Hospital Militar Central

BACKGROUND: Therapies to interrupt the progression of early coronavirus disease 2019 (Covid-19) remain elusive. Among them, convalescent plasma administered to hospitalized patients has been unsuccessful, perhaps because antibodies should be administered earlier in the course of illness. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in older adult patients within 72 hours after the onset of mild Covid-19 symptoms. The primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and steady enrollment of trial patients became virtually impossible. RESULTS: A total of 160 patients underwent randomization. In the intention-to-treat population, severe respiratory disease developed in 13 of 80 patients (16%) who received convalescent plasma and 25 of 80 patients (31%) who received placebo (relative risk, 0.52; 95% confidence interval [CI], 0.29 to 0.94; P = 0.03), with a relative risk reduction of 48%. A modified intention-to-treat analysis that excluded 6 patients who had a primary end-point event before infusion of convalescent plasma or placebo showed a larger effect size (relative risk, 0.40; 95% CI, 0.20 to 0.81). No solicited adverse events were observed. CONCLUSIONS: Early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults reduced the progression of Covid-19. (Funded by the Bill and Melinda Gates Foundation and the Fundación INFANT Pandemic Fund; Dirección de Sangre y Medicina Transfusional del Ministerio de Salud number, PAEPCC19, Plataforma de Registro Informatizado de Investigaciones en Salud number, 1421, and ClinicalTrials.gov number, NCT04479163.).

OBJECTIVE: To update the 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for the spectrum of manifestations affecting patients with psoriatic arthritis (PsA). METHODS: GRAPPA rheumatologists, dermatologists, and PsA patients drafted overarching principles for the management of PsA, based on consensus achieved at face-to-face meetings and via online surveys. We conducted literature reviews regarding treatment for the key domains of PsA (arthritis, spondylitis, enthesitis, dactylitis, skin disease, and nail disease) and convened a new group to identify pertinent comorbidities and their effect on treatment. Finally, we drafted treatment recommendations for each of the clinical manifestations and assessed the level of agreement for the overarching principles and treatment recommendations among GRAPPA members, using an online questionnaire. RESULTS: Six overarching principles had ≥80% agreement among both health care professionals (n = 135) and patient research partners (n = 10). We developed treatment recommendations and a schema incorporating these principles for arthritis, spondylitis, enthesitis, dactylitis, skin disease, nail disease, and comorbidities in the setting of PsA, using the Grading of Recommendations, Assessment, Development and Evaluation process. Agreement of >80% was reached for approval of the individual recommendations and the overall schema. CONCLUSION: We present overarching principles and updated treatment recommendations for the key manifestations of PsA, including related comorbidities, based on a literature review and consensus of GRAPPA members (rheumatologists, dermatologists, other health care providers, and patient research partners). Further updates are anticipated as the therapeutic landscape in PsA evolves.

BACKGROUND: Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. METHODS: In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestation to receive a single intramuscular injection of 120 μg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points. RESULTS: At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively). CONCLUSIONS: RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316.).

BACKGROUND: PATIENTS with rheumatoid arthritis (RA) are at increased risk of developing comorbid conditions. OBJECTIVES: To evaluate the prevalence of comorbidities and compare their management in RA patients from different countries worldwide. STUDY DESIGN: international, cross-sectional. PATIENTS: consecutive RA patients. DATA COLLECTED: demographics, disease characteristics (activity, severity, treatment), comorbidities (cardiovascular, infections, cancer, gastrointestinal, pulmonary, osteoporosis and psychiatric disorders). RESULTS: Of 4586 patients recruited in 17 participating countries, 3920 were analysed (age, 56±13 years; disease duration, 10±9 years (mean±SD); female gender, 82%; DAS28 (Disease Activity Score using 28 joints)-erythrocyte sedimentation rate, 3.7±1.6 (mean±SD); Health Assessment Questionnaire, 1.0±0.7 (mean±SD); past or current methotrexate use, 89%; past or current use of biological agents, 39%. The most frequently associated diseases (past or current) were: depression, 15%; asthma, 6.6%; cardiovascular events (myocardial infarction, stroke), 6%; solid malignancies (excluding basal cell carcinoma), 4.5%; chronic obstructive pulmonary disease, 3.5%. High intercountry variability was observed for both the prevalence of comorbidities and the proportion of subjects complying with recommendations for preventing and managing comorbidities. The systematic evaluation of comorbidities in this study detected abnormalities in vital signs, such as elevated blood pressure in 11.2%, and identified conditions that manifest as laboratory test abnormalities, such as hyperglycaemia in 3.3% and hyperlipidaemia in 8.3%. CONCLUSIONS: Among RA patients, there is a high prevalence of comorbidities and their risk factors. In this multinational sample, variability among countries was wide, not only in prevalence but also in compliance with recommendations for preventing and managing these comorbidities. Systematic measurement of vital signs and laboratory testing detects otherwise unrecognised comorbid conditions.

