Hospital Universitari Joan XXIII de Tarragona

OBJECTIVE: To evaluate interactions among leptin, adiponectin, resistin, ghrelin, and proinflammatory cytokines [tumor necrosis factor receptors (TNFRs), interleukin-6 (IL-6)] in nonmorbid and morbid obesity. RESEARCH METHODS AND PROCEDURES: We measured these hormones by immunoenzyme or radiometric assays in 117 nonmorbid and 57 morbidly obese patients, and in a subgroup of 34 morbidly obese patients before and 6 months after gastric bypass surgery. Insulin resistance by homeostasis model assessment, lipid profile, and anthropometrical measurements were also performed in all patients. RESULTS: Average plasma lipids in morbidly obese patients were elevated. IL-6, leptin, adiponectin, and resistin were increased and ghrelin was decreased in morbidly obese compared with nonmorbidly obese subjects. After adjusting for age, gender, and BMI in nonmorbidly obese, adiponectin was positively associated with HDLc and gender and negatively with weight (beta = -0.38, p < 0.001). Leptin and resistin correlated positively with soluble tumor necrosis factor receptor (sTNFR) 1 (beta = 0.24, p = 0.01 and beta = 0.28, p = 0.007). In the morbidly obese patients, resistin and ghrelin were positively associated with sTNFR2 (beta = 0.39, p = 0.008 and beta = 0.39, p = 0.01). In the surgically treated morbidly obese group, body weight decreased significantly and was best predicted by resistin concentrations before surgery (beta = 0.45, p = 0.024). Plasma lipids, insulin resistance, leptin, sTNFR1, and IL-6 decreased and adiponectin and ghrelin increased significantly. Insulin resistance improved after weight loss and correlated with high adiponectin levels. DISCUSSION: TNFalpha receptors were involved in the regulatory endocrine system of body adiposity independently of leptin and resistin axis in nonmorbidly obese patients. Our results suggest coordinated roles of adiponectin, resistin, and ghrelin in the modulation of the obesity proinflammatory environment and that resistin levels before surgery treatment are predictive of the extent of weight loss after bypass surgery.

We performed a prospective, international, observational study of 844 hospitalized patients with blood cultures positive for Streptococcus pneumoniae. Fifteen percent of isolates had in vitro intermediate susceptibility to penicillin (minimum inhibitory concentration [MIC], 0.12-1 microg/mL), and 9.6% of isolates were resistant (MIC, >or=2 microg/mL). Age, severity of illness, and underlying disease with immunosuppression were significantly associated with mortality; penicillin resistance was not a risk factor for mortality. The impact of concordant antibiotic therapy (i.e., receipt of a single antibiotic with in vitro activity against S. pneumoniae) versus discordant therapy (inactive in vitro) on mortality was assessed at 14 days. Discordant therapy with penicillins, cefotaxime, and ceftriaxone (but not cefuroxime) did not result in a higher mortality rate. Similarly, time required for defervescence and frequency of suppurative complications were not associated with concordance of beta-lactam antibiotic therapy. beta-Lactam antibiotics should still be useful for treatment of pneumococcal infections that do not involve cerebrospinal fluid, regardless of in vitro susceptibility, as determined by current NCCLS breakpoints.

INTRODUCTION: Patients with influenza A (H1N1)v infection have developed rapidly progressive lower respiratory tract disease resulting in respiratory failure. We describe the clinical and epidemiologic characteristics of the first 32 persons reported to be admitted to the intensive care unit (ICU) due to influenza A (H1N1)v infection in Spain. METHODS: We used medical chart reviews to collect data on ICU adult patients reported in a standardized form. Influenza A (H1N1)v infection was confirmed in specimens using real-time reverse transcriptase-polymerase-chain-reaction (RT PCR) assay. RESULTS: Illness onset of the 32 patients occurred between 23 June and 31 July, 2009. The median age was 36 years (IQR = 31 - 52). Ten (31.2%) were obese, 2 (6.3%) pregnant and 16 (50%) had pre-existing medical complications. Twenty-nine (90.6%) had primary viral pneumonitis, 2 (6.3%) exacerbation of structural respiratory disease and 1 (3.1%) secondary bacterial pneumonia. Twenty-four patients (75.0%) developed multiorgan dysfunction, 7 (21.9%) received renal replacement techniques and 24 (75.0%) required mechanical ventilation. Six patients died within 28 days, with two additional late deaths. Oseltamivir administration delay ranged from 2 to 8 days after illness onset, 31.2% received high-dose (300 mg/day), and treatment duration ranged from 5 to 10 days (mean 8.0 +/- 3.3). CONCLUSIONS: Over a 5-week period, influenza A (H1N1)v infection led to ICU admission in 32 adult patients, with frequently observed severe hypoxemia and a relatively high case-fatality rate. Clinicians should be aware of pulmonary complications of influenza A (H1N1)v infection, particularly in pregnant and young obese but previously healthy persons.

