Determinants of empirical antipseudomonal antibiotic prescription for adults with pneumonia in the emergency department.

BACKGROUND: Antipseudomonal antibiotics should be restricted to patients at risk of Pseudomonas aeruginosa infection. However, the indications in different guidelines on community-acquired pneumonia (CAP) are discordant. Our objectives were to assess the prevalence of antipseudomonal antibiotic prescriptions and to identify determinants of empirical antibiotic choices in the emergency department. METHODS: Observational, retrospective, one-year cohort study in hospitalized adults with pneumonia. Antibiotic choices and clinical and demographic data were recorded on a standardized form. Antibiotics with antipseudomonal activity were classified into two groups: a) ß-lactam antipseudomonals (ß-APS), including carbapenems, piperacillin / tazobactam or cefepime (in monotherapy or combination) and b) monotherapy with antipseudomonal quinolones. RESULTS: Data were recorded from 549 adults with pneumonia, with Pseudomonas aeruginosa being isolated in only nine (1.6%). Most (85%) prescriptions were compliant with SEPAR guidelines and 207 (37%) patients received antibiotics with antipseudomonal activity (14% ß-APS and 23% levofloxacin). The use of ß-APS was independently associated with ICU admission (OR 8.16 95% CI 3.69-18.06) and prior hospitalization (OR 6.76 95% CI 3.02-15.15), while levofloxacin was associated with negative pneumococcal urine antigen tests (OR 3.41 95% CI 1.70-6.85) but negatively associated with ICU admission (OR 0.26 95% CI 0.08-0.86). None of these factors were associated with P aeruginosa episodes. In univariate analysis, prior P aeruginosa infection/colonization (2/9 vs 6/372, p = 0.013), severe COPD (3/9 vs 26/372, p = 0.024), multilobar involvement (7/9 vs 119/372, p = 0.007) and prior antibiotic (6/9 vs 109/372, p = 0.025) were significantly associated with P aeruginosa episodes. CONCLUSIONS: Antipseudomonal prescriptions were common, in spite of the very low incidence of Pseudomonas aeruginosa. The rationale for prescription was influenced by both severity-of-illness and pneumococcal urine antigen test (levofloxacin) and prior hospitalization and ICU admission (ß-APS). However, these factors were not associated with P aeruginosa episodes. Only prior P aeruginosa infection/colonization and severe COPD seem to be reliable indicators in clinical practice.

Rectal, central venous, gastric and bladder pressures versus esophageal pressure for the measurement of cough strength: a prospective clinical comparison.

BACKGROUND: Cough pressure, an expression of expiratory muscle strength, is usually measured with esophageal or gastric balloons, but these invasive catheters can be uncomfortable for the patient or their placement impractical. Because pressure in the thorax and abdomen are expected to be similar during a cough, we hypothesized that measurement at other thoracic or abdominal locations might also be similar as well as useful in clinical scenarios. This study aimed to compare cough pressures measured at thoracic and abdominal sites that could serve as alternatives to esophageal pressures (Pes). METHODS: Nine patients scheduled for laparotomy were asked to cough as forcefully as possible from total lung capacity in supine position. Three cough maneuvers were performed while Pes (the gold standard) as well as gastric, central venous, bladder and rectal pressures (Pga, Pcv, Pbl, and Prec, respectively) were measured simultaneously. The intraclass correlation coefficient (ICC) was used to evaluate the repeatability of the measurements in each patient at each site and evaluate agreement between alternative sites (Pga, Pcv, Pbl, and Prec) and Pes. Bland-Altman plots were used to compare Pes and the measurements at the other sites. RESULTS: Median (first quartile, third quartile) maximum pressures were as follows: Pes 112 (89,148), Pga 105 (92,156), Pcv 102 (91,149), Pbl 118 (93,157), and Prec 103 (88,150) cmH2O. The ICCs showed excellent within-site repeatability of the measurements (p < 0.001) and excellent agreement between alternative sites and Pes (p < 0.004). The Bland-Altman plots showed minimal differences between Pes, Pga, Pcv, and Prec. However, Pbl was higher than the other pressures in most patients, and the difference between Pes and Pbl was slightly larger. CONCLUSIONS: Cough pressure can be measured in the esophagus, stomach, superior vena cava or rectum, since their values are similar. It can also be measured in the bladder, although the value will be slightly higher. These results potentially facilitate the assessment of dynamic expiratory muscle strength with fewer invasive catheter placements in most hospitalized patients, thus providing an option that will be particularly useful in those undergoing thoracic or abdominal surgery. TRIAL REGISTRATION: NCT02957045 registered at November 7, 2016. Retrospectively registered.