RATIONALE: Recent literature in mechanical ventilation includes strong evidence from randomized trials. Little information is available regarding the influence of these trials on usual clinical practice. OBJECTIVES: To describe current mechanical ventilation practices and to assess the influence of interval randomized trials when compared with findings from a 1998 cohort. METHODS: A prospective international observational cohort study, with a nested comparative study performed in 349 intensive care units in 23 countries. We enrolled 4,968 consecutive patients receiving mechanical ventilation over a 1-month period. We recorded demographics and daily data related to mechanical ventilation for the duration of ventilation. We systematically reviewed the literature and developed 11 practice-change hypotheses for the comparative cohort study before seeing these results. In assessing practice changes, we only compared data from the 107 intensive care units (1,675 patients) that also participated in the 1998 cohort (1,383 patients). MEASUREMENTS AND MAIN RESULTS: In 2004 compared with 1998, the use of noninvasive ventilation increased (11.1 vs. 4.4%, P < 0.001). Among patients with acute respiratory distress syndrome, tidal volumes decreased (7.4 vs. 9.1 ml/kg, P < 0.001) and positive end-expiratory pressure levels increased slightly (8.7 vs. 7.7 cm H(2)O, P = 0.02). More patients were successfully extubated after their first attempt of spontaneous breathing (77 vs. 62%, P < 0.001). Use of synchronized intermittent mandatory ventilation fell dramatically (1.6 vs. 11%, P < 0.001). Observations confirmed 10 of our 11 practice-change hypotheses. CONCLUSIONS: The strong concordance of predicted and observed practice changes suggests that randomized trial results have advanced mechanical ventilation practices internationally.

BACKGROUND: Respiratory syncytial virus (RSV) infection causes considerable illness in older adults. The efficacy and safety of an investigational bivalent RSV prefusion F protein-based (RSVpreF) vaccine in this population are unknown. METHODS: In this ongoing, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults (≥60 years of age) to receive a single intramuscular injection of RSVpreF vaccine at a dose of 120 μg (RSV subgroups A and B, 60 μg each) or placebo. The two primary end points were vaccine efficacy against seasonal RSV-associated lower respiratory tract illness with at least two or at least three signs or symptoms. The secondary end point was vaccine efficacy against RSV-associated acute respiratory illness. RESULTS: At the interim analysis (data-cutoff date, July 14, 2022), 34,284 participants had received RSVpreF vaccine (17,215 participants) or placebo (17,069 participants). RSV-associated lower respiratory tract illness with at least two signs or symptoms occurred in 11 participants in the vaccine group (1.19 cases per 1000 person-years of observation) and 33 participants in the placebo group (3.58 cases per 1000 person-years of observation) (vaccine efficacy, 66.7%; 96.66% confidence interval [CI], 28.8 to 85.8); 2 cases (0.22 cases per 1000 person-years of observation) and 14 cases (1.52 cases per 1000 person-years of observation), respectively, occurred with at least three signs or symptoms (vaccine efficacy, 85.7%; 96.66% CI, 32.0 to 98.7). RSV-associated acute respiratory illness occurred in 22 participants in the vaccine group (2.38 cases per 1000 person-years of observation) and 58 participants in the placebo group (6.30 cases per 1000 person-years of observation) (vaccine efficacy, 62.1%; 95% CI, 37.1 to 77.9). The incidence of local reactions was higher with vaccine (12%) than with placebo (7%); the incidences of systemic events were similar (27% and 26%, respectively). Similar rates of adverse events through 1 month after injection were reported (vaccine, 9.0%; placebo, 8.5%), with 1.4% and 1.0%, respectively, considered by the investigators to be injection-related. Severe or life-threatening adverse events were reported in 0.5% of vaccine recipients and 0.4% of placebo recipients. Serious adverse events were reported in 2.3% of participants in each group through the data-cutoff date. CONCLUSIONS: RSVpreF vaccine prevented RSV-associated lower respiratory tract illness and RSV-associated acute respiratory illness in adults (≥60 years of age), without evident safety concerns. (Funded by Pfizer; RENOIR ClinicalTrials.gov number, NCT05035212; EudraCT number, 2021-003693-31.).

