similar in the two groups. (Funded by the Medical Research Council and others; RESCUEicp Current Controlled Trials number, ISRCTN66202560 .).

Dysfunctional CD8+ T cells present in chronic virus infections can express programmed death 1 (PD-1) molecules, and the inhibition of the engagement of PD-1 with its ligand (PD-L1) has been reported to enhance the antiviral function of these T cells. We took advantage of the wide fluctuations in levels of viremia which are typical of chronic hepatitis B virus (HBV) infection to comprehensively analyze the impact of prolonged exposure to different virus quantities on virus-specific T-cell dysfunction and on its reversibility through the blocking of the PD-1/PD-L1 pathway. We confirm that chronic HBV infection has a profound effect on the HBV-specific T-cell repertoire. Despite the use of a comprehensive panel of peptides covering all HBV proteins, HBV-specific T cells were rarely observed directly ex vivo in samples from patients with chronic infection, in contrast to those from patients with acute HBV infection. In chronic HBV infection, virus-specific T cells were detected mainly in patients with lower levels of viremia. These HBV-specific CD8+ T cells expressed PD-1, and their function was improved by the blocking of PD-1/PD-L1 engagement. Thus, a broad spectrum of anti-HBV immunity is expressed by patients with chronic HBV infection and this spectrum is proportional to HBV replication levels and can be improved by blocking the PD-1/PD-L1 pathway. This information may be useful for the design of immunotherapeutic strategies to complement and optimize available antiviral therapies.

BACKGROUND: The effect of intensified platelet inhibition for patients with unstable angina or myocardial infarction without ST-segment elevation who do not undergo revascularization has not been delineated. METHODS: In this double-blind, randomized trial, in a primary analysis involving 7243 patients under the age of 75 years receiving aspirin, we evaluated up to 30 months of treatment with prasugrel (10 mg daily) versus clopidogrel (75 mg daily). In a secondary analysis involving 2083 patients 75 years of age or older, we evaluated 5 mg of prasugrel versus 75 mg of clopidogrel. RESULTS: At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P=0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P=0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group. CONCLUSIONS: Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).

Muscle tissue may be damaged following intense prolonged training as a consequence of both metabolic and mechanical factors. Serum levels of skeletal muscle enzymes or proteins are markers of the functional status of muscle tissue, and vary widely in both pathological and physiological conditions. Creatine kinase, lactate dehydrogenase, aldolase, myoglobin, troponin, aspartate aminotransferase, and carbonic anhydrase CAIII are the most useful serum markers of muscle injury, but apoptosis in muscle tissues subsequent to strenuous exercise may be also triggered by increased oxidative stress. Therefore, total antioxidant status can be used to evaluate the level of stress in muscle by other markers, such as thiobarbituric acid-reactive substances, malondialdehyde, sulfhydril groups, reduced glutathione, oxidized glutathione, superoxide dismutase, catalase and others. As the various markers provide a composite picture of muscle status, we recommend using more than one to provide a better estimation of muscle stress.

Hepatitis B virus (HBV) is a noncytopathic virus, and the recognition of infected hepatocytes by HBV-specific CD8 cells has been assumed to be the central mechanism causing both liver damage and virus control. To understand the role of cytotoxic T cells in the pathogenesis of HBV infection, we used functional assays that require T cell expansion in vitro and human histocompatibility leukocyte antigen (HLA)-peptide tetramers that allow direct ex vivo quantification of circulating and liver-infiltrating HBV-specific CD8 cells. Two groups of patients with persistent HBV infection were studied: one without liver inflammation and HBV replication, the other with liver inflammation and a high level of HBV replication. Contrary to expectation, a high frequency of intrahepatic HBV-specific CD8 cells was found in the absence of hepatic immunopathology. In contrast, virus-specific T cells were more diluted among liver infiltrates in viremic patients, but their absolute number was similar because of the massive cellular infiltration. Furthermore, inhibition of HBV replication was associated with the presence of a circulating reservoir of CD8(+) cells able to expand after specific virus recognition that was not detectable in highly viremic patients with liver inflammation. These results show that in the presence of an effective HBV-specific CD8 response, inhibition of virus replication can be independent of liver damage. When the HBV-specific CD8 response is unable to control virus replication, it may contribute to liver pathology not only directly but by causing the recruitment of nonvirus-specific T cells.

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Hepatitis C virus (HCV)-specific CD8 cell exhaustion may represent a mechanism of HCV persistence. The inhibitory receptor PD-1 has been reported to be up-regulated in exhausted CD8 cells. Therefore, we studied PD-1 expression longitudinally during acute HCV infection. Most HCV-specific CD8 cells expressed PD-1 at the time of acute illness, irrespective of the final outcome. PD-1 expression declined with the acquisition of a memory phenotype and recovery of an efficient CD8 cell function in resolving HCV infections, whereas high levels were maintained when HCV persisted and HCV-specific CD8 cells remained dysfunctional. Blocking PD-1/PDL-1 interaction with an anti-PDL-1 antibody improved the capacity of expansion of virus-specific CD8 cells.