Improvement of antibiotic therapy and ICU survival in severe non-pneumococcal community-acquired pneumonia: a matched case-control study.

INTRODUCTION: We aimed to compare intensive care unit mortality due to non-pneumococcal severe community-acquired pneumonia between the periods 2000-2002 and 2008-2014, and the impact of the improvement in antibiotic strategies on outcomes. METHODS: This was a matched case-control study enrolling 144 patients with non-pneumococcal severe pneumonia: 72 patients from the 2000-2002 database (CAPUCI I group) were paired with 72 from the 2008-2014 period (CAPUCI II group), matched by the following variables: microorganism, shock at admission, invasive mechanical ventilation, immunocompromise, chronic obstructive pulmonary disease, and age over 65 years. RESULTS: The most frequent microorganism was methicillin-susceptible Staphylococcus aureus (22.1%) followed by Legionella pneumophila and Haemophilus influenzae (each 20.7%); prevalence of shock was 59.7%, while 73.6% of patients needed invasive mechanical ventilation. Intensive care unit mortality was significantly lower in the CAPUCI II group (34.7% versus 16.7%; odds ratio (OR) 0.78, 95% confidence interval (CI) 0.64-0.95; p = 0.02). Appropriate therapy according to microorganism was 91.5% in CAPUCI I and 92.7% in CAPUCI II, while combined therapy and early antibiotic treatment were significantly higher in CAPUCI II (76.4 versus 90.3% and 37.5 versus 63.9%; p < 0.05). In the multivariate analysis, combined antibiotic therapy (OR 0.23, 95% CI 0.07-0.74) and early antibiotic treatment (OR 0.07, 95% CI 0.02-0.22) were independently associated with decreased intensive care unit mortality. CONCLUSIONS: In non-pneumococcal severe community-acquired pneumonia , early antibiotic administration and use of combined antibiotic therapy were both associated with increased intensive care unit survival during the study period.

Diagnosis and treatment of bacteremia and endocarditis due to Staphylococcus aureus. A clinical guideline from the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC).

Both bacteremia and infective endocarditis caused by Staphylococcus aureus are common and severe diseases. The prognosis may darken not infrequently, especially in the presence of intracardiac devices or methicillin-resistance. Indeed, the optimization of the antimicrobial therapy is a key step in the outcome of these infections. The high rates of treatment failure and the increasing interest in the influence of vancomycin susceptibility in the outcome of infections caused by both methicillin-susceptible and -resistant isolates has led to the research of novel therapeutic schemes. Specifically, the interest raised in recent years on the new antimicrobials with activity against methicillin-resistant staphylococci has been also extended to infections caused by susceptible strains, which still carry the most important burden of infection. Recent clinical and experimental research has focused in the activity of new combinations of antimicrobials, their indication and role still being debatable. Also, the impact of an appropriate empirical antimicrobial treatment has acquired relevance in recent years. Finally, it is noteworthy the impact of the implementation of a systematic bundle of measures for improving the outcome. The aim of this clinical guideline is to provide an ensemble of recommendations in order to improve the treatment and prognosis of bacteremia and infective endocarditis caused by S. aureus, in accordance to the latest evidence published.

Executive summary of the diagnosis and treatment of bacteremia and endocarditis due to Staphylococcus aureus. A clinical guideline from the Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC).