The endothelium is a thin monocellular layer that covers all the inner surface of the blood vessels, separating the circulating blood from the tissues. It is not an inactive organ, quite the opposite. It works as a receptor-efector organ and responds to each physical or chemical stimulus with the release of the correct substance with which it may maintain vasomotor balance and vascular-tissue homeostasis. It has the property of producing, independently, both agonistic and antagonistic substances that help to keep homeostasis and its function is not only autocrine, but also paracrine and endocrine. In this way it modulates the vascular smooth muscle cells producing relaxation or contraction, and therefore vasodilatation or vasoconstriction. The endothelium regulating homeostasis by controlling the production of prothrombotic and antithrombotic components, and fibrynolitics and antifibrynolitics. Also intervenes in cell proliferation and migration, in leukocyte adhesion and activation and in immunological and inflammatory processes. Cardiovascular risk factors cause oxidative stress that alters the endothelial cells capacity and leads to the so called endothelial "dysfunction" reducing its capacity to maintain homeostasis and leads to the development of pathological inflammatory processes and vascular disease. There are different techniques to evaluate the endothelium functional capacity, that depend on the amount of NO produced and the vasodilatation effect. The percentage of vasodilatation with respect to the basal value represents the endothelial functional capacity. Taking into account that shear stress is one of the most important stimulants for the synthesis and release of NO, the non-invasive technique most often used is the transient flow-modulate "endothelium-dependent" post-ischemic vasodilatation, performed on conductance arteries such as the brachial, radial or femoral arteries. This vasodilatation is compared with the vasodilatation produced by drugs that are NO donors, such as nitroglycerine, called "endothelium independent". The vasodilatation is quantified by measuring the arterial diameter with high resolution ultrasonography. Laser-Doppler techniques are now starting to be used that also consider tissue perfusion. There is so much proof about endothelial dysfunction that it is reasonable to believe that there is diagnostic and prognostic value in its evaluation for the late outcome. There is no doubt that endothelial dysfunction contributes to the initiation and progression of atherosclerotic disease and could be considered an independent vascular risk factor. Although prolonged randomized clinical trials are needed for unequivocal evidence, the data already obtained allows the methods of evaluation of endothelial dysfunction to be considered useful in clinical practice and have overcome the experimental step, being non-invasive increases its value making it use full for follow-up of the progression of the disease and the effects of different treatments.

BACKGROUND: Respiratory syncytial virus (RSV) can cause substantial morbidity and mortality among older adults. An mRNA-based RSV vaccine, mRNA-1345, encoding the stabilized RSV prefusion F glycoprotein, is under clinical investigation. METHODS: In this ongoing, randomized, double-blind, placebo-controlled, phase 2-3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive one dose of mRNA-1345 (50 μg) or placebo. The two primary efficacy end points were the prevention of RSV-associated lower respiratory tract disease with at least two signs or symptoms and with at least three signs or symptoms. A key secondary efficacy end point was the prevention of RSV-associated acute respiratory disease. Safety was also assessed. RESULTS: Overall, 35,541 participants were assigned to receive the mRNA-1345 vaccine (17,793 participants) or placebo (17,748). The median follow-up was 112 days (range, 1 to 379). The primary analyses were conducted when at least 50% of the anticipated cases of RSV-associated lower respiratory tract disease had occurred. Vaccine efficacy was 83.7% (95.88% confidence interval [CI], 66.0 to 92.2) against RSV-associated lower respiratory tract disease with at least two signs or symptoms and 82.4% (96.36% CI, 34.8 to 95.3) against the disease with at least three signs or symptoms. Vaccine efficacy was 68.4% (95% CI, 50.9 to 79.7) against RSV-associated acute respiratory disease. Protection was observed against both RSV subtypes (A and B) and was generally consistent across subgroups defined according to age and coexisting conditions. Participants in the mRNA-1345 group had a higher incidence than those in the placebo group of solicited local adverse reactions (58.7% vs. 16.2%) and of systemic adverse reactions (47.7% vs. 32.9%); most reactions were mild to moderate in severity and were transient. Serious adverse events occurred in 2.8% of the participants in each trial group. CONCLUSIONS: A single dose of the mRNA-1345 vaccine resulted in no evident safety concerns and led to a lower incidence of RSV-associated lower respiratory tract disease and of RSV-associated acute respiratory disease than placebo among adults 60 years of age or older. (Funded by Moderna; ConquerRSV ClinicalTrials.gov number, NCT05127434.).

BACKGROUND: Respiratory syncytial virus (RSV) is the dominant cause of severe lower respiratory tract infection in infants, with the most severe cases concentrated among younger infants. METHODS: Healthy pregnant women, at 28 weeks 0 days through 36 weeks 0 days of gestation, with an expected delivery date near the start of the RSV season, were randomly assigned in an overall ratio of approximately 2:1 to receive a single intramuscular dose of RSV fusion (F) protein nanoparticle vaccine or placebo. Infants were followed for 180 days to assess outcomes related to lower respiratory tract infection and for 364 days to assess safety. The primary end point was RSV-associated, medically significant lower respiratory tract infection up to 90 days of life, and the primary analysis of vaccine efficacy against the primary end point was performed in the per-protocol population of infants (prespecified criterion for success, lower bound of the 97.52% confidence interval [CI] of ≥30%). RESULTS: A total of 4636 women underwent randomization, and there were 4579 live births. During the first 90 days of life, the percentage of infants with RSV-associated, medically significant lower respiratory tract infection was 1.5% in the vaccine group and 2.4% in the placebo group (vaccine efficacy, 39.4%; 97.52% CI, -1.0 to 63.7; 95% CI, 5.3 to 61.2). The corresponding percentages for RSV-associated lower respiratory tract infection with severe hypoxemia were 0.5% and 1.0% (vaccine efficacy, 48.3%; 95% CI, -8.2 to 75.3), and the percentages for hospitalization for RSV-associated lower respiratory tract infection were 2.1% and 3.7% (vaccine efficacy, 44.4%; 95% CI, 19.6 to 61.5). Local injection-site reactions among the women were more common with vaccine than with placebo (40.7% vs. 9.9%), but the percentages of participants who had other adverse events were similar in the two groups. CONCLUSIONS: RSV F protein nanoparticle vaccination in pregnant women did not meet the prespecified success criterion for efficacy against RSV-associated, medically significant lower respiratory tract infection in infants up to 90 days of life. The suggestion of a possible benefit with respect to other end-point events involving RSV-associated respiratory disease in infants warrants further study. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov NCT02624947.).