The goal of this consensus initiated by the European Crohn’s and Colitis Organisation [ECCO] and European Society of Colo-Proctology [ESCP] was to establish European consensus guidelines for the surgical treatment of Crohn’s disease [CD]. The strategy to reach the consensus involved several steps and follows the standard operating procedures for consensus guidelines of ECCO. An open call for chairs and participants for this consensus was made among members of the ESCP, surgeons of ECCO, and ECCO members. Participants were selected by the Guidelines’ Committee of ECCO [GuiCom] and the guideline committee of the ESCP on the basis of their publication record and personal statement. Five working groups [WGs] were formed: WG 1, perioperative management; WG 2, upper gastrointestinal tract and small bowel; WG 3, large bowel; WG 4, perianal CD; and WG 5, special conditions. Participants were asked to answer relevant questions on current practice and areas of controversy related to the surgical treatment of CD based on their experience as well as evidence from the literature [Delphi procedure].1 In parallel, the WG members performed a systematic literature search of their topic with the appropriate key words using Medline/PubMed/ISI/Scopus, and the Cochrane database, as well as their own files. Provisional guideline statements [with supporting text] were then written by the WG chairs based on answers to the questionnaire and were subsequently circulated among the WG members, prompting discussion and exchange of available evidence. The proposed statements and the supporting text were submitted to an online platform for discussion and two online voting rounds were conducted. The first round involved all participants of the consensus development process and, for the second voting round, all national representatives of ECCO and ESCP were invited to participate. The consensus participants finally met in Dublin on September 22, 2015 for face-to-face discussion and voting for consensus on the statements. This was done by projecting the statements and revising them on screen until consensus was reached. Consensus was defined as agreement by more than 80% of participants; the consensus statements were numbered for convenience in the document. The level of evidence was graded according that published by the Oxford Centre for Evidence-based Medicine 2011 [http://www.cebm.net/mod_product/design/files/CEBM-Levels-of-Evidence-2.1.pdf]. The final manuscript was written by the WG chairs [OZ, GS, JW, WB, ZS] in conjunction with the WG members and revised for consistency by WB and AD. Officially, WB is representing the ECCO and AD the ESCP. It was agreed to publish the consensus guideline in JCC and to post links to the original publication in JCC on the websites of ECCO and the ESCP. The surgical treatment of CD was covered in the Third European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016. Part 1: Diagnosis and Medical Management, and Part 2: Surgical Management and Special Situations.2 The following guidelines add to the surgical aspects of the multidisciplinary management of Crohn’s disease. The present document is to be seen as complementary to the surgical section published in the 2016 consensus. Some consensus statements are modified or expanded and others are entirely new. In order to have a complete overview,2 the surgical statements of the existing Third European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical Management, and Part 2: Surgical Management and Special Situations3 are added, without supporting text. A number of statements account for the general management of CD, and are listed in this section. If a patient has a relapse, escalation of the maintenance treatment can be considered to prevent disease progression [EL2]. Steroids should not be used to maintain remission [EL1]. Surgery should always be considered as an option in localised disease [EL4]. Whether there is a higher rate of postoperative complications from abdominal surgery during or after anti-tumour necrosis factor [TNF] therapy remains controversial [EL3]. Prednisolone 20 mg daily or equivalent for more than 6 weeks is a risk factor for surgical complications [EL2]. Therefore, corticosteroids should be weaned if possible [EL5]. Laparoscopy, when feasible, should be the preferred approach in surgery for CD. It results in reduced morbidity, shorter hospital stay, reduction in adhesions and hernia formation, and improved cosmesis [EL1] Anti-TNF therapy is associated with higher postoperative septic complications after abdominal surgery for CD. The safest period for omission of anti-TNF therapy is unknown [EL2] The impact of preoperative medical therapy on postoperative surgical complications has been widely studied. Prednisolone 20 mg daily or equivalent for more than 6 weeks before surgery is a significant risk factor for surgical complications. Therefore, steroids should be weaned if possible. Conversely, thiopurines can safely be continued in the perioperative period. In the past, the association of anti-TNF therapy before surgery with postoperative complications was controversial, but recent studies and meta-analysis have shown an increased risk of postoperative sepsis, intra-abdominal abscesses, anastomotic leak, wound infections, and readmission in CD patients. The of steroids and anti-TNF the risk for complications. are available to the safest period of before surgery in order to the risk related to anti-TNF with and to are for surgery in CD CD can present with complications surgery in of with and of with should of the with or without is the of in is a of of gastrointestinal tract should be using and If are or surgery is with CD surgery should and to before of be in of should be used for or treatment of surgery are risk for and have been shown to after and are for should with CD present with should be daily and by a and in without [EL5]. or to medical treatment should for an surgery in CD a from of should be for and and by a multidisciplinary a and Medical treatment for should be and and should be daily to of or of should of for surgical treatment are to the management of in by an or should be with surgery is in of complete or if is In of to medical surgery can be after the patient is is by a and of or and to and steroids should be considered in If there are of or surgery be and a of the should be In the of the patient present with several of by there is to medical is to disease and and the and be before Surgery is the preferred option in with localised CD with but significant evidence of in a patient for surgery is a for if there is significant evidence of The of is and on the of small to surgery treatment with or for shorter than with should be first by medical In of of surgery is with and of disease are first with as in the ECCO guidelines for medical treatment of If are not by medical treatment or are surgery should be The to medical is to as there are medical that have not been The of should be the surgical risk should this to The medical and surgical treatment in of a can be and are discussion for and to the are An surgery and medical treatment in with disease and in treatment in the In with surgery should be considered an In CD, surgery should be considered an In with significant to and there is a higher risk of to medical This should be the risk of surgery following medical In with intra-abdominal have several with a an or disease are more to An from the treatment in in the The of an in an patient should not be considered an for surgery or Surgery should be considered in with CD in or if for is reduced a period of in of an medical and therapy In with CD, is a for surgery as the of be It is to that treatment with as an are before the of surgery is surgery is not and the disease after or increased of maintenance as or be considered as for should be with surgery is if to treatment or is not a in CD and septic complications. should be with for CD, medical therapy is not with and is surgery be if not to treatment Surgery for septic complications a significant risk of anastomotic leak, abscesses, and A of the of and a in the first and in the second should be considered in is a significant risk factor for postoperative complications. should be before surgery or If surgery is in a a is have or more of their in a period are considered and from preoperative by or is a significant risk factor for postoperative anastomotic leak, as wound and level is not a of as level be by or should be used in to the is and for preoperative in should be considered for In surgery a of the with of a by of is can safely be continued in the perioperative period and [EL2] available literature association the of and an increased risk of surgical of thiopurines before surgery is not abdominal surgery for CD, is to have a recent of the disease and and from the and are procedures in the of a recent should be by the multidisciplinary has in recent and present is widely used for the of CD and and and have and for the of and as the of for CD as can disease and disease and complications as abscesses, and The and It patient and a of for of the In with is the of and preferred as should be in patients. In localised is an but significant and have been shown to in abdominal surgery with recent of should perioperative therapy of steroids have been considered the perioperative standard of the for on This practice is based on two from the of postoperative of surgery with steroids before surgery have a is evidence to this practice of the preoperative several and a Cochrane not of preoperative This widely used practice should be and a should be to the evidence. has a be an for with CD surgery are a higher risk for and should be considered [EL2] with CD surgery are a higher risk for and the of and should be considered for is for patients. In the risk of is to risk an and an this are published for the and of related to CD surgery in Therefore, the and to be considered of the of after surgery is for CD, and in postoperative studies have the of after with a shorter hospital and this the of after surgery should be possible to the surgical management of CD patients. has the of after surgery in surgery of CD. 20 for CD with with with perioperative stay, to first and first were shorter in the of preoperative preoperative of and to and to 6 before of of and with and is for in with CD the upper tract more in than in but for surgery not to be increased [EL2] gastrointestinal Crohn’s disease is a of of CD. This has been in an of of with the European In this of the as and of the upper and upper was in of and of upper disease or with the of In with CD without upper in the upper tract were in to of the the of the upper in with CD, there are on the of surgery for this disease Therefore, that more upper CD not more surgical in CD have an of with a large number of with or without or and are all The is the be in the of gastrointestinal disease. with of CD to be present a have upper and perianal and surgeons working in an multidisciplinary to be with The for surgical treatment of is The or should be during multidisciplinary with an CD is a and in the of CD is more in disease with The of of CD from to in and in The of and from to but the of remains is in the of all and to a of CD, and to CD and It is if there is a to upper in Medical and surgical treatment of is as or small the of therapy is used for medical but disease a surgical A of and have been and and with as the are with the the level of the the level of the or to the Some have been The of has been without The of covered has been in with an a risk of and can be are are by In to be CD of the the and If surgery is and is in Crohn’s In CD of the and and are considered surgical of the second and are when with or have to be considered as is the or the is of should be with the possible [EL4]. CD disease of the and is an and the and are to the of the basis of and the of is to in of patients. In or is in and of The are upper abdominal and and are with and and anti-TNF have been to be The for surgery in CD is for complications. The of the The are in the and in of in the second and in in the and in of have in in the and are by a with An to is a are when feasible, with as there is of a or anastomotic The of CD in a is the and the have been as of from a of the or In is to relevant the is in of and Surgery be as as with and of and has been in recent surgical is for but all have the of CD is to the small number of in the medical after surgery is not It is to have and the and and of all the of the small before on In with not all the present with the level of or the of and or The and for CD are and should be used in the surgical impact on the postoperative treatment and the and are all for of small CD with but their and are to be and It is not to more than there were in the preoperative a can be used to the and with the to a is for is a to in CD, with and is when the of the is in disease with the small be [EL3]. Diagnosis during and are risk for risk of surgery and surgical for small CD [EL2] with complications were to have more with an risk of and surgical evidence for this in the and with disease are as the level of disease This be for and Crohn’s but with and a have a surgical Surgical as as and and are in have of and and of the the and the of the small of CD, the treatment should be on the basis of the of [EL2] The first of surgical for CD be a complete of the A complete and is to or all the CD have been a approach can be The of as localised and the of a are for in a that CD surgical is by the of from and involved were first in CD by and in and then by and several have been for of and of the small and and are to for are disease of a large of small of more than without an associated or anastomotic a from and in can be used as a treatment In with the surgical is based on a of small and disease of the with is not a to in In with of the are for and the for to the the and the of of the is are the and the to as the of the for of the and of the of are surgery is in and localised CD of the small should be with or [EL2] The preferred treatment of of the small when feasible, are [EL2] the treatment of to the of is the [EL2]. as is the preferred for the treatment of or and [EL2]. In a systematic and more than were The rate was from to and rate was from to of the in the meta-analysis of as the first surgical The is the used The is the used The has been to have a higher to the of a with and The complications after are small intra-abdominal septic complications and and and intra-abdominal with a rate of The risk to postoperative complications are intra-abdominal septic with and In and or of were not significant risk of of the small a have been Therefore, with section before a is not The of is the of the and a has been as and surgery for by Surgery is the preferred option in with localised Crohn’s disease with but significant evidence of [EL4]. small Crohn’s disease with a abdominal should be with and or surgical by if [EL3]. is the preferred [EL1]. Crohn’s disease a for should not be [EL5]. A approach is to be preferred for in Crohn’s disease appropriate is In more or there is evidence to surgery as the of first [EL3]. is a preferred for the management of and anastomotic It should be in with surgical [EL3]. and disease disease disease and are risk for surgery in Crohn’s disease. The following are considered of postoperative after of treatment disease perianal in and [EL3]. treatment with thiopurines [EL2] is associated with reduced risk of first with anti-TNF the risk of surgery [EL2]. is the standard in the of postoperative by the and of and the [EL2]. is the first after surgery treatment be [EL2]. and small are as for postoperative [EL3]. with Crohn’s disease should be of the risk associated with and should be and [EL1]. treatment is after in with risk factor for [EL2]. prevent postoperative the of are thiopurines [EL2] or [EL2]. is an option for with an [EL2]. have been shown to be after but are well [EL1]. should be [EL2]. with to disease by and or can be with Surgery for disease has a surgical rate than A approach is to be preferred for in CD appropriate is should be in more or disease [EL2] This the for in Crohn’s disease in with the in the ECCO evidence that in more the approach can be performed studies of were with a and a of of in of to to of hospital stay, perioperative and morbidity, for hernia and and open and the rate of CD, the of in the upper gastrointestinal tract during from have shown and of in disease and with In the of is In and are with and [EL2] It is the to after Some studies a of the and the results of are to and are In of disease with abscesses, is with of the and of of surgery for disease to more surgery and that a has rate and postoperative complications with not It that anastomotic is an anastomotic is is in and in anastomotic is in and of the and is to be as as with a rate of Surgery of surgery 1, 3, and and and are and has been If the in the be that should be in with surgical in weeks to after and the to is an based on the of groups according to with a of or have a risk of and surgical by after surgery is a risk factor for postoperative and anti-TNF to be to in and surgical Anti-TNF be the in and of a in the of has an risk of intra-abdominal septic complications and The of for is and is to CD and In the be in the of or disease. It is to to a after a and a multidisciplinary of a in CD has been to have a risk of intra-abdominal and are on the basis of their the of by the Surgery is for associated with are on the basis of their Surgery should be after the following and of and when and are in CD. is the preferred for the of with the and are on the basis of their the of by the are on the basis of their to the impact of their on and Surgery is in with In on the risk of surgery is more be to and to not surgical in disease is to the of in more disease in the or and surgery of the risk of or of the upper and the of and If surgery is for localised disease than a of the then of the is [EL3]. can be considered for a patient with an for surgery when disease two of the [EL3]. in the is not [EL3]. A studies with for that procedures are with in of postoperative or the for a was seen in after The reduced after was by without in and of results of are to with and the approach is studies that of a of perianal and have been as risk for is in the literature for when disease two widely of the but with has been associated with risk of and when two or more are The of have of the after If the is should be with an of Crohn’s disease after present higher and An be in selected and with Crohn’s of small disease and existing or evidence of management by is to maintain an in [EL4]. In selected with of perianal or small a can be as a treatment option with of to with but the rate is increased of with with that higher with in to with in large of were the first to a of with CD but a surgery with and recent studies have shown that the rate can be to that seen in in selected with of perianal or small disease. in a of more than that with an Crohn’s have an of small and to 80% have a after a of when the disease was or with CD with perianal or small disease be an with to the risk of and septic complications has to be with the In the of the is for an can be The of is to with an for It is to a with a and with a of CD after have higher and In this of multidisciplinary management is to maintain with CD after an have higher complications and than with to have more anastomotic and and the can be more when with and The development of Crohn’s in the should medical is for surgery in this of or and is the surgery is not in the of CD with CD present with more than among the sepsis, or small can be with and but surgery is not as is associated with The treatment of for large is or is not The of a the risk of the of a of the and there is the risk for are on for the management of large The treatment of for of the large is In of surgical should be or an of for large can be but there is evidence in the literature to the of there is for in the large to the of risk for Therefore, is to the of the A of the large of were of the or anastomotic The of for has not been by In a can be [EL5]. with or medical therapy can be considered The of has been in It has been associated with remission in the of with Crohn’s the the of medical can be after the evidence for remission is studies are of have with or after but in selected surgery with a to with a in there is has not been shown to have the as the in the disease is to medical The of in is on several medical and disease but not a formation, has been shown to be a strategy in in to has been to This has been for all surgical in CD, for but this to as Surgery in or in to medical treatment has in improved Surgery in has not been shown to have the impact on is for but the of a for an should account the of their disease and current and medical disease in CD was first by and in and of a of or and disease or The impact of from and disease to and or and an medical and surgical In the of perianal in CD and with on from disease or the of or The risk for complications on disease In of disease with the of disease is as as The first was published by the of CD among of in from to the of was to be a of of were an open and the of perianal CD before the of are the of the disease. with or CD, in and and that perianal or in of patients. An from all the with CD of the and and perianal disease of before or after the of The impact of and was were more to perianal disease than The was among and a second in the from a risk of after after after and after 20 of a or before the of CD. to were from were with of of the perianal surgery and of and and or of disease. It is unknown perianal in with CD the of this of surgery in the of is It is not after should there is a a of a period to the results of surgical in perianal after of their The to after was In of the have a perianal after and to have a higher risk for of perioperative reduced the rate of is considered the for the of perianal CD [EL2]. If is is a [EL2]. The and of are increased when with [EL1]. is not [EL3]. If a perianal is is considered the standard in the of an [EL5]. the of has and should be used in the [EL2]. is consensus for perianal in CD. In a of or [EL5]. In an be [EL5]. The of a perianal should be and if present should be [EL5]. perianal in with is the preferred In disease not to thiopurines or can be used as therapy [EL4]. after surgical treatment of is for [EL2]. The of on Crohn’s disease should be if in conjunction with appropriate surgical management of [EL5]. before surgical is for surgical of is for In and should be performed [EL4]. In the to medical or surgical treatment in is [EL2]. [EL2] or in with is to the of [EL5]. or or a of and medical therapy should be used as maintenance to medical treatment should be considered for a with as the and surgery [EL5]. Surgery is for if associated with and and if and [EL5]. not surgical treatment [EL5]. If a patient has a surgery is [EL5]. CD with should be before and after surgery to prevent [EL5]. The for surgery to a in CD a with with and a defined tract The appropriate surgical treatment of perianal be to be to the an with an associated or the of of and the of and the of associated disease In of be medical or the be using This the the tract to and of the The used surgical of tract and treatment In the of CD, be considered when with the of the than of have an associated with their and this be before a CD are more to have for a and to are seen in 80% of and, with to and are Medical therapy to is to the of tract after The approach should be to and prevent perianal should not be as this can to The of surgical should be to the of the and of the and the of the The of treatment is to the tract in order to prevent and to A number of can be to approach the for surgical treatment with Crohn’s perianal with to of the number of and of the and The to the strategy of a of surgical or and This that not all are for the patient with perianal for a is not possible in a The to perianal are and the The experience to has been with the The surgical procedures be considered as first by open the tract and by [with or without is for