Bacteremia and infective endocarditis caused by Staphylococcus aureus are common and severe diseases. Optimization of treatment is fundamental in the prognosis of these infections. The high rates of treatment failure and the increasing interest in the influence of vancomycin susceptibility in the outcome of infections caused by both methicillin-susceptible and -resistant isolates have led to research on novel therapeutic schemes. The interest in the new antimicrobials with activity against methicillin-resistant staphylococci has been extended to susceptible strains, which still carry the most important burden of infection. New combinations of antimicrobials have been investigated in experimental and clinical studies, but their role is still being debated. Also, the appropriateness of the initial empirical therapy has acquired relevance in recent years. The aim of this guideline is to update the 2009 guidelines and to provide an ensemble of recommendations in order to improve the treatment of staphylococcal bacteremia and infective endocarditis, in accordance with the latest published evidence.

Blood culture differential time to positivity enables safe catheter retention in suspected catheter-related bloodstream infection: a randomized controlled trial.

OBJECTIVE: To evaluate the clinical usefulness and safety of the differential-time-to-positivity (DTP) method for managing the suspicion of catheter-related bloodstream infection (CR-BSI) in comparison with a standard method that includes catheter removal in critically ill patients. METHODS-DESIGN: A prospective randomized study was carried out. SETTING: A 16-bed clinical-surgical ICU (July 2007-February 2009). INTERVENTIONS: Patients were randomly assigned to one of two groups at the time CR-BSI was suspected. In the standard group, a standard strategy requiring catheter withdrawal was used to confirm or rule out CR-BSI. In the DTP group, DTP without catheter withdrawal was used to confirm or rule out CR-BSI. MEASUREMENTS: clinical and microbiological data, CR-BSI rates, unnecessary catheter removals, and complications due to new puncture or to delays in catheter removal. RESULTS: Twenty-six patients were analyzed in each group. In the standard group, 6 of 37 suspected episodes of CR-BSI were confirmed and 5 colonizations were diagnosed. In the DTP group, 5 of 26 suspected episodes of CR-BSI were confirmed and four colonizations were diagnosed. In the standard group, all catheters (58/58, 100%) were removed at the time CR-BSA was suspected, whereas in the DTP group, only 13 catheters (13/41, 32%) were removed at diagnosis, and 10 due to persistent septic signs (10/41, 24%). In cases of confirmed CR-BSI, there were no differences between the two groups in the evolution of inflammatory parameters during the 48hours following the suspicion of CR-BSI. CONCLUSIONS: In critically ill patients with suspected CR-BSI, the DTP method makes it possible to keep the central venous catheter in place safely.

Risks for multidrug-resistant pathogens in the ICU.

PURPOSE OF REVIEW: The impact of multidrug-resistant organisms (MDROs) is rising and often underestimated. The epidemiology of MDROs is extremely complex and multifactorial. There is increasing antibiotic resistance, mainly related to antibiotic pressure and patients' characteristics. RECENT FINDINGS: Emphasis on MDRO epidemiology is needed to better understand current strategies of prevention and management. Among them, antibiotic stewardship has been one of the most successful strategies. It is important to note that there is a controversial issue when considering community and healthcare-related infections. In addition, different strategies have been determined to find the impact and optimal use of recently launched antibiotics for MDRO treatment. SUMMARY: Infections with MDROs can prolong hospital stay, promote antibiotic use and prolong duration of mechanical ventilation. Some points should be further explored in clinical research such as the heterogeneity of healthcare-associated pneumonia and the need of new drug development. Resistance to non fermentative Gram-negative bacilli, rising minimum inhibitory concentration in methicillin-resistant Staphylococcus aureus and spread of MDROs in patients without known risk factors suggest a review of guideline validation, taking into account ecology and severity of patient illness to provide timely and appropriate empiric therapy.

Impact of appropriate antimicrobial treatment on transition from ventilator-associated tracheobronchitis to ventilator-associated pneumonia.