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

The obesity pandemic continues expanding unabated. Currently, 66% of adults in the United States are overweight or obese, and this figure is expected to rise to 75% by 2015 (1). Although obesity is a well- recognized risk factor for mortality from cardiovascular disease and cancer (2,3,4), it is uncertain whether it could influence the acute risk of death in critically ill patients. While some studies conducted in intensive care units (ICUs) indicate increased risk of death for overweight or obese patients (5,6,7,8), others have reported inverse (9,10,11,12,13,14,15,16,17) or null (18,19,20,21) associations. It is relevant to examine to what extent obesity is a risk factor for mortality in critically ill patients, given that BMI has been proposed as a criterion to routinely predict survival of patients at the time of admission to the ICU (5,12,22). We conducted a systematic review and meta-analysis of published research papers that addressed the association between overweight or obesity and mortality in critically ill adults. The aims of the review were to investigate whether overweight and obesity are independent predictors of mortality, duration of stay, or multiple organ dysfunction (MOD) in patients admitted to the ICU. The systematic review included observational studies that examined the associations between BMI as a categorical variable and mortality among critically ill adult patients (age >18 years). Secondary endpoints included the duration of stay in the ICU and the incidence of MOD. BMI (kg/m2) exposure categories were defined according to the World Health Organization's (WHO) proposed cutoff points (23) as follows: underweight, <18.5; normal, 18.5–24.9; overweight, 25–29.9; obese, 30–39.9; and severely obese, ≥40. We searched for articles published in English and indexed in MEDLINE from 1966 to June 2007 and EMBASE from 1980 to June 2007 with the use of the following strategy: (“critical illness” or “critical care,” or “critically ill patients” or “critically ill*”) and (“body mass index” or “BMI,” or “obesity” or “obese,” or “morbid obesity” or “morbidly obese,” or “overweight”) and (“mortality” or “ICU mortality” or “intensive care unit mortality,” or “length of stay” or “duration of stay,” or “MOD” or “multiple organ failure”). Both authors independently assessed the titles and abstracts and selected potentially eligible studies for full-text review. We designed a data capture form that included the study population (patients with medical conditions, surgical conditions, trauma, acute lung injury, or combinations of patients), the BMI exposure and reference categories used, and the outcomes reported. Data collection was carried out independently by the authors. After an additional review of the studies, we resolved discrepancies by consensus. All the studies that fulfilled inclusion criteria assessed the exposure (BMI) on admission to the ICU. We obtained an initial summary measure of association between BMI and mortality for all the studies, by estimating the odds ratio (OR) and 95% confidence intervals for each category of BMI >25, compared to normal BMI. We used both fixed and random effects models to obtain these estimates. We evaluated whether the study population and the categorization of BMI were significant sources of heterogeneity across studies. Only the use of different BMI categories significantly explained heterogeneity, hence we conducted subgroup analyses according to categories of BMI. From each study, we extracted the risk of mortality adjusted for potential confounders when this was available. The majority of studies adjusted the estimates for disease severity on admission to the ICU, by using the Acute Physiology and Chronic Health Evaluation score. We assessed the presence of publication bias with the use of the Begg-Mazumdar test (24). Analyses were carried out with the use of CMA (Biostat, Englewood, NJ) and Stata version 9.0. Our search strategy yielded an initial list of 260 publications (Figure 1). Thirty-seven of these publications met the inclusion criteria after the title and abstract review and were selected for a full-text review. Twenty-three studies were selected for data extraction after further exclusions. Nine studies reported mortality by the end of hospital stay, while another eleven studies included the mortality endpoint by the end of ICU stay. Three studies reported mortality after 1 month from ICU admission. : Studies selection process. The study populations varied markedly (Table 1). Three studies included patients with medical conditions (respiratory or heart failure, infection/sepsis, and neurological, metabolic, or kidney disorders); another two studies were conducted among surgical patients (vascular, cardiothoracic, or general surgery, transplantation, neurosurgery, and other assorted surgical procedures), one study analyzed medical and surgical patients separately, six included a combination of medical and surgical patients, three were done in patients with acute lung injury, and eight studies included trauma patients. Twelve of the twenty-three studies selected for data extraction examined the risk of mortality in relation to BMI by using 18.5–24.9 as the reference category. Tremblay et al. (10) and Ray et al. (13) used slightly different lower cutoff points but were also included in the calculation of pooled estimates. By pooling the studies according to BMI categories (Table 2), we found a decreasing trend in the risk of mortality when BMI was between 25 and 39.9 compared to BMI between 18.5 and 24.9. The pooled OR estimate for the 25–29.9 category compared to 18.5–24.9 was 0.91 (P = 0.01) (Figure 2a). The estimate for the 30–39.9 BMI category was 0.82 (P = 0.03), but the interpretation is hampered by significant heterogeneity of the studies in this comparison (Table 2). There was no apparent association between severe obesity (BMI ≥ 40) and mortality (OR = 0.94; P = 0.26) (Figure 2b). We found no evidence of publication bias for the main