Adhesive small bowel obstruction (ASBO) is a common surgical emergency, causing high morbidity and even some mortality. The adhesions causing such bowel obstructions are typically the footprints of previous abdominal surgical procedures. The present paper presents a revised version of the Bologna guidelines to evidence-based diagnosis and treatment of ASBO. The working group has added paragraphs on prevention of ASBO and special patient groups. The guideline was written under the auspices of the World Society of Emergency Surgery by the ASBO working group. A systematic literature search was performed prior to the update of the guidelines to identify relevant new papers on epidemiology, diagnosis, and treatment of ASBO. Literature was critically appraised according to an evidence-based guideline development method. Final recommendations were approved by the workgroup, taking into account the level of evidence of the conclusion. Adhesion formation might be reduced by minimally invasive surgical techniques and the use of adhesion barriers. Non-operative treatment is effective in most patients with ASBO. Contraindications for non-operative treatment include peritonitis, strangulation, and ischemia. When the adhesive etiology of obstruction is unsure, or when contraindications for non-operative management might be present, CT is the diagnostic technique of choice. The principles of non-operative treatment are nil per os, naso-gastric, or long-tube decompression, and intravenous supplementation with fluids and electrolytes. When operative treatment is required, a laparoscopic approach may be beneficial for selected cases of simple ASBO. Younger patients have a higher lifetime risk for recurrent ASBO and might therefore benefit from application of adhesion barriers as both primary and secondary prevention. This guideline presents recommendations that can be used by surgeons who treat patients with ASBO. Scientific evidence for some aspects of ASBO management is scarce, in particular aspects relating to special patient groups. Results of a randomized trial of laparoscopic versus open surgery for ASBO are awaited.

As a consequence of improved technology, there is growing clinical interest in the use of multi-detector row computed tomography (MDCT) for non-invasive coronary angiography. Indeed, the accuracy of MDCT to detect or exclude coronary artery stenoses has been high in many published studies. This report of a Writing Group deployed by the Working Group Nuclear Cardiology and Cardiac CT (WG 5) of the European Society of Cardiology and the European Council of Nuclear Cardiology summarizes the present state of cardiac CT technology, as well as the currently available data concerning its accuracy and applicability in certain clinical situations. Besides coronary CT angiography, the use of CT for the assessment of cardiac morphology and function, evaluation of perfusion and viability, and analysis of heart valves is discussed. In addition, recommendations for clinical applications of cardiac CT imaging are given and limitations of the technique are described.

BACKGROUND: Compression stockings are recommended for prophylaxis against venous thromboembolism in patients undergoing neurosurgery, but anticoagulant agents have not gained wide acceptance because of concern about intracranial bleeding. METHODS: In a multicenter, randomized, double-blind trial, we assessed the efficacy and safety of enoxaparin in conjunction with the use of compression stockings in the prevention of venous thromboembolism in patients undergoing elective neurosurgery. Enoxaparin (40 mg once daily) or placebo was given subcutaneously for not less than seven days beginning within 24 hours after the completion of surgery. The primary end point was symptomatic, objectively confirmed venous thromboembolism or deep-vein thrombosis assessed by bilateral venography, which was performed in all patients on day 8+/-1. Bleeding side effects were carefully assessed. RESULTS: Among the 307 patients assigned to treatment groups, 129 of the 154 patients receiving placebo (84 percent) and 130 of the 153 patients receiving enoxaparin (85 percent) had venographic studies adequate for analysis. An additional patient in the placebo group died before venography of autopsy-confirmed pulmonary embolism. In this analysis, 42 patients given placebo (32 percent) and 22 patients given enoxaparin (17 percent) had deep-vein thrombosis (relative risk in the enoxaparin group, 0.52; 95 percent confidence interval, 0.33 to 0.82; P=0.004). The rates of proximal deep-vein thrombosis were 13 percent in patients receiving placebo and 5 percent in patients receiving enoxaparin (relative risk in the enoxaparin group, 0.41; 95 percent confidence interval, 0.17 to 0.95; P=0.04). Two patients in the placebo group died of autopsy-confirmed pulmonary embolism on days 9 and 16. Major bleeding occurred in four patients receiving placebo (intracranial bleeding in all four) and four patients (intracranial bleeding in three) receiving enoxaparin (3 percent of each group). CONCLUSIONS: Enoxaparin combined with compression stockings is more effective than compression stockings alone for the prevention of venous thromboembolism after elective neurosurgery and does not cause excessive bleeding.