INTRODUCTION: Two small randomized controlled trials have suggested beneficial effects of antibiotic treatment in patients with ventilator-associated tracheobronchitis (VAT). The primary aim of this study is to determine the impact of appropriate antibiotic treatment on transition from VAT to ventilator-associated pneumonia (VAP) in critically ill patients. The secondary objective was to determine the incidence of VAP in patients with VAT. METHODS: This was a prospective observational multicenter study. All patients with a first episode of VAT were eligible. Patients with tracheostomy at intensive care unit (ICU) admission, and those with VAP prior to VAT were excluded. VAT was defined using all the following criteria: fever > 38 °C with no other cause, purulent tracheal secretions, positive tracheal aspirate (≥ 10(5) cfu/mL), and absence of new infiltrate on chest X ray. Only VAP episodes diagnosed during the 96 h following VAT, and caused by the same bacteria, were taken into account. Antibiotic treatment was at the discretion of attending physicians. Risk factors for transition from VAT to VAP were determined using univariate and multivariate analysis. All variables from univariate analysis with P values <0.1 were incorporated in the multivariate logistic regression analysis. RESULTS: One thousand seven hundred and ten patients were screened for this study. Eighty-six, and 123 patients were excluded for tracheostomy at ICU admission, and VAP prior to VAT; respectively. One hundred and twenty two (7.1%) patients were included. 17 (13.9%) patients developed a subsequent VAP. The most common microorganisms in VAT patients were Pseudomonas aeruginosa (30%), Staphylococcus aureus (18%), and Acinetobacter baumannii (10%). Seventy-four (60%) patients received antimicrobial treatment, including 58 (47.5%) patients who received appropriate antimicrobial treatment. Appropriate antibiotic treatment was the only factor independently associated with reduced risk for transition from VAT to VAP (OR [95% CI] 0.12[0.02-0.59], P = 0.009). The number of patients with VAT needed to treat to prevent one episode of VAP, or one episode of VAP related to P. aeruginosa was 5, and 34; respectively. CONCLUSIONS: Appropriate antibiotic treatment is independently associated with reduced risk for transition from VAT to VAP.

Almitrine fails to improve oxygenation during one-lung ventilation with sevoflurane anesthesia.

OBJECTIVE: Almitrine enhances hypoxic pulmonary vasoconstriction (HPV) and can improve hypoxemia related to one-lung ventilation (OLV). Studies using almitrine have been conducted without inhaled anesthetics because they could inhibit HPV, counteracting the effect of almitrine. This hypothesis, however, has not been confirmed. This study's aim was to evaluate whether almitrine could improve oxygenation when administered during OLV with sevoflurane anesthesia. DESIGN: A prospective, randomized, double-blind, placebo-controlled trial. SETTING: A tertiary care, university teaching hospital. PARTICIPANTS: Thirty adult patients undergoing open-chest thoracic surgery. INTERVENTIONS: Patients were assigned randomly to receive almitrine or placebo during OLV. Respiratory and hemodynamic variables were recorded continuously. Anesthesia was maintained with sevoflurane and remifentanil. Intraoperative techniques and medical teams were the same all over the study. MEASUREMENTS AND MAIN RESULTS: Respiratory and hemodynamic variables were measured during two-lung ventilation and during open-chest OLV. Two-way repeated-measures analysis of variance was used to compare the effects of almitrine and placebo. During OLV, PaO2 and shunt fraction worsened in all patients without significant differences between groups. At 30-minutes of OLV, PaO2 was 184±67 mmHg in the almitrine group and 145±56 mmHg in the placebo group, while shunt fraction were 31%±6% and 36%±13%, respectively. Mean pulmonary artery pressure was higher in the almitrine group (31±5 v 24±5 mmHg, p<0.001). CONCLUSIONS: During anesthesia with sevoflurane for open-chest OLV, almitrine failed to improve oxygenation and increased pulmonary artery pressure. The combination of sevoflurane and almitrine should, therefore, be avoided.

Evolution over a 15-year period of clinical characteristics and outcomes of critically ill patients with community-acquired bacteremia.