comparisons of mortality risk by BMI categories, namely, 25–29.9, 30–39.9, or ≥40 compared to 18.5–24.9. : Pooled odds ratio (OR) for mortality in (a) overweight (BMI: 25–29.9) and (b) severely obese (BMI > 40) critically ill patients compared to normal BMI patients (18.5–24.9). The OR for overweight patients from a random effects model was 0.91 (95% confidence interval (CI) = 0.84, 0.98; P = 0.01). The OR for severely obese patients was 0.94 (95% CI = 0.82, 1.07; P = 0.26). Eleven studies reported the average length of stay in the ICU for the BMI categories considered (Table 3). Five studies (5,9,14,20,25) found significantly longer durations of stay in obese or severely obese patients, compared to those of normal BMI, while six studies did not show significant differences (7,13,16,17,18,26). The pooled average durations of stay in the ICU were significantly longer for underweight, overweight, and severely obese patients compared to those of normal BMI (Table 4). Obese patients (BMI 30–39.9) also appeared to have longer lengths of stay, but the estimates were not statistically significant. There was evidence of heterogeneity across studies in this BMI category. Six studies reported associations between BMI and MOD (Table 5), including Brown et al.'s re-analyses (27) of Neville et al.'s report (7). Four studies found significantly increased risk of MOD associated with overweight or obesity (12,14,21,27). We found an apparently inverse association between overweight or obesity and mortality in critically ill adults, while severe obesity was not significantly related to this outcome. By contrast, overweight and severely obese patients appeared to have longer stays in the ICU and increased risk of MOD, compared to patients of normal weight. The interpretation of these associations needs to be cautious, since the observational studies reviewed may suffer from common methodological limitations. Reverse causation could explain apparent benefits of overweight and obesity in critically ill patients, since preexisting conditions that led to the most serious diseases could have caused weight loss prior to ICU admission. Studies conducted in patients who suffered traumatic injuries offer an opportunity to assess whether reverse causality is likely to explain the inverse association between overweight or obesity and mortality, since these patients may not have had serious preexisting conditions. In these studies, obesity was either a risk factor for mortality (7,8,25,27) or was not significantly related to this outcome (14,19,21,26), suggesting that reverse causality cannot be ruled out. The timing when body weight was assessed also deserves to be considered in the interpretation of results, given that increased body weight measured at the time of ICU admission could represent fluid retention from prior in-hospital treatment, rather than usual weight. The apparently “protective” impact of obesity on mortality would seem contradictory to its positive relation with ICU stay, an indicator of ICU complications. It could be argued that leaner patients die shortly after ICU admission and, therefore, have both shorter stays and greater mortality than obese patients. On the other hand, longer duration of stay in obese patients, independent of mortality, could be related to their greater dependence on mechanical ventilation due to increased airway resistance, abnormal chest elasticity, and inefficiency of the respiratory muscles (5). A contradiction with the increased incidence of MOD is more difficult to reconcile. Some authors argued that obese patients receive superior care at the ICU (26), as they may be considered “high risk,” and, therefore, they may have reduced mortality even if their incidence of complications is greater than that of normal weight patients. Obesity has been found to be protective against mortality in patients suffering from chronic, debilitating conditions, including congestive heart failure, end-stage renal disease, advanced malignancies, and HIV/AIDS—a phenomenon called the “obesity paradox” (28,29). One explanation for this paradox is that high BMI may confer survival benefits by providing nutritional reserves in these patients. It is conceivable that a similar mechanism may be at play in some critically ill patients, who are suddenly exposed to intense inflammatory and metabolic stress. Alternatively, specific hormonal mechanisms could play a role in the relation between obesity and mortality. Obese patients have higher levels of leptin, and Bornstein and colleagues reported a positive association between leptin concentrations and survival of septic patients (30), suggesting that leptin could play a role in the adaptive response to critical illness. Under the “obesity paradox” hypothesis, the fact that obesity is not as “protective” in trauma patients compared to those admitted to the ICU for medical or surgical reasons could be explained if the former are younger than the latter, as nutritional reserves may offer greater benefits to elderly patients than to younger ones. Some authors have proposed the inclusion of BMI in the algorithms that are routinely used on admission to the ICU to predict survival (5,12,22). This suggestion has been made in light of the studies that found positive associations between obesity and mortality. The results of our review indicate that there is no sufficiently robust evidence at this point to support the inclusion of BMI as a predictor of mortality for any critically ill patient in such algorithms. Future studies assessing the relation between obesity and mortality in critically ill adults should incorporate measures of the “usual” nutritional status prior to the occurrence of diseases that may have led to ICU admission. Measurements of body composition or adiposity other than BMI are not routinely obtained in patients admitted to the ICU; some of these measurements could also contribute to elucidate the association between obesity and mortality in future investigations. The authors declared no conflict of interest.