OBJECTIVE: Pseudomonas aeruginosa is a frequent cause of ventilator-associated pneumonia. Recent evidence suggests that production of type III secretion proteins is correlated with increased pathogenicity in both cellular and animal models of infection. The objective of this study was to determine whether this system contributes to disease severity in humans with ventilator-associated pneumonia. DESIGN: Retrospective pilot cohort study. SETTING: University hospital. PATIENTS: Thirty-five mechanically ventilated patients with bronchoscopically confirmed ventilator-associated pneumonia caused by P. aeruginosa. MEASUREMENTS AND MAIN RESULTS: Ventilator-associated pneumonia was categorized as severe (patients died or had a recurrence of their pneumonia despite appropriate antibiotic therapy) or mild (patients uneventfully recovered from their pneumonia). The type III secretion genotypes and phenotypes of isolates cultured from the patients with ventilator-associated pneumonia were determined. Whereas every examined isolate harbored type III secretion genes, only 27 (77%) were capable of secreting detectable amounts of type III proteins in vitro. Twenty-two (81%) of the patients infected with these 27 isolates had severe disease. Of the eight isolates that did not secrete type III proteins, only three (38%) were cultured from patients with severe disease. Thus, infection with a type-III-secreting isolate correlated with severe disease (p < .05). In vitro assays indicated that ExoU, the type III effector protein most closely linked to mortality in animal models, was secreted in detectable amounts in vitro by 10 (29%) of the 35 examined isolates. Nine (90%) of these 10 isolates were cultured from patients with severe disease (p < .05 when compared with the nonsecreting isolates). In contrast, ExoS was secreted by 16 (46%) of the 35 examined isolates. Twelve (75%) of these 16 isolates were cultured from patients with severe disease (p = .14 when compared with the nonsecreting isolates). CONCLUSIONS: In patients with ventilator-associated pneumonia, type-III-secreting isolates were associated with worse clinical outcomes, suggesting that this secretion system plays an important role in human disease. Our findings support the hypothesis that antibodies targeted against these proteins may be useful as adjunctive therapy in intubated patients with P. aeruginosa colonization or infection.