OBJECTIVE: In recent years, outcomes for critically ill patients with severe sepsis have improved; however, no data have been reported about the outcome of patients admitted for community-acquired bacteremia. We aimed to analyze the changes in the prevalence, characteristics, and outcome of critically ill patients with community-acquired bacteremia over the past 15 yrs. DESIGN: A secondary analysis of prospective cohort studies in critically ill patients in three annual periods (1993, 1998, and 2007). SETTING: Forty-seven ICUs at secondary and tertiary care hospitals. PATIENTS: All adults admitted to the participating ICUs with at least one true-positive blood culture finding within the first 48 hrs of admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 829 patients was diagnosed with community-acquired bacteremia during the study periods (148, 196, and 485 in the three periods). The prevalence density rate of community-acquired bacteremia increased from nine per 1000 ICU admissions in 1993 to 24.4 episodes per 1,000 ICU admissions in 2007 (p < 0.001). The prevalence of septic shock also increased from 4.6 episodes/1,000 admissions in 1993 to 14.6 episodes/1,000 admissions in 2007 (p < 0.001). Patients with community-acquired bacteremia were significantly older and had more comorbidities. No significant differences were observed in the presence of Gram-positive and Gram-negative micro-organisms among the three study periods. Mortality related to community-acquired bacteremia decreased over the three study periods: 42%, 32.2%, and 22.9% in 1993, 1998, and 2007, respectively (p < 0.01). The occurrence of septic shock and the number of comorbidities were independently associated with worse outcome. Appropriate antibiotic therapy and development of community-acquired bacteremia in 1998 and 2007 were independently associated with better survival. CONCLUSIONS: The prevalence of community-acquired bacteremia in ICU patients has increased. Despite a higher percentage of more severe and older patients, the mortality associated with community-acquired bacteremia decreased. Improved management of severe sepsis might explain the improvements in outcomes.

[Nosocomial pneumonia]. / Neumonía nosocomial.

The hospital acquired pneumonia (HAP) is one of the most common infections acquired among hospitalised patients. Within the HAP, the ventilator-associated pneumonia (VAP) is the most common nosocomial infection complication among patients with acute respiratory failure. The VAP and HAP are associated with increased mortality and increased hospital costs. The rise in HAP due to antibiotic-resistant bacteria also causes an increase in the incidence of inappropriate empirical antibiotic therapy, with an associated increased risk of hospital mortality. It is very important to know the most common organisms responsible for these infections in each hospital and each Intensive Care Unit, as well as their antimicrobial susceptibility patterns, in order to reduce the incidence of inappropriate antibiotic therapy and improve the prognosis of patients. Additionally, clinical strategies aimed at the prevention of HAP and VAP should be employed in hospital settings caring for patients at risk for these infections.

Clinical, Microbiological and Treatment Characteristics of Severe Postoperative Respiratory Infections: An Observational Cohort Study.

Respiratory infections are frequent and life-threatening complications of surgery. This study aimed to evaluate the clinical, microbiological and treatment characteristics of severe postoperative pneumonia (POP) and tracheobronchitis (POT) in a large series of patients. This single-center, prospective observational cohort study included patients with POP or POT requiring intensive care unit admission in the past 10 years. We recorded demographic, clinical, microbiological and therapeutic data. A total of 207 patients were included, and 152 (73%) were men. The mean (SD) age was 70 (13) years and the mean (SD) ARISCAT score was 46 (19). Ventilator-associated pneumonia was reported in 21 patients (10%), hospital-acquired pneumonia was reported in 132 (64%) and tracheobronchitis was reported in 54 (26%). The mean (SD) number of days from surgery to POP/POT diagnosis was 6 (4). The mean (SD) SOFA score was 5 (3). Respiratory microbiological sampling was performed in 201 patients (97%). A total of 177 organisms were cultured in 130 (63%) patients, with a high proportion of Gram-negative and multi-drug resistant (MDR) bacteria (20%). The most common empirical antibiotic therapy was a triple-drug regimen covering MDR Gram-negative bacteria and MRSA. In conclusion, surgical patients are a high-risk population with a high proportion of early onset severe POP/POT and nosocomial bacteria isolation.

Antibiotic consumption at 46 VINCat hospitals from 2007 to 2009, stratified by hospital size and clinical services.