Background: Candida auris is a multidrug-resistant yeast associated with hospital outbreaks worldwide. During 2015-2016, multiple outbreaks were reported in Colombia. We aimed to understand the extent of contamination in healthcare settings and to characterize the molecular epidemiology of C. auris in Colombia. Methods: We sampled patients, patient contacts, healthcare workers, and the environment in 4 hospitals with recent C. auris outbreaks. Using standardized protocols, people were swabbed at different body sites. Patient and procedure rooms were sectioned into 4 zones and surfaces were swabbed. We performed whole-genome sequencing (WGS) and antifungal susceptibility testing (AFST) on all isolates. Results: Seven of the 17 (41%) people swabbed were found to be colonized. Candida auris was isolated from 37 of 322 (11%) environmental samples. These were collected from a variety of items in all 4 zones. WGS and AFST revealed that although isolates were similar throughout the country, isolates from the northern region were genetically distinct and more resistant to amphotericin B (AmB) than the isolates from central Colombia. Four novel nonsynonymous mutations were found to be significantly associated with AmB resistance. Conclusions: Our results show that extensive C. auris contamination can occur and highlight the importance of adherence to appropriate infection control practices and disinfection strategies. Observed genetic diversity supports healthcare transmission and a recent expansion of C. auris within Colombia with divergent AmB susceptibility.

OBJECTIVES: The prevalence of septic acute kidney injury and impact on functional status of PICU survivors are unknown. We used data from an international prospective severe sepsis study to elucidate functional outcomes of children suffering septic acute kidney injury. DESIGN: Secondary analysis of patients in the Sepsis PRevalence, OUtcomes, and Therapies point prevalence study: acute kidney injury was defined on the study day using Kidney Disease Improving Global Outcomes definitions. Patients with no acute kidney injury or stage 1 acute kidney injury ("no/mild acute kidney injury") were compared with those with stage 2 or 3 acute kidney injury ("severe acute kidney injury"). The primary outcome was a composite of death or new moderate disability at discharge defined as a Pediatric Overall Performance Category score of 3 or higher and increased by 1 from baseline. SETTING: One hundred twenty-eight PICUs in 26 countries. PATIENTS: Children with severe sepsis in the Sepsis PRevalence, OUtcomes, and Therapies study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred two (21%) of 493 patients had severe acute kidney injury. More than twice as many patients with severe acute kidney injury died or developed new moderate disability compared with those with no/mild acute kidney injury (64% vs 30%; p < 0.001). Severe acute kidney injury was independently associated with death or new moderate disability (adjusted odds ratio, 2.5; 95% CI, 1.5-4.2; p = 0.001) after adjustment for age, region, baseline disability, malignancy, invasive mechanical ventilation, albumin administration, and the pediatric logistic organ dysfunction score. CONCLUSIONS: In a multinational cohort of critically ill children with severe sepsis and high mortality rates, septic acute kidney injury is independently associated with further increased death or new disability.

Although a rare cause of invasive candidiasis, Candida guilliermondii has been reported to exhibit decreased susceptibility to antifungal agents. Aside from case reports and small surveys, there is little information regarding the epidemiology and antifungal susceptibility profile of C. guilliermondii. We report geographic and temporal trends in the isolation and antifungal susceptibilities of 1,029 C. guilliermondii clinical isolates collected from 127 medical centers as part of the ARTEMIS DISK Antifungal Surveillance Program. In addition, we report the in vitro susceptibility of 132 bloodstream isolates of C. guilliermondii to caspofungin. C. guilliermondii represented 1.4% of the 75,761 isolates collected from 2001 to 2003 and was most common among isolates from Latin America (3.7% versus 0.6 to 1.1%). Decreased susceptibility to fluconazole was noted (75% susceptible; range, 68 to 77% across regions), and voriconazole was more active in vitro against C. guilliermondii than fluconazole (91% susceptible; range, 88 to 93% across regions). Fluconazole was least active against isolates from dermatology (58%) and surgical (69%) services and against isolates associated with skin and soft tissue infection (68%, compared to 85% susceptible for bloodstream isolates). There was no evidence of increasing azole resistance over time among C. guilliermondii isolates tested from 2001 to 2003. Of 132 bloodstream isolates of C. guilliermondii tested against caspofungin, most were inhibited by < or =2 microg/ml (96%; MIC50/MIC90, 0.5/1.0 microg/ml). C. guilliermondii, a species that exhibits reduced susceptibility to fluconazole, is the sixth most frequently isolated Candida species from this large survey and may be an emerging pathogen in Latin America.