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological change characterized by the accumulation of triglycerides in hepatocytes and has frequently been associated with obesity, type 2 diabetes mellitus, hyperlipidemia, and insulin resistance. It is an increasingly recognized condition that has become the most common liver disorder in developed countries, affecting over one-third of the population and is associated with increased cardiovascular- and liver-related mortality. NAFLD is a spectrum of disorders, beginning as simple steatosis. In about 15% of all NAFLD cases, simple steatosis can evolve into non-alcoholic steatohepatitis, a medley of inflammation, hepatocellular injury, and fibrosis, often resulting in cirrhosis and even hepatocellular cancer. However, the molecular mechanism underlying NAFLD progression is not completely understood. Its pathogenesis has often been interpreted by the "double-hit" hypothesis. The primary insult or the "first hit" includes lipid accumulation in the liver, followed by a "second hit" in which proinflammatory mediators induce inflammation, hepatocellular injury, and fibrosis. Nowadays, a more complex model suggests that fatty acids (FAs) and their metabolites may be the true lipotoxic agents that contribute to NAFLD progression; a multiple parallel hits hypothesis has also been suggested. In NAFLD patients, insulin resistance leads to hepatic steatosis via multiple mechanisms. Despite the excess hepatic accumulation of FAs in NAFLD, it has been described that not only de novo FA synthesis is increased, but FAs are also taken up from the serum. Furthermore, a decrease in mitochondrial FA oxidation and secretion of very-low-density lipoproteins has been reported. This review discusses the molecular mechanisms that underlie the pathophysiological changes of hepatic lipid metabolism that contribute to NAFLD.