The aim of the study was to assess the evolution of antibiotic consumption in acute care hospitals in Catalonia (population 7.5 million), according to hospital size and department, during the period 2007-2009. The methodology used for monitoring antibiotic consumption was the ATC/DDD system, and the unit of measurement was DDD/100 occupied bed-days (DDD/100 OBD). Hospitals were stratified according to size: I) large university hospitals (with more than 500 beds); II) medium-sized hospitals (between 200 and 500 beds); and III) small hospitals (fewer than 200 beds). The consumption was also analyzed and stratified according to department: medical, surgical and intensive care unit (ICU). Specific training in data management on antibiotic consumption was given to all participant hospitals before the implementation of the program. The mean antibiotic (J01) consumption, calculated in DDD/100 OBD, increased although without statistical significance (p=0.640): 74.68 (2007), 75.13 (2008) and 78.04 (2009). The values of the medians expressed in DDD/100 OBD in group I were 83.27 (in 2007), 82.16 (2008) and 86.93 (2009), in group II 72.60 (2007), 70.78 (2008) and 75.17 (2009) and in group III 65.66 (2007), 69.32 (2008) and 72.39 (2009). Antibiotic consumption was higher in large hospitals than in medium-sized or small hospitals. Catalan hospitals recorded an increase of 4.49% from 2007 to 2009, especially due to the rising use of carbapenems, cephalosporins, monobactams and the other antibiotic groups.

Device-associated infection rates in Adult Intensive Care Units in Catalonia: VINCat Program findings.

Hospital-acquired infections are a leading cause of morbidity and mortality, especially in the intensive care unit (ICU). Surveillance of device-associated infections plays a major role in infection control programs. In 2006, the Surveillance Program of Nosocomial Infections in Catalonia (VINCat Program) was started, with the major aim of reducing infection rates through a process of active monitoring. The study period comprised calendar years 2008 (with 21 ICUs participating), 2009 (with 21 ICUs participating), and 2010 (with 28 ICUs participating). Each participating hospital was required to have an infection control team made up of at least one physician, an infection surveillance nurse, and a microbiology laboratory. Hospitals were classified into three groups according to their size. Central venous catheter-associated bloodstream infection (CVC-BSI) and ventilator-associated pneumonia (VAP) were chosen as the device-associated infections to analyze. Incidence rates of device-associated infections were calculated by dividing the total number of device-associated infection (VAP or CVC-BSI) days by the total number of days use for the relevant device. Mechanical ventilation use ranged from 0.10 to 0.85 days (overall, 0.35), and central venous catheter use ranged from 0.18 to 0.98 days (overall, 0.65). Incidence rates of VAP ranged from 7.2 ± 3.7 to 10.7 ± 9.6 episodes of VAP/1000 ventilator days. Incidence rates of CVC-BSl ranged from 1.9 ± 1.6 to 2.7 ± 2.0 episodes of CVC-associated bloodstream infection/1000 central venous catheter days. The implementation of the VINCat Program allowed monitoring of nosocomial device-associated infections in ICUs in Catalonia and enabled corrective measures in ICUs with increased incidences of device-associated infections.

Impact of early oseltamivir treatment on outcome in critically ill patients with 2009 pandemic influenza A.