AIMS: The aim was to validate, update, and extend the Diamond-Forrester model for estimating the probability of obstructive coronary artery disease (CAD) in a contemporary cohort. METHODS AND RESULTS: Prospectively collected data from 14 hospitals on patients with chest pain without a history of CAD and referred for conventional coronary angiography (CCA) were used. Primary outcome was obstructive CAD, defined as ≥ 50% stenosis in one or more vessels on CCA. The validity of the Diamond-Forrester model was assessed using calibration plots, calibration-in-the-large, and recalibration in logistic regression. The model was subsequently updated and extended by revising the predictive value of age, sex, and type of chest pain. Diagnostic performance was assessed by calculating the area under the receiver operating characteristic curve (c-statistic) and reclassification was determined. We included 2260 patients, of whom 1319 had obstructive CAD on CCA. Validation demonstrated an overestimation of the CAD probability, especially in women. The updated and extended models demonstrated a c-statistic of 0.79 (95% CI 0.77-0.81) and 0.82 (95% CI 0.80-0.84), respectively. Sixteen per cent of men and 64% of women were correctly reclassified. The predicted probability of obstructive CAD ranged from 10% for 50-year-old females with non-specific chest pain to 91% for 80-year-old males with typical chest pain. Predictions varied across hospitals due to differences in disease prevalence. CONCLUSION: Our results suggest that the Diamond-Forrester model overestimates the probability of CAD especially in women. We updated the predictive effects of age, sex, type of chest pain, and hospital setting which improved model performance and we extended it to include patients of 70 years and older.

// Carolina Simioni 1 , Giorgio Zauli 1 , Alberto M. Martelli 2 , Marco Vitale 3, 4 , Gianni Sacchetti 5 , Arianna Gonelli 1 and Luca M. Neri 1 1 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy 2 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy 3 Department of Medicine and Surgery, University of Parma, Parma, Italy 4 CoreLab, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy 5 Department of Life Sciences and Biotechnology, Pharmaceutical Biology Laboratory, University of Ferrara, Ferrara, Italy Correspondence to: Luca M. Neri, email: luca.neri@unife.it Keywords: exercise training; nutraceuticals; flavonoids intake; aging; antioxidant supplementation Received: January 26, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: March 08, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: March 30, 2018 ABSTRACT Physical exercise is considered to be one of the beneficial factors of a proper lifestyle and is nowadays seen as an indispensable element for good health, able to lower the risk of disorders of the cardiovascular, endocrine and osteomuscular apparatus, immune system diseases and the onset of potential neoplasms. A moderate and programmed physical exercise has often been reported to be therapeutic both in the adulthood and in aging, since capable to promote fitness. Regular exercise alleviates the negative effects caused by free radicals and offers many health benefits, including reduced risk of all-cause mortality, sarcopenia in the skeletal muscle, chronic disease, and premature death in elderly people. However, physical performance is also known to induce oxidative stress, inflammation, and muscle fatigue. Many efforts have been carried out to identify micronutrients and natural compounds, also known as nutraceuticals, able to prevent or attenuate the exercise-induced oxidative stress and inflammation. The aim of this review is to discuss the benefits deriving from a constant physical activity and by the intake of antioxidant compounds to protect the body from oxidative stress. The attention will be focused mainly on three natural antioxidants, which are quercetin, resveratrol and curcumin. Their properties and activity will be described, as well as their benefits on physical activity and on aging, which is expected to increase through the years and can get favorable benefits from a constant exercise activity.

Chronic hepatitis B virus (HBV) infection is a major health concern worldwide, frequently leading to liver cirrhosis, liver failure, and hepatocellular carcinoma. Evidence suggests that high viral antigen load may play a role in chronicity. Production of viral proteins is thought to depend on transcription of viral covalently closed circular DNA (cccDNA). In a human clinical trial with an RNA interference (RNAi)-based therapeutic targeting HBV transcripts, ARC-520, HBV S antigen (HBsAg) was strongly reduced in treatment-naïve patients positive for HBV e antigen (HBeAg) but was reduced significantly less in patients who were HBeAg-negative or had received long-term therapy with nucleos(t)ide viral replication inhibitors (NUCs). HBeAg positivity is associated with greater disease risk that may be moderately reduced upon HBeAg loss. The molecular basis for this unexpected differential response was investigated in chimpanzees chronically infected with HBV. Several lines of evidence demonstrated that HBsAg was expressed not only from the episomal cccDNA minichromosome but also from transcripts arising from HBV DNA integrated into the host genome, which was the dominant source in HBeAg-negative chimpanzees. Many of the integrants detected in chimpanzees lacked target sites for the small interfering RNAs in ARC-520, explaining the reduced response in HBeAg-negative chimpanzees and, by extension, in HBeAg-negative patients. Our results uncover a heretofore underrecognized source of HBsAg that may represent a strategy adopted by HBV to maintain chronicity in the presence of host immunosurveillance. These results could alter trial design and endpoint expectations of new therapies for chronic HBV.

Knowledge of the immunological events necessary to control hepatitis B virus (HBV) infection has accelerated in recent years, but their translation towards therapeutic strategies able to achieve a durable HBV suppression has been challenging. The scenario of how HBV deals with the host immunity is presented and used to discuss how the immune response can be harnessed to potentially achieve infection control.