INTRODUCTION: Human host immune response following infection with the new variant of A/H1N1 pandemic influenza virus (nvH1N1) is poorly understood. We utilize here systemic cytokine and antibody levels in evaluating differences in early immune response in both mild and severe patients infected with nvH1N1. METHODS: We profiled 29 cytokines and chemokines and evaluated the haemagglutination inhibition activity as quantitative and qualitative measurements of host immune responses in serum obtained during the first five days after symptoms onset, in two cohorts of nvH1N1 infected patients. Severe patients required hospitalization (n = 20), due to respiratory insufficiency (10 of them were admitted to the intensive care unit), while mild patients had exclusively flu-like symptoms (n = 15). A group of healthy donors was included as control (n = 15). Differences in levels of mediators between groups were assessed by using the non parametric U-Mann Whitney test. Association between variables was determined by calculating the Spearman correlation coefficient. Viral load was performed in serum by using real-time PCR targeting the neuraminidase gene. RESULTS: Increased levels of innate-immunity mediators (IP-10, MCP-1, MIP-1beta), and the absence of anti-nvH1N1 antibodies, characterized the early response to nvH1N1 infection in both hospitalized and mild patients. High systemic levels of type-II interferon (IFN-gamma) and also of a group of mediators involved in the development of T-helper 17 (IL-8, IL-9, IL-17, IL-6) and T-helper 1 (TNF-alpha, IL-15, IL-12p70) responses were exclusively found in hospitalized patients. IL-15, IL-12p70, IL-6 constituted a hallmark of critical illness in our study. A significant inverse association was found between IL-6, IL-8 and PaO2 in critical patients. CONCLUSIONS: While infection with the nvH1N1 induces a typical innate response in both mild and severe patients, severe disease with respiratory involvement is characterized by early secretion of Th17 and Th1 cytokines usually associated with cell mediated immunity but also commonly linked to the pathogenesis of autoimmune/inflammatory diseases. The exact role of Th1 and Th17 mediators in the evolution of nvH1N1 mild and severe disease merits further investigation as to the detrimental or beneficial role these cytokines play in severe illness.