OBJECTIVE: To evaluate the efficacy and safety of etoricoxib and indomethacin in the treatment of patients with acute gout. METHODS: A randomized, double-blind, active-comparator study was conducted at 42 sites. A total of 189 men and women (> or =18 years of age) who were experiencing an acute attack (< or =48 hours) of clinically diagnosed gout were treated for 8 days with etoricoxib, 120 mg/day (n = 103), or indomethacin, 50 mg 3 times a day (n = 86). The primary efficacy end point was the patient's assessment of pain in the study joint (0-4-point Likert scale) over days 2-5. Safety was assessed by adverse experiences (AEs) occurring during the trial. RESULTS: Etoricoxib demonstrated clinical efficacy comparable to that of indomethacin in terms of the patient's assessment of pain in the study joint. The difference in the mean change from baseline over days 2-5 was -0.08 (95% confidence interval -0.29, 0.13) (P = 0.46), which fell within the prespecified comparability bounds of -0.5 to 0.5. Secondary end points over the 8-day study, including the onset of efficacy, reduction in signs of inflammation, and patient's and investigator's global assessments of response to therapy, confirmed the comparable efficacy of the two treatments. The etoricoxib-treated patients had a numerically lower incidence of AEs (43.7%) than did the indomethacin-treated patients (57.0%) and a significantly lower incidence of drug-related AEs (16.5% versus 37.2%; P < 0.05). CONCLUSION: Etoricoxib at a dosage of 120 mg once daily was confirmed to be an effective treatment for acute gout. Etoricoxib was comparable in efficacy to indomethacin at a dosage of 50 mg 3 times daily, and it was generally safe and well tolerated.

Antidromic atrioventricular reentrant tachycardia Any regular atrial or junctional reentrant tachycardias with: aberration/bundle branch block pre-excitation/bystander accessory pathway Ventricular tachycardia/flutter Irregular Atrial fibrillation or atrial tachycardia with varying block conducted with aberration Antidromic atrioventricular reentrant tachycardia with a variable VA conduction Pre-excited AF Polymorphic VT Torsade de pointes Ventricular fibrillation Procedures with text in italics are classified as cumbersome, while those shown in normal text are easily applicable. A, atrial; H, His; cPPI, corrected postpacing interval; RBBB, right bundle branch block; SA, stimulus to atrium interval; SR, sinus rhythm; TCL, tachycardia cycle length; V, ventricular; VA, ventriculo-atrial. Modified from Katritsis and Josephson. 17

BACKGROUND: CT-P13 (Remsima®, Inflectra®) is a biosimilar of the infliximab reference product (RP; Remicade®). The aim of this study was to compare the 54-week efficacy, immunogenicity, safety, pharmacokinetics (PK) and pharmacodynamics (PD) of CT-P13 and RP in patients with active rheumatoid arthritis (RA). METHODS: In this multinational phase III double-blind study, patients with active RA and an inadequate response to methotrexate (MTX) were randomized (1:1) to receive CT-P13 (3 mg/kg) or RP (3 mg/kg) at weeks 0, 2, 6 and then every 8 weeks to week 54 in combination with MTX (12.5-25 mg/week). Efficacy endpoints included American College of Rheumatology (ACR)20, ACR50 and ACR70 response rates, Disease Activity Score in 28 joints (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), European League Against Rheumatism (EULAR) response rates, patient-reported outcomes and joint damage progression. Immunogenicity, safety and PK/PD outcomes were also assessed. RESULTS: Of 606 randomized patients, 455 (CT-P13 233, RP 222) were treated up to week 54. At week 54, ACR20 response rate was highly similar between groups (CT-P13 74.7 %, RP 71.3 %). ACR50 and ACR70 response rates were also comparable between groups (CT-P13 43.6 % and 21.3 %, respectively; RP 43.1 % and 19.9 %, respectively). DAS28, SDAI and CDAI decreased from baseline to week 54 to a similar extent with CT-P13 and RP. Radiographic progression measured by Sharp scores as modified by van der Heijde was also comparable. With both treatments, patient assessments of pain, disease activity and physical ability, as well as mean scores on the Medical Outcomes Study Short Form Health Survey (SF-36), improved markedly at week 14 and remained stable thereafter up to week 54. The proportion of patients positive for antidrug antibodies at week 54 was similar between the two groups: 41.1 % and 36.0 % with CT-P13 and RP, respectively. CT-P13 was well tolerated and had a similar safety profile to RP. PK/PD results were also comparable between CT-P13 and RP. CONCLUSIONS: CT-P13 and RP were comparable in terms of efficacy (including radiographic progression), immunogenicity and PK/PD up to week 54. The safety profile of CT-P13 was also similar to that of RP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01217086 . Registered 4 Oct 2010.