High viral and/or antigen load may be an important cause of the T cell hyporesponsiveness to hepatitis B virus (HBV) antigens that is often observed in patients with chronic HBV infection. Reduction of viral and antigen load by lamivudine treatment represents an ideal model for investigating this hypothesis. HLA class II restricted T cell responses and serum levels of HBV-DNA, HBsAg, and HBeAg were studied before and during lamivudine treatment in 12 patients with hepatitis B e antigen positive chronic active hepatitis B to assess possible correlations between viral and/or antigen load and vigor of the T cell response. Cell proliferation to HBV nucleocapsid antigens and peptides and frequency of circulating HBV nucleocapsid-specific T cells were assessed to characterize CD4-mediated responses. A highly significant enhancement of the CD4-mediated response to HBV nucleocapsid antigens was already detectable in most patients 7-14 d after the start of lamivudine treatment. This effect was dramatic and persistent in 10 patients but undetectable in 2. It occurred concomitant with a rapid and marked reduction of viremia. Interestingly, lamivudine also enhanced the responses to mitogens and recall antigens, showing that its effect was not limited to HBV-specific T cells. In conclusion, an efficient antiviral T cell response can be restored by lamivudine treatment in patients with chronic hepatitis B concurrently with reduction of viremia, indicating the importance of viral load in the pathogenesis of T cell hyporesponsiveness in these patients. Since lamivudine treatment can overcome T cell hyporeactivity, combining lamivudine with treatments directed to stimulate the T cell response may represent an effective strategy to induce eradication of chronic HBV infection.