Fifty-seven patients developed an episode of catheter-related infection (CRI) in the bloodstream during their stay in the intensive care unit (cases) and were prospectively observed to establish the attributable mortality, increase in length of stay, and excess costs. Costs were estimated by multiplying the number of excess days of stay by the reimbursement provided. The outcomes for these cases were compared with those for matched control subjects without CRI. Eight cases were excluded as no control was found. Of the 49 cases, 31 were coagulase-negative staphylococci (CNS). The level of severity was similar for both groups (APACHE II 15.5 +/- 7. 2 versus 15.2 +/- 7.3). There were no significant differences (p > 0. 20) in the mortality observed in the hospital for the cases (22.4%, 95% confidence interval [CI] 0.3% to 34.9%) and the control subjects (34.7%, 95% CI 21.2% to 40.1%). Among the survivors, the hospital stay was increased by 19.6 d (95% CI -1.1; 40.4). This represents an added cost of 3,124 Euros per episode of CRI among the survivors. In conclusion, our cohort study failed to show a difference in attributable mortality due to CRI in intensive care unit patients. Nevertheless, these infections lead to an increase in hospital stay of approximately 20 d. Each episode of CRI represents an additional cost of more than 3,000 Euros.

BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. METHODS: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P<0.002, respectively). CONCLUSIONS: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.

Diffuse large B-cell lymphomas (DLBCLs) can be divided into germinal-center B cell-like (GCB) and activated-B cell-like (ABC) subtypes by gene-expression profiling (GEP), with the latter showing a poorer outcome. Although this classification can be mimicked by different immunostaining algorithms, their reliability is the object of controversy. We constructed tissue microarrays with samples of 157 DLBCL patients homogeneously treated with immunochemotherapy to apply the following algorithms: Colomo (MUM1/IRF4, CD10, and BCL6 antigens), Hans (CD10, BCL6, and MUM1/IRF4), Muris (CD10 and MUM1/IRF4 plus BCL2), Choi (GCET1, MUM1/IRF4, CD10, FOXP1, and BCL6), and Tally (CD10, GCET1, MUM1/IRF4, FOXP1, and LMO2). GEP information was available in 62 cases. The proportion of misclassified cases by immunohistochemistry compared with GEP was higher when defining the GCB subset: 41%, 48%, 30%, 60%, and 40% for Colomo, Hans, Muris, Choi, and Tally, respectively. Whereas the GEP groups showed significantly different 5-year progression-free survival (76% vs 31% for GCB and activated DLBCL) and overall survival (80% vs 45%), none of the immunostaining algorithms was able to retain the prognostic impact of the groups (GCB vs non-GCB). In conclusion, stratification based on immunostaining algorithms should be used with caution in guiding therapy, even in clinical trials.

BACKGROUND: Alcoholic cardiomyopathy (ACM) is defined by a dilated and impaired left ventricle due to chronic excess alcohol consumption. It is largely unknown which factors determine cardiac toxicity on exposure to alcohol. OBJECTIVES: This study sought to evaluate the role of variation in cardiomyopathy-associated genes in the pathophysiology of ACM, and to examine the effects of alcohol intake and genotype on dilated cardiomyopathy (DCM) severity. METHODS: The authors characterized 141 ACM cases, 716 DCM cases, and 445 healthy volunteers. The authors compared the prevalence of rare, protein-altering variants in 9 genes associated with inherited DCM. They evaluated the effect of genotype and alcohol consumption on phenotype in DCM. RESULTS: ), but similar between patients with ACM and DCM (19.4%; p = 0.12) and with a predominant burden of titin truncating variants (TTNtv) (9.9%). Separately, we identified an interaction between TTN genotype and excess alcohol consumption in a cohort of DCM patients not meeting ACM criteria. On multivariate analysis, DCM patients with a TTNtv who consumed excess alcohol had an 8.7% absolute reduction in ejection fraction (95% confidence interval: -2.3% to -15.1%; p < 0.007) compared with those without TTNtv and excess alcohol consumption. The presence of TTNtv did not predict phenotype, outcome, or functional recovery on treatment in ACM patients. CONCLUSIONS: TTNtv represent a prevalent genetic predisposition for ACM, and are also associated with a worse left ventricular ejection fraction in DCM patients who consume alcohol above recommended levels. Familial evaluation and genetic testing should be considered in patients presenting with ACM.

BACKGROUND: In spite of the frequency of chronic urticaria there are very few epidemiological studies of its prevalence and distribution. OBJECTIVE: We wanted to approach the real prevalence of chronic urticaria in a population-based study and to depict demographic distribution and personal perception of the disease. We also wanted to describe the frequency of acute urticaria episodes in the population studied. METHODS: We conducted a population-based study among adults in Spain. We questioned 5003 individuals after calculating a sample size for a maximum variability (conservative approach p=q=0.5). RESULTS: We found a 0.6% (95% CI: 0.4-0.8) prevalence of chronic urticaria. The prevalence is significantly higher in women than in men with a OR=3.82 (95%CI 1.56-9.37). Chronic urticaria is a self-limited disease, yet in 8.7% of cases chronic urticaria lasts from one to 5 years and in 11.3%, for more than 5 years. The average age of onset is 40 years. CONCLUSIONS: We offer large epidemiology study data on the prevalence of chronic urticaria. The prevalence of chronic urticaria has not yet been defined in an adult population-based study. With this work we offer such data to describe the prevalence and features of this disease.

