Background: Necrotizing soft-tissue infection (NSTI) is a severe and fast-progressing bacterial i... more Background: Necrotizing soft-tissue infection (NSTI) is a severe and fast-progressing bacterial infection. Prognostic biomarkers may provide valuable information in treatment guidance and decision-making, but none have provided sufficient robustness to have a clinical impact. YKL-40 may reflect the ongoing pathological inflammatory processes more accurately than traditional biomarkers as it is secreted by the activated immune cells, but its prognostic yields in NSTI remains unknown. For this purpose, we investigated the association between plasma YKL-40 and 30-day mortality in patients with NSTI, and assessed its value as a marker of disease severity. We determined plasma YKL-40 levels in patients with NSTI (n = 161) and age-sex matched controls (n = 65) upon admission and at day 1, 2 and 3. Results: Baseline plasma YKL-40 was 1191 ng/mL in patients with NSTI compared with 40 ng/mL in controls (p < 0.001). YKL-40 was found to be significantly higher in patients with septic shock (1942 vs. 720 ng/mL, p < 0.001), and in patients receiving renal-replacement therapy (2382 vs. 1041 ng/mL, p < 0.001). YKL-40 correlated with Simplified Acute Physiology Score II (Rho 0.33, p < 0.001). Baseline YKL-40 above 1840 ng/mL was associated with increased risk of 30-day mortality in age-sex-comorbidity adjusted analysis (OR 3.77, 95% CI; 1.59-9.24, p = 0.003), but after further adjustment for Simplified Acute Physiology Score II no association was found between YKL-40 and early mortality. High plasma YKL-40 to be associated with disease severity, renal-replacement therapy and risk of death in patients with NSTI. However, YKL-40 is not an independent predictor of 30-day mortality.
Acute Physiology Score II was included in the analysis [hazard ratio 3.16 (95% confidence interva... more Acute Physiology Score II was included in the analysis [hazard ratio 3.16 (95% confidence interval 1.03-9.73), p = 0.045]. Conclusions: All PRMs were significantly lower in patients with NSTI than in controls. Only baseline Ficolin-2 was associated with short-and long-term mortality. A high baseline Ficolin-2 level indicated a 94% chance of surviving the first 28 days after admission.
Objectives Application of hyperbaric oxygen (HBO 2 ) treatment in the multidisciplinary setting o... more Objectives Application of hyperbaric oxygen (HBO 2 ) treatment in the multidisciplinary setting of necrotising soft-tissue infection (NSTI) is debated as a considerable number of studies are of low quality with marked prognostication bias due to inadequately addressing disease severity. The objective of this study was to associate HBO 2 treatment with mortality in patients with NSTI including disease severity as a prognostic variable. Design Nationwide population-based register study. Setting Denmark. Participants Danish residents with NSTI patients between January 2011 and June 2016. Primary and secondary outcome measures Thirtyday mortality was compared between patients receiving and patients not receiving HBO 2 treatment using inverse probability of treatment weighting and propensity-score matching with predetermined variables (age, sex and weighted Charlson comorbidity score, presence of septic shock and Simplified Acute Physiology Score II (SAPS II)). Results A total of 671 NSTI patients were included with a median age of 63 (52-71), 61% male sex, 30% had septic shock and a median SAPS II of 46 (34-58). Patients who received HBO 2 treatment (n=266) were younger and had lower SAPS II, but a larger fraction had septic shock compared with patients not receiving HBO 2 treatment. Overall, all-cause 30-day mortality was 19% (95% CI 17% to 23%). The statistical models were in general acceptably balanced with covariates reaching <0.1 absolute standardised mean differences and patients receiving HBO 2 treatment were associated with lower 30-day mortality (OR 0.40, 95% CI 0.30 to 0.53, p<0.001). Conclusions In analyses using inverse probability of treatment weighting and propensity score analysis, patients treated with HBO 2 treatment were associated with improved 30-day survival.
Background: New biomarkers are needed to assess the severity of necrotizing soft tissue infection... more Background: New biomarkers are needed to assess the severity of necrotizing soft tissue infection (NSTI) at an early stage and to individualize treatment strategies. We assessed pentraxin-3 (PTX3) as a marker of disease severity and risk of death in patients with NSTI. Methods: We conducted a prospective, observational study in the intensive care unit at Copenhagen University Hospital, where treatment of NSTI is centralized at a national level. We compared PTX3, procalcitonin and C-reactive protein in septic shock versus nonshock patients and in amputated versus nonamputated patients using the Mann-Whitney U test. The prognostic value of the markers for 180-day mortality was assessed using Cox regression analyses. Results: Patients with NSTI (n = 135) were included over 25 months with up to 2.5-year follow-up; 71 % had septic shock, amputation was undertaken in 20 % and the 180-day mortality was 27 %. Baseline plasma PTX3 level was significantly higher in patients with septic shock (67.3 versus 24.6 ng/mL, p < 0.0001) and in patients who underwent amputation (118.6 versus 43.6 ng/mL, p = 0.019). No significant differences in baseline procalcitonin or C-reactive protein levels were found according to amputation (25.2 versus 7.0 μg/L, p = 0.060 and 202 versus 225 mg/L, p = 0.123), respectively. Baseline PTX3 level above the median was associated with death (p = 0.009, log-rank test) and the univariate Cox regression analysis revealed a significant association between PTX3 level upon admission and 180-day mortality (hazard ratio 2.60 (95 % confidence interval 1.28-5.29), p = 0.008). When adjusted for age, sex, chronic disease and Simplified Acute Physiology Score II, no significant association was found. Conclusions: High PTX3 level is associated with septic shock, amputation and risk of death in patients with NSTI, but it is not an independent predictor of 180-day mortality in this patient group.
Background Streptococcus pyogenes (group A streptococci; GAS) is the main causative pathogen of m... more Background Streptococcus pyogenes (group A streptococci; GAS) is the main causative pathogen of monomicrobial necrotizing soft tissue infections (NSTIs). To resist immuno-clearance, GAS adapt their genetic information and/or phenotype to the surrounding environment. Hyper-virulent streptococcal pyrogenic exotoxin B (SpeB) negative variants caused by covRS mutations are enriched during infection. A key driving force for this process is the bacterial Sda1 DNase. Methods Bacterial infiltration, immune cell