Introduction A panel of experts met in Paris on 18 April to present research and practice protocols, and to discuss topics of current interest related to the treatment of HIV/hepatitis C virus (HCV) co-infection. The information presented focussed on the following main aspects: The magnitude of the problem of HIV/HCV co-infection The differences and similarities between HIV and HCV disease paradigms, thereby allowing extrapolation of the lessons learned in HIV on the care of patients with HCV or HIV/HCV co-infections Strategies for managing HIV in HCV-co-infected patients using antiretroviral drugs Current standards for HCV treatment and ongoing management Strategies for treating HCV in HIV-co-infected patients using pegylated interferon (peg-IFN) plus ribavirin, and the management of possible adverse effects Special challenges in HIV/HCV co-infection, including non-responders to IFN/ribavirin, patients with cirrhosis, extrahepatic manifestations, and hepatitis B virus co-infection. The bulk of the meeting was devoted to a discussion of the specifics of HIV/HCV co-infection treatment, answering the questions: why? how? who? when? After presentations and discussions, a consensus of opinion regarding general treatment strategy was formulated. Hepatitis C virus treatment in co-infected patients: why? AIDS-related morbidity and mortality in HIV-infected patients continue to decrease as a result of effective antiretroviral therapy and prophylaxis for traditional opportunistic infections [1]. HIV-infected patients now have hope for a prolonged AIDS-free survival. Concurrently, however, the morbidity and mortality from co-morbid HCV infection within this population is on the increase. The magnitude of the co-infection problem becomes clear when its prevalence and impact on morbidity and mortality are considered [2–9]. Prevalence of hepatitis C virus–HIV co-infection In the United States, it is estimated that 30% of the 800 000 HIV-infected living individuals are co-infected with HCV [10,11]. Similar rates (33%) have been estimated for western Europe, although the number of HIV-infected individuals is less well defined [12]. However, the magnitude of the problem is alarming in countries such as Spain, where at least half of the 130 000 HIV-infected patients are estimated to be HIV/HCV co-infected [12]. In fact, among some sub-groups of HIV-infected patients, such as injection drug users, the prevalence of co-infection is as high as 70–90% [11–13]. Hepatitis C virus and clinical progression of HIV disease The Swiss Cohort Study demonstrated that HCV accelerates the progression of HIV disease [14]. This prospective study of patients starting highly active antiretroviral therapy (HAART) found that HCV was independently associated with an increased risk of progression to AIDS and death. This finding was not related to a lower usage or much poorer tolerance of antiretroviral drugs among individuals with hepatitis C, which is in agreement with findings from other European groups [15]. Therefore, hepatitis C might be considered to be a co-factor for HIV disease progression. On the other hand, the Johns Hopkins Cohort Study found that co-infected patients who had a baseline CD4 cell count of between 50 and 200 cells/mm3 progressed to death more quickly than their HIV-mono-infected counterparts [16]. This observation probably highlighted the fact that HCV-positive patients, most of whom were intravenous drug addicts, had significantly less exposure to HAART, with a delay in treatment until CD4 cell counts dropped below 50 cells/mm3. In contrast with this potential deleterious effect of hepatitis C on HIV disease progression, recent reports [17,18] have pointed out that the hepatitis G virus, an agent closely related to HCV, seem to exert a protective effect on the course of HIV disease. As treatment of HCV with IFN is equally effective against hepatitis G, its clearance might negatively influence HIV infection. Hepatitis C virus and response to highly active antiretroviral therapy The Swiss Cohort Study also demonstrated that HCV may impair immune reconstitution after effective HAART [14]. HCV-positive individuals were less likely to achieve a CD4 cell increase of at least 50 cells/mm3 at one year after the start of HAART compared with HCV-negative individuals. This observation has not, however, been confirmed by others [19], and warrants further studies. HIV and acceleration of hepatitis C virus liver disease HIV accelerates HCV-related liver disease [20–25]. Progression that typically takes up to 30 years or longer in HCV-mono-infected individuals has been shown to take less than half that time in co-infected individuals. An early study by Martin et al. [26] identified the development of cirrhosis within 3 years after HCV diagnosis in three co-infected patients. In 1993, Eyster et al. [27] found that liver failure was accelerated by HIV in HCV-infected haemophiliac individuals. The following year, Telfer et al. [28] published a retrospective study, which found that the median time from first exposure to HCV to clinical demise was only 16.5 years in co-infected haemophiliac individuals. In a large study of HCV-mono-infected and HIV/HCV co-infected individuals, Sánchez-Quijano et al. [29] found that within 15 years of initial HCV infection, 25% of those who were co-infected with HIV developed cirrhosis compared with only 6.5% of those without HIV infection. Similar data were obtained by Soto et al. [30], who followed a large group of HCV-mono-infected and co-infected patients. In the first 10 years, 14.9% of co-infected patients developed cirrhosis compared with only 2.6% of HCV-mono-infected patients. Overall, cirrhotic HIV-infected patients with HCV do very poorly. In a study conducted by Di Martino and colleagues [31], HIV/HCV-co-infected patients with cirrhosis were more likely to decompensate and die than patients who were HIV negative. Interestingly, HCV treatment with IFN plus ribavirin appeared to be protective in most instances, with protection extending to those with HIV. This suggests retrospectively that although HCV treatment is less effective in cirrhotic patients from an antiviral perspective, it may delay decompensation [32]. Hepatocellular carcinoma in co-infected patients Hepatocellular carcinoma (HCC) appears to occur at a younger age and after a shorter duration of HCV infection in co-infected individuals. This was the finding in a case–control study in which seven co-infected individuals with HCC were analysed [33]. The mean age at HCC diagnosis was 42 years in the co-infected group compared with 69 years in the control group. The estimated mean length of HCV infection before HCC diagnosis was 18 years in the co-infected group, compared with 28 years in the control group. End-stage liver disease mortality in co-infected patients A number of studies have demonstrated the association of HIV co-infection with an increased risk of morbidity and mortality caused by end-stage liver disease (ESLD) (Table 1) [2–9]. Iribarren et al. [34] reviewed the causes of death among a population of 1600 co-infected patients in a Spanish hospital over a 21 month period. Of the 44 total deaths, liver disease was responsible for up to 25%. Recent studies from Italy [3] and Spain [2,4] have compared the percentage of total in-hospital deaths caused by ESLD before 1995 with in-hospital deaths occurring within a time period after 1995. Although the total number of in-hospital deaths declined from the first time period to the later, the percentage of deaths caused by ESLD increased from 13 to 35% in the Italian study, and from 5 to 45% in the Spanish studies.Table 1: Mortality caused by end-stage liver disease among HIV-infected individuals. Similar results were seen in a US study [6]. In 1991, 11% of deaths in the studied HIV population were caused by ESLD. By 1998, ESLD was the leading cause of death, causing 50% of deaths (Table 1). Of those patients who died in 1998 of ESLD, 90% were HCV positive. In France, Cacoub et al. [8] documented a fivefold increase in deaths caused by liver disease in the time period before 1995 compared with after 1997, despite an overall declining death rate among co-infected individuals (Table 1). In 1997, Darby et al. [35] published a cohort study demonstrating the impact of co-infection among young men with haemophilia. HIV-infected patients, regardless of the severity of haemophilia, were found to be approximately sevenfold more likely to die of liver disease. Lesens et al. [36] also demonstrated a sevenfold increased risk of death in a 1999 prospective study of 147 HCV-positive haemophiliac individuals. Interestingly, co-infected patients with genotype 1 may have a more