BACKGROUND: We assessed the strategy of substituting nevirapine, efavirenz, or abacavir for a protease inhibitor in patients infected with human immunodeficiency virus type 1 (HIV-1) in whom virologic suppression had been achieved. METHODS: We randomly assigned 460 adults who were taking two nucleoside reverse-transcriptase inhibitors and at least one protease inhibitor and whose plasma HIV-1 RNA levels had been less than 200 copies per milliliter for at least the previous six months to switch from the protease inhibitor to nevirapine (155 patients), efavirenz (156), or abacavir (149). The primary end point was death, progression to the acquired immunodeficiency syndrome, or an increase in HIV-1 RNA levels to 200 copies or more per milliliter. RESULTS: At 12 months, the Kaplan-Meier estimates of the likelihood of reaching the end point were 10 percent in the nevirapine group, 6 percent in the efavirenz group, and 13 percent in the abacavir group (P=0.10 according to an intention-to-treat analysis). HIV-1 RNA could be amplified in 21 of the 29 patients in whom virologic failure developed during treatment with study medication (72 percent), and resistance mutations to the study medication and to at least one of the nucleoside reverse-transcriptase inhibitors in the regimen that failed were detected in all but 1 of the 21 patients. Twenty-three of the 29 patients with virologic failure during treatment with study medication had received prior suboptimal therapy with nucleoside reverse-transcriptase inhibitors. Fewer patients in the abacavir group (6 percent) than in the nevirapine group (17 percent) or the efavirenz group (17 percent) discontinued the study medication because of adverse events (P=0.01). The proportion of patients with fasting lipid levels warranting therapeutic intervention decreased significantly in the abacavir group, but the prevalence of clinical lipodystrophy did not change significantly in the three groups. CONCLUSIONS: When therapy was switched from a protease inhibitor to nevirapine, efavirenz, or abacavir in patients with virologic suppression, there was a trend toward a higher rate of virologic failure among those given abacavir.

Risk associated to FLT3 internal tandem duplication (FLT3-ITD) in patients with acute myeloid leukemia (AML) may depend on mutational burden and its interaction with other mutations. We analyzed the effect of FLT3-ITD/FLT3 wild-type (FLT3wt) ratio depending on NPM1 mutation (NPM1mut) in 303 patients with intermediate-risk cytogenetics AML treated with intensive chemotherapy. Among NPM1mut patients, FLT3wt and low ratio (<0.5) subgroups showed similar overall survival, relapse risk, and leukemia-free survival, whereas high ratio (≥0.5) patients had a worse outcome. In NPM1wt AML, FLT3-ITD subgroups showed a comparable outcome, with higher risk of relapse and shortened overall survival than FLT3wt patients. Allogeneic stem cell transplantation in CR1 was associated with a reduced relapse risk in all molecular subgroups with the exception of NPM1mut AML with absent or low ratio FLT3-ITD. In conclusion, effect of FLT3 burden is modulated by NPM1 mutation, especially in patients with a low ratio.

The human intestine is home to a diverse range of bacterial and fungal species, forming an ecological community that contributes to normal physiology and disease susceptibility. Here, the fungal microbiota (mycobiome) in obese and non-obese subjects was characterized using Internal Transcribed Spacer (ITS)-based sequencing. The results demonstrate that obese patients could be discriminated by their specific fungal composition, which also distinguished metabolically "healthy" from "unhealthy" obesity. Clusters according to genus abundance co-segregated with body fatness, fasting triglycerides and HDL-cholesterol. A preliminary link to metabolites such as hexadecanedioic acid, caproic acid and N-acetyl-L-glutamic acid was also found. Mucor racemosus and M. fuscus were the species more represented in non-obese subjects compared to obese counterparts. Interestingly, the decreased relative abundance of the Mucor genus in obese subjects was reversible upon weight loss. Collectively, these findings suggest that manipulation of gut mycobiome communities might be a novel target in the treatment of obesity.

OBJECTIVE: To evaluate the trend in incidence of Pseudomonas aeruginosa bacteremia, underlying conditions of patients, mortality rate, and factors associated with poor outcome. PATIENTS AND METHODS: Medical charts of 189 consecutive episodes of P aeruginosa bacteremia, detected between January 1, 1991, and December 31, 1994, were prospectively evaluated. Associated risk factors, treatment, and outcome were recorded. RESULTS: Pseudomonas aeruginosa bacteremia represented 5.7% of the total number of bacteremias, 6.9% of nosocomial bacteremias, and 23.6% of nosocomial gram-negative bacteremias. There were 1.5 episodes per 1000 discharges. These numbers were slightly lower than those recorded at our hospital 10 years earlier. Human immunodeficiency virus infection was the most frequent underlying disease (28/189 [15%]). Overall mortality was 18% (34/189). The presence of fatal underlying disease (P < .001), surgery (P = .001), pneumonia (P = .02), and severe sepsis (P < .001) were associated with poor prognosis, the mortality of the patients with these variables being 28%, 28%, 47%, and 62%, respectively. The presence of inappropriate definitive antimicrobial treatment became an independent factor predictive of death (P = .04) only when the subset of patients with intravenous catheter-associated bacteremia was excluded from the analysis. The survival rate was no greater in patients who received 2 or more antibiotics active in vitro against P aeruginosa than in those who received only 1. Neutropenia was not associated with increased mortality. The use of colony-stimulating factors did not affect the outcome of the neutropenic patients. CONCLUSIONS: The rate of P aeruginosa bacteremia is falling slightly at our hospital. The emergence of the human immunodeficiency virus epidemic has had a considerable impact on both epidemiology and mortality. The presence of severe underlying disease, surgery, pneumonia, and, especially, severe sepsis are associated with a poor outcome. With the exclusion of patients with intravenous catheter-associated P aeruginosa bacteremia, the administration of an appropriate antimicrobial therapy is essential to a good outcome. Treatment with 1 active antibiotic seems to be sufficient.