INTRODUCTION: Ureteral trauma is rare, accounting for less than 1% of all urologic traumas. However, a missed ureteral injury can result in significant morbidity and mortality. The purpose of this article is to review the literature since 1961 with the primary objective to present the largest medical literature review, to date, regarding ureteral trauma. Several anatomic and physiologic considerations are paramount regarding ureteral injuries management. LITERATURE REVIEW: Eighty-one articles pertaining to traumatic ureteral injuries were reviewed. Data from these studies were compiled and analyzed. The majority of the study population was young males. The proximal ureter was the most frequently injured portion. Associated injuries were present in 90.4% of patients. Admission urinalysis demonstrated hematuria in only 44.4% patients. Intravenous ureterogram (IVU) failed to diagnose ureteral injuries either upon admission or in the operating room in 42.8% of cases. Ureteroureterostomy, with or without indwelling stent, was the surgical procedure of choice for both trauma surgeons and urologists (59%). Complications occurred in 36.2% of cases. The mortality rate was 17%. CONCLUSION: The mechanism for ureteral injuries in adults is more commonly penetrating than blunt. The upper third of the ureter is more often injured than the middle and lower thirds. Associated injuries are frequently present. CT scan and retrograde pyelography accurately identify ureteral injuries when performed together. Ureteroureterostomy, with or without indwelling stent, is the surgical procedure of choice of both trauma surgeons and urologists alike. Delay in diagnosis is correlated with a poor prognosis.

Sphingosine kinase (SphK) is a key enzyme in the sphingolipid metabolic pathway responsible for phosphorylating sphingosine into sphingosine-1-phosphate (S1P). SphK/S1P play a critical role in angiogenesis, inflammation, and various pathologic conditions. Recently, S1P(1) receptor was found to be expressed in rheumatoid arthritis (RA) synovium, and S1P signaling via S1P(1) enhances synoviocyte proliferation, COX-2 expression, and prostaglandin E(2) production. Here, we examined the role of SphK/S1P in RA using a potent SphK inhibitor, N,N-dimethylsphingosine (DMS), and a molecular approach against one of its isoenzymes, SphK1. We observed that levels of S1P in the synovial fluid of RA patients were significantly higher than those of osteoarthritis patients. Additionally, DMS significantly reduced the levels of TNF-alpha, IL-6, IL-1beta, MCP-1, and MMP-9 in cell-contact assays using both Jurkat-U937 cells and RA PBMCs. In a murine collagen-induced arthritis model, i.p. administration of DMS significantly inhibited disease severity and reduced articular inflammation and joint destruction. Treatment of DMS also down-regulated serum levels IL-6, TNF-alpha, IFN-gamma, S1P, and IgG1 and IgG2a anti-collagen Ab. Furthermore, DMS-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Moreover, similar reduction in incidence and disease activity was observed in mice treated with SphK1 knock-down via small interfering RNA approach. Together, these results demonstrate SphK modulation may provide a novel approach in treating chronic autoimmune conditions such as RA by inhibiting the release of pro-inflammatory cytokines.

We determined the efficacy of the use of permethrin-impregnated uniforms for prevention of malaria and leishmaniasis in a double-blind, randomized study of Colombian soldiers on patrol. In the study of malaria, soldiers were issued impregnated uniforms (i.e., a shirt, an undershirt, pants, socks, and a hat) or uniforms washed in water; the soldiers wore the uniforms day and night for a mean of 4.2 weeks and were observed for an additional 4 weeks. Three (3%) of 86 soldiers wearing impregnated uniforms contracted malaria, whereas 12 (14%) of 86 soldiers wearing control uniforms contracted malaria (P = .015). In the study of leishmaniasis (soldiers were in the area of endemicity for 6.6 weeks and were observed for 12 weeks thereafter), 4 (3%) of 143 soldiers wearing impregnated uniforms and 18 (12%) of 143 soldiers wearing control uniforms acquired disease (P = .002). In the leishmaniasis study, and presumably in the malaria study, breakthrough infections in the treated group were primarily due to bites in unclothed regions of the body (face and hands). Permethrin-treated uniforms were virtually nontoxic (there were only two cases of mild skin irritation among 229 subjects), and impregnation is quick and inexpensive. Impregnation of clothing with permethrin is suggested for nonimmune populations who are likely to be exposed to malaria or leishmaniasis over a period of 1-2 months.