rapid progression of liver disease than individuals carrying other HCV genotypes [37]. Immune status influences hepatitis C virus liver disease Rockstroh et al. [38] looked at the association between immune function and the development of HCV liver disease. The study concluded either that immunosuppression accelerates the progression of liver disease or that once liver failure begins, deterioration with respect to AIDS also begins, progressing to death more rapidly. The finding of a greater severity of HCV liver disease as the immunodeficiency progresses has been confirmed by others [39]. Accordingly, the 1999 US Public Health Service/Infectious Diseases Society of America guidelines recognized HCV co-infection as an important opportunistic pathogen among HIV-infected patients [36,40]. Impact of highly active antiretroviral therapy on hepatitis C virus liver disease The impact of HAART on the progression of HCV liver disease is controversial. One possibility is that antiretroviral therapy could increase hepatic necroinflammatory activity and thereby accelerate the progression of HCV-related liver disease. Vento et al. [41] reported an increased mean Knodell score (from 8 to 13) in patients after starting HAART. Conversely, other studies have suggested that the use of HIV protease inhibitors (PI) may be associated with an improvement in liver histology with respect to those without PI [42,43]. This benefit may probably equally be seen with other potent antiretroviral regimens without PI. Prospective studies involving paired liver biopsies are needed to address the impact of HAART and immune reconstitution on HCV-related liver disease. Hepatotoxicity of highly active antiretroviral therapy in co-infected patients The association of chronic HCV with hepatotoxicity during HAART is well established [44,45]. Hepatitis C is an independent risk factor for hepatotoxicity with HAART (Table 2) [46–52]. Overall, significant liver enzyme elevations are seen in approximately 15% of individuals receiving antiretroviral drugs. Severe hepatotoxicity, however, leading to drug discontinuation, occurs in less than 10% of cases. Two mechanisms have been involved (Table 3), the first of which represents a hypersensitivity reaction, often affecting the skin and other organs, and occurring a few days to weeks after beginning antiretroviral therapy. A second mechanism with delayed onset (typically appearing several months after beginning therapy) is limited to the liver, and represents an intrinsic toxic effect of the drugs in use, and therefore is dose related [52]. Drugs such as nevirapine can produce liver toxicity by both mechanisms; whereas abacavir tends to involve just the first mechanism, often in the context of a multiorganic reaction. Drugs such as stavudine may cause liver toxicity through a cumulative effect.Table 2: Major studies assessing the risk of severe hepatic damage after beginning antiretroviral therapy. Table 3: Mechanisms of liver toxicity using antiretroviral drugs [32]. More rarely, in HCV chronic carriers experiencing a dramatic CD4 cell increase after beginning antiretroviral therapy, increases in transaminases can reflect an immune reconstitution syndrome [53], resembling what has been described in individuals with latent cytomegalovirus or mycobacterial infections. Further research is needed to determine the mechanism by which HCV infection or HCV-related liver disease increases the risk of HAART-associated liver injury. Hepatitis C virus-RNA dynamics in HIV infection and impact of highly active antiretroviral therapy Overall, serum HCV-RNA titres are 1.5 to twofold higher in HIV/HCV co-infected individuals with respect to individuals with single HCV infections [54–56], probably reflecting an impairment in the control of HCV replication in the setting of immunodeficiency. Whether this increase in HCV viral burden contributes to explaining the greater liver injury noticed in HIV/HCV co-infected patients is unknown, although there is no clear correlation between the extent of liver fibrosis and the level of HCV RNA. In individuals who begin potent antiretroviral therapy, serum HCV-RNA levels tend to increase during the first 3 months [57–59], decreasing slowly thereafter, first returning to baseline levels and even decreasing much later [60] (Fig. 1). Antiretroviral therapy may thus indirectly benefit the prognosis of HCV-related liver disease, reducing HCV replication on the long term. However, the relationship of HCV load and the progression of liver disease is uncertain.Fig. 1.: Dynamics of serum hepatitis C virus RNA in HIV infection and impact of antiretroviral treatment.Hepatitis C virus treatment in co-infected patients: how? The primary goal of HCV treatment is to achieve a sustained virological response that permits fibrosis regression, the disappearance of extrahepatic manifestations, and a reduction of the risk of transmission [61]. Moreover, in patients without sustained virological response, the progression of fibrosis could be ameliorated through suppressive maintenance therapy [32,62]. Until recently, IFN plus ribavirin combination therapy was the standard of care for the treatment of HCV infection [11,61]. Peg-IFN plus ribavirin combination therapy is, however, currently the preferred option, as it allows one to achieve the highest virological response rates to date: 41–42% for genotype 1 and 76–80% for genotypes 2 and 3 (Table 4) [63,64]. In addition to inducing virological response, peg-IFN/ribavirin also allows fibrosis regression in viral sustained responders [64,65]. In non-responders, in whom the first goal is not achieved, viral eradication, the second goal, slows fibrosis progression, and the prevention of clinical outcomes (ESLD, HCC, and death) [32] might be attained with maintenance therapy using peg-IFN monotherapy.Table 4: Sustained virological response to pegylated interferons in HIV-negative individuals with chronic hepatitis C. Factors associated with sustained virological response The achievement of sustained response depends on host and viral factors. Poynard et al. [65] identified five independent predictors of sustained response to IFN/ribavirin. Genotype 2 or 3 is the most important predictor. The remaining four predictors were: low viral load (< 3.5 million copies/ml), no or just portal fibrosis, female sex, and age below 40 years. Subsequent analyses demonstrated that female sex as a predictor was an issue of body mass index rather than sex. Ribavirin doses particularly need to be adequate to weight if optimal response rates are to be achieved [64]. For instance, when using adequate ribavirin doses, up to 48% of individuals with genotype 1 and up to 88% of those with genotypes 2/3 reached sustained response using peg-IFN plus ribavirin [64]. Additional predictive factors of response related to HIV include CD4 cell counts greater than 500 cells/mm3, plasma HIV-RNA levels below 10 000 copies/ml, and no alcohol consumption [23,66]. Treatment considerations related to CD4 cell counts Co-infected patients with CD4 cell counts greater than 500 cells/mm3 should be treated for HCV eradication. In individuals with CD4 cell counts of less than 500/mm3, treatment is less effective [66], but may be considered in order to reduce the risk of hepatotoxicity of antiretroviral drugs and the higher risk of progression to liver failure among patients with lower CD4 cell counts [38,39]. Overall, current HCV treatment in HIV/HCV co-infected patients can normalize alanine aminotransferase (ALT) levels and clean HCV RNA by 50%, decrease the progression of fibrosis by 60%, and decrease the risk of dying by 16% [20–25,42,43]. Weight-based dosing Dosing on the basis of the patient's body weight seems to be the key to optimized success with minimal side-effects using peg-IFN/ribavirin: peg-IFN alfa-2b (1.5 μg/kg per week) or peg-IFN alfa-2a (180 μg per week) plus ribavirin (> 10.6 mg/kg per day) represents the most effective HCV treatment option [63,64,67]. This is especially important when considering the weight variation among population groups. For example, Americans weigh an average of 10 kg more than Europeans. Weight-based dosing not only ensures that patients receive enough drug, it also ensures that they do not receive too much drug, thereby reducing the risk of adverse events that may result if a standard dose is given to a low-weight patient. An adequate ribavirin dose, particularly at the beginning of treatment, is linked to an increased likelihood of sustained virological response. In a recent multicentre trial [68], greater ribavirin use at week 4 of treatment was associated with a greater response rate at week 24. Considering these findings, an adequate