BACKGROUND: Inflammatory bowel disease impairs patients' perception of health and has a negative impact on health-related quality of life (HRQOL). Most studies include patients from a single hospital. This may bias limit results through the use of small patient samples and/or samples within a restricted disease spectrum. METHODS: HRQOL was measured in patients with ulcerative colitis (UC) and Crohn's disease (CD) from 9 hospitals located in different geographical areas in Spain using 2 questionnaires: the Spanish version of the Inflammatory Bowel Disease Questionnaire (IBDQ) and the EuroQol. Results are expressed as medians. RESULTS: The study included 1156 patients (528 patients with UC and 628 with CD; median age, 35 yr; slight predominance of women, 617 versus 539). HRQOL worsened in parallel with disease severity to a similar extent in both UC (IBDQ scores of 6.1, 4.7, and 4.0 for the 3 disease severity groups, respectively) and CD (IBDQ scores of 6.1, 5.0, and 4.1, respectively). A similar inverse relation between clinical activity and quality of life was observed when EuroQol preference values were used. All 5 dimensions of the IBDQ showed significantly lower scores in patients with active UC and CD than in patients in remission. The pattern of scores by IBDQ dimensions differed between patients in relapse (who scored worse on the digestive symptoms dimension) and patients in remission. Variables related with disease activity, time of evolution since diagnosis and female sex, were significantly associated with having a worse perception of HRQOL. The type of disease or geographical area of residence did not influence results on the IBDQ. CONCLUSIONS: UC and CD impair patients' HRQOL, and the degree of impairment depends on disease activity but is independent of the type of disease and place of residence.

Polymorphism at the ADH2 and ADH3 loci of alcohol dehydrogenase (ADH) has been shown to have an effect on the predisposition to alcoholism in Asian individuals. However, the results are not conclusive for white individuals. We have analyzed the ADH genotype of 876 white individuals from Spain (n = 251), France (n = 160), Germany (n = 184), Sweden (n = 88), and Poland (n = 193). Peripheral blood samples from healthy controls and groups of patients with viral cirrhosis and alcohol-induced cirrhosis, as well as alcoholics with no liver disease, were collected on filter paper. Genotyping of the ADH2 and ADH3 loci was performed using polymerase chain reaction-restriction fragment length polymorphism methods on white cell DNA. In healthy controls, ADH2*2 frequencies ranged from 0% (France) to 5.4% (Spain), whereas ADH3*1 frequencies ranged from 47. 6% (Germany) to 62.5% (Sweden). Statistically significant differences were not found, however, between controls from different countries, nor between patients with alcoholism and/or liver disease. When all individuals were grouped in nonalcoholics (n = 451) and alcoholics (n = 425), ADH2*2 frequency was higher in nonalcoholics (3.8%) than in alcoholics (1.3%) (P =.0016), whereas the ADH3 alleles did not show differences. Linkage disequilibrium was found between ADH2 and ADH3, resulting in an association of the alleles ADH2*2 and ADH3*1, both coding for the most active enzymatic forms. In conclusion, the ADH2*2 allele decreases the risk for alcoholism, whereas the ADH2*2 and ADH3*1 alleles are found to be associated in the European population.

OBJECTIVE: To evaluate de-escalation of antibiotic therapy in patients with ventilator-associated pneumonia. DESIGN: Prospective observational study during a 43-month period. SETTING: Medical-surgical intensive care unit. PATIENTS: One hundred and fifteen patients admitted to the intensive care unit with clinical diagnosis of ventilator-associated pneumonia. All the episodes of ventilator-associated pneumonia received initial broad-spectrum coverage followed by reevaluation according to clinical response and microbiology. Quantitative cultures obtained by bronchoscopic examination or tracheal aspirates were used to modify therapy. INTERVENTIONS: : None. MEASUREMENTS AND MAIN RESULTS: One hundred and twenty-one episodes of ventilator-associated pneumonia were diagnosed. Change of therapy was documented in 56.2%, including de-escalation (the most frequent cause) in 31.4% (increasing to 38% if isolates were sensitive). Overall intensive care unit mortality rate was 32.2%. Inappropriate antibiotic therapy was identified in 9% of cases and was associated with 14.4% excess intensive care unit mortality. Quantitative tracheal aspirates and bronchoscopic samples (58 protected specimen brush and three bronchoalveolar lavage) were associated with 32.7% and 29.5% intensive care unit mortality and 29.3% and 34.4% de-escalation rate. De-escalation was lower (p < .05) in the presence of nonfermenting Gram-negative bacillus (2.7% vs. 49.3%) and in the presence of late-onset pneumonia (12.5% vs. 40.7%). When the pathogen remained unknown, half of the patients died and de-escalation was not performed. CONCLUSION: De-escalation was the most important cause of antibiotic modification, being more feasible in early-onset pneumonia and less frequent in the presence of nonfermenting Gram-negative bacillus. The impact of quantitative tracheal aspirates or bronchoscopic techniques was comparable in terms of mortality.

In accordance with the recommendations of, amongst others, the Surviving Sepsis Campaign and the recently published European treatment guidelines for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), in the event of a patient with such infections, empirical antibiotic treatment must be appropriate and administered as early as possible. The aim of this manuscript is to update treatment protocols by reviewing recently published studies on the treatment of nosocomial pneumonia in the critically ill patients that require invasive respiratory support and patients with HAP from hospital wards that require invasive mechanical ventilation. An interdisciplinary group of experts, comprising specialists in anaesthesia and resuscitation and in intensive care medicine, updated the epidemiology and antimicrobial resistance and established clinical management priorities based on patients' risk factors. Implementation of rapid diagnostic microbiological techniques available and the new antibiotics recently added to the therapeutic arsenal has been reviewed and updated. After analysis of the categories outlined, some recommendations were suggested, and an algorithm to update empirical and targeted treatment in critically ill patients has also been designed. These aspects are key to improve VAP outcomes because of the severity of patients and possible acquisition of multidrug-resistant organisms (MDROs).