OBJECTIVES: The impact of oseltamivir on mortality in critically ill patients with 2009 pandemic influenza A (2009 H1N1) is not clear. The main objective of this study was to investigate the relationship between the timing of antiviral administration and intensive care unit (ICU) outcomes. METHODS: Prospective, observational study of a cohort of ICU patients with confirmed 2009 H1N1 infection. Clinical data, treatment and outcome were compared between patients receiving early treatment (ET) with oseltamivir, initiated within 2 days, and patients administered late treatment (LT), initiated after this timepoint. Multivariate analysis and propensity score were used to determine the effect of oseltamivir on ICU mortality. RESULTS: Six hundred and fifty-seven patients were enrolled. Four hundred and four (61.5%) patients required mechanical ventilation (MV; mortality 32.6%). Among them, 385 received effective antiviral therapy and were included in the study group. All patients received oseltamivir for a median duration of 10 days (interquartile range 8-14 days). Seventy-nine (20.5%) ET patients were compared with 306 LT patients. The two groups were comparable in terms of main clinical variables. ICU length of stay (22.7 ±â€Š16.7 versus 18.4 ±â€Š14.2 days; P = 0.03), hospital length of stay (34.0 ±â€Š20.3 versus 27.2 ±â€Š18.2 days; P = 0.001) and MV days (17.4 ±â€Š15.2 versus 14.0 ±â€Š12.4; P = 0.04) were higher in the LT group. ICU mortality was also higher in LT (34.3%) than in ET (21.5%; OR = 1.9; 95% CI 1.06-3.41). A multivariate model identified ET (OR = 0.44; 95% CI 0.21-0.87) as an independent variable associated with reduced ICU mortality. These results were confirmed by propensity score analysis (OR = 0.44; 95% CI 0.22-0.90; P < 0.001). CONCLUSIONS: Our findings suggest that early oseltamivir administration was associated with favourable outcomes among critically ill ventilated patients with 2009 H1N1 virus infection.

Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy.

Glycogen synthesis is normally absent in neurons. However, inclusion bodies resembling abnormal glycogen accumulate in several neurological diseases, particularly in progressive myoclonus epilepsy or Lafora disease. We show here that mouse neurons have the enzymatic machinery for synthesizing glycogen, but that it is suppressed by retention of muscle glycogen synthase (MGS) in the phosphorylated, inactive state. This suppression was further ensured by a complex of laforin and malin, which are the two proteins whose mutations cause Lafora disease. The laforin-malin complex caused proteasome-dependent degradation both of the adaptor protein targeting to glycogen, PTG, which brings protein phosphatase 1 to MGS for activation, and of MGS itself. Enforced expression of PTG led to glycogen deposition in neurons and caused apoptosis. Therefore, the malin-laforin complex ensures a blockade of neuronal glycogen synthesis even under intense glycogenic conditions. Here we explain the formation of polyglucosan inclusions in Lafora disease by demonstrating a crucial role for laforin and malin in glycogen synthesis.

Validity of the Spanish 8-item short-form generic health-related quality-of-life questionnaire in surgical patients: a population-based study.

BACKGROUND: Health-related quality of life is usually reported for specific rather than heterogeneous populations such as those treated in routine anesthesia practice. The 8-item short-form generic health-related quality-of-life questionnaire (SF-8) is a candidate instrument for this setting. The authors evaluated the feasibility, reliability, validity, and responsiveness to change of the Spanish version of SF-8 in a population-based surgical cohort. METHODS: Recruiting patients from a large population-based study of risk factors for pulmonary complications, before surgery, the authors administered the 1-week recall SF-8 to 2,991 patients undergoing nonobstetric elective or emergency surgery in 59 hospitals, each of which collected data on seven randomly assigned days in 2006. The SF-8 was administered again 3 months later. Reliability was evaluated using the Cronbach alpha coefficient and validity by comparing physical and mental component summary SF-8 scores with clinical variables. Responsiveness after surgery was evaluated using the standardized response mean. RESULTS: Cronbach alpha for the overall test was 0.92. Physical and mental component summary scores and all individual scores were lower (worse quality of life) in women (P < 0. 01) and decreased with age (P < 0.01). Preoperative scores were lower for those in worse clinical condition (higher body mass index, American Society of Anesthesiologists physical status class, or surgical risk scores), with preoperative respiratory symptoms, and in emergency situations (P < 0.01). The standardized response mean ranged from 0.1 to 0.5. CONCLUSIONS: The SF-8 is a feasible, reliable, valid, and responsive instrument for assessing health-related quality of life in a broad-spectrum surgical population.

Prediction of postoperative pulmonary complications in a population-based surgical cohort.