dose of ribavirin, particularly at the start of therapy, should not be modified without first trying other strategies to increase tolerance, such as the use of epoetin alfa [69]. Concern about ribavirin use in co-infected patients There has been concern about the use of ribavirin in HIV/HCV co-infected patients because of dose-dependent anaemia and drug–drug interactions [23,70]. Ribavirin-induced anaemia may be more significant in co-infected patients [21,22]. This risk, however, should not preclude treatment, because it can quite often be successfully managed with erythropoietin [69] or by ribavirin dose reduction. Prospective studies examining the efficacy of this approach are ongoing. Concerns regarding interactions between ribavirin and antiretroviral drugs are more complex. Ribavirin, a guanosine nucleoside analogue, is known to inhibit the intracellular phosphorylation of zidovudine, stavudine and zalcitabine in vitro. There is concern that this may cause anti-HIV antagonism in vivo. However, to date, clinical data have not supported these in-vitro observations [70,71]. In addition, ribavirin enhances the phosphorylation of didanosine (Fig. 2), which may be of benefit in increasing the anti-HIV effect [72]. However, recent case reports have led to concern about the possible increased risk of pancreatitis and mitochondrial toxicity in patients taking ribavirin and didanosine [73–76]. Therefore, patients receiving ribavirin in combination with nucleoside analogues such as zidovudine or didanosine should be observed closely, and in some cases, consideration may be given to modyfing HAART to avoid the combination of these drugs. Another aspect that is still unclear regards the potential compromise in the effect of ribavirin on HCV as a result of the concomitant use of zidovudine or stavudine, because all these compounds share the same phosphorylation pathways. Prospective studies are underway to evaluate the clinical and pharmacological interactions of HAART and peg-IFN/ribavirin therapy.Fig. 2.: Metabolic pathways leading to the potentiation of didanosine by ribavirin. Ribavirin inhibits inosine monophosphate (IMP) dehydrogenase. This leads to an increase of the IMP pool, which acts as a phosphate donor for the conversion of didanosine (ddI) into dideoxy-IMP (ddIMP). This compound is then metabolized into the triphosphorylated metabolites dideoxy-adenosine monophosphate (ddAMP), dideoxy-adenosine 5'-diphosphate (ddADP) and dideoxy-adenosine triphosphate (ddATP). The increased concentrations of ddATP inhibits both HIV reverse transcriptase and mitochondrial DNA polymerase γ.Warning on the risk of lactic acidosis acidosis is of the of associated with mitochondrial toxicity of mitochondrial toxicity may not be and include and lactic analogues not only in the of more but in their potential for causing disease there is no of mitochondrial toxicity of lactic acidosis with the use of ribavirin without other nucleoside A 1995 study observed patients over 5 years with anti-HIV and found a rate of lactic acidosis of per A more recent study found per among patients observed over 18 with nucleoside only patients taking stavudine and didanosine were the increased to per The and has reports of of lactic acidosis associated with nucleoside Of were associated with a single nucleoside and with [69]. Overall, stavudine and didanosine were the most associated with lactic and of the cases, A mortality rate of among these reported to the US and the severity of the Ribavirin is a potent of inosine monophosphate (IMP) which leads to levels of the active of a key involved in mitochondrial toxicity (Fig. of the of ribavirin as a for has not been as the development of ribavirin that of lactic acidosis with ribavirin have been described in individuals with HCV of lactic acidosis or mitochondrial toxicity associated with ribavirin have been identified up to however, in HIV/HCV-co-infected individuals of had data reported that the specifics of what drugs the patients were were on a fact that suggests the possibility that was the One was not receiving nucleoside and that was with and was to continue with of the were also on stavudine, and of the were on abacavir is a analogue, it is involved in the same as didanosine (Fig. it could with ribavirin. However, current data that abacavir has a very low potential for mitochondrial toxicity treating HIV/HCV co-infected patients need to be of the potential risk of lactic acidosis associated with the concomitant use of ribavirin and nucleoside Although this has been seen only in combination with the risk may also in combination with other nucleoside into these the use of ribavirin with particularly with clinical and should of serum and levels in HIV/HCV co-infected patients to didanosine and ribavirin. in co-infected patients Until 2 years IFN was the only drug for the treatment of chronic hepatitis C. Overall, response rates to IFN observed in co-infected patients were to those observed in HIV-negative patients (Table However, response rates were significantly lower among HIV/HCV co-infected patients with low CD4 cell counts In combination therapy the standard of care for the treatment of chronic hepatitis C [61]. on the and efficacy of combination therapy in co-infected individuals is (Table and Table co-infected patients treated with standard were followed by et al. at 18 months had a sustained virological response. et al. noticed a sustained response rate of taking in 18 HIV/HCV to a course of IFN studies and others were a of to determine with adequate CD4 HCV could be in a co-infected patient. in a prospective study, et al. followed co-infected patients who were non-responders to IFN at 3 After months on combination therapy, one achieved and HCV-RNA Treatment response to interferon in HIV/hepatitis C virus co-infected patients. Table Treatment response to interferon plus ribavirin in HIV/hepatitis C virus co-infected patients. Table to interferon plus ribavirin in HIV/hepatitis C virus co-infected patients who or to after a course of interferon data that patients receiving achieve a higher sustained response rate than patients receiving IFN/ribavirin, especially in those with HCV genotype 1 In an ongoing study from the Hepatitis HCV-RNA after weeks of therapy in 35% of patients receiving IFN plus ribavirin compared with only of those receiving standard IFN three plus ribavirin. This the that exposure to rather than three is more effective for viral eradication. findings that an with IFN are by an ongoing large Spanish trial In patients who after a course of IFN with an overall rate of response of one (Table in co-infected patients The first of the and efficacy of combination therapy with peg-IFN plus ribavirin in individuals has shown that the overall rate of response was The trial is conducted in Spain, and individuals have The rate of for these patients should be at the of the The study is a prospective multicentre trial currently in date, patients have been to receive either IFN 3 three a week plus ribavirin 800 or peg-IFN 1.5 μg/kg per week plus ribavirin 800 for to weeks after the onset of treatment, the HIV viral load has in both treatment groups. CD4 cell total and counts all declined after the onset of HCV treatment, with no between the groups. of severe adverse events have been in the peg-IFN/ribavirin group, in the group, and one before events and for drug The of in 13 in the peg-IFN/ribavirin group and in the group. Of these cases, were by the as a result of and a not to start the trial studies with peg-IFN/ribavirin in co-infected patients are ongoing. The trial to include and an study include patients. The first results of these studies are to be in of therapy The duration of therapy should be to the patient's virological response at weeks of treatment and the number of predictors of response HCV RNA is by polymerase treatment should be and other strategies is and the has than four predictors of response, treatment should continue the has four or more treatment may be at Moreover, results from a recent trial suggested that the of HCV RNA after weeks on peg-IFN plus ribavirin is highly predictive of a of further sustained response. Therefore, treatment might be at this early drug exposure and This observation is of in patients, most of whom are other drugs. Further studies are needed to this of anaemia with erythropoietin The of ribavirin is levels below in to 35% of patients receiving therapy Although this is managed by ribavirin dose reduction or discontinuation, erythropoietin therapy has to be an effective treatment In addition, the ribavirin dose is more likely to in patients with anaemia treated with what is known about the of adequate and

Acute appendicitis (AA) is among the most common cause of acute abdominal pain. Diagnosis of AA is challenging; a variable combination of clinical signs and symptoms has been used together with laboratory findings in several scoring systems proposed for suggesting the probability of AA and the possible subsequent management pathway. The role of imaging in the diagnosis of AA is still debated, with variable use of US, CT and MRI in different settings worldwide. Up to date, comprehensive clinical guidelines for diagnosis and management of AA have never been issued. In July 2015, during the 3rd World Congress of the WSES, held in Jerusalem (Israel), a panel of experts including an Organizational Committee and Scientific Committee and Scientific Secretariat, participated to a Consensus Conference where eight panelists presented a number of statements developed for each of the eight main questions about diagnosis and management of AA. The statements were then voted, eventually modified and finally approved by the participants to The Consensus Conference and lately by the board of co-authors. The current paper is reporting the definitive Guidelines Statements on each of the following topics: 1) Diagnostic efficiency of clinical scoring systems, 2) Role of Imaging, 3) Non-operative treatment for uncomplicated appendicitis, 4) Timing of appendectomy and in-hospital delay, 5) Surgical treatment 6) Scoring systems for intra-operative grading of appendicitis and their clinical usefulness 7) Non-surgical treatment for complicated appendicitis: abscess or phlegmon 8) Pre-operative and post-operative antibiotics.