BACKGROUND: Current knowledge of the risk for postoperative pulmonary complications (PPCs) rests on studies that narrowly selected patients and procedures. Hypothesizing that PPC occurrence could be predicted from a reduced set of perioperative variables, we aimed to develop a predictive index for a broad surgical population. METHODS: Patients undergoing surgical procedures given general, neuraxial, or regional anesthesia in 59 hospitals were randomly selected for this prospective, multicenter study. The main outcome was the development of at least one of the following: respiratory infection, respiratory failure, bronchospasm, atelectasis, pleural effusion, pneumothorax, or aspiration pneumonitis. The cohort was randomly divided into a development subsample to construct a logistic regression model and a validation subsample. A PPC predictive index was constructed. RESULTS: Of 2,464 patients studied, 252 events were observed in 123 (5%). Thirty-day mortality was higher in patients with a PPC (19.5%; 95% [CI], 12.5-26.5%) than in those without a PPC (0.5%; 95% CI, 0.2-0.8%). Regression modeling identified seven independent risk factors: low preoperative arterial oxygen saturation, acute respiratory infection during the previous month, age, preoperative anemia, upper abdominal or intrathoracic surgery, surgical duration of at least 2 h, and emergency surgery. The area under the receiver operating characteristic curve was 90% (95% CI, 85-94%) for the development subsample and 88% (95% CI, 84-93%) for the validation subsample. CONCLUSION: The risk index based on seven objective, easily assessed factors has excellent discriminative ability. The index can be used to assess individual risk of PPC and focus further research on measures to improve patient care.

Impact of Lymphocyte and Neutrophil Counts on Mortality Risk in Severe Community-Acquired Pneumonia with or without Septic Shock.

BACKGROUND: Community-acquired pneumonia (CAP) is a frequent cause of death worldwide. As recently described, CAP shows different biological endotypes. Improving characterization of these endotypes is needed to optimize individualized treatment of this disease. The potential value of the leukogram to assist prognosis in severe CAP has not been previously addressed. METHODS: A cohort of 710 patients with CAP admitted to the intensive care units (ICUs) at Hospital of Mataró and Parc Taulí Hospital of Sabadell was retrospectively analyzed. Patients were split in those with septic shock (n = 304) and those with no septic shock (n = 406). A single blood sample was drawn from all the patients at the time of admission to the emergency room. ICU mortality was the main outcome. RESULTS: Multivariate analysis demonstrated that lymphopenia <675 cells/mm3 or <501 cells/mm3 translated into 2.32- and 3.76-fold risk of mortality in patients with or without septic shock, respectively. In turn, neutrophil counts were associated with prognosis just in the group of patients with septic shock, where neutrophils <8850 cells/mm3 translated into 3.6-fold risk of mortality. CONCLUSION: lymphopenia is a preserved risk factor for mortality across the different clinical presentations of severe CAP (sCAP), while failing to expand circulating neutrophils counts beyond the upper limit of normality represents an incremental immunological failure observed just in those patients with the most severe form of CAP, septic shock.

Trends in the incidence and mortality of patients with community-acquired septic shock 2003-2016.

PURPOSE: To evaluate the incidence and mortality of adult patients with community-acquired septic shock (CASS) and the influence of source control (SC) and other risk factors on the outcome. MATERIAL AND METHODS: The study included patients with CASS admitted to the ICU at a university hospital (2003-2016). Multivariate analyses were performed to identify risk factors of ICU mortality. RESULTS: A total of 625 patients were included. The incidence showed an average annual increase of 4.9% and the mortality an average annual decrease of 1.4%. The patients who required SC showed a lower mortality (20.4%) than patients who did not require SC (31.3%) (p = 0.002). However, the evolution in mortality was different: Mortality decreased in patients who did not require SC (from 56.3% to 20%; p = 0.02), but did not differ in those who required SC (from 21.4% to 27.6%; p = 0.43). In the multivariate analysis, severity at admission, age, alcoholism, cirrhosis, ARDS, neutropenia and thrombocytopenia were associated with worse outcome, whereas appropriate antibiotic treatment and adequate SC were independently associated with better survival. CONCLUSIONS: The incidence of CASS increased and the ICU mortality decreased during the study period. The mortality was mainly due to a decrease in mortality in infections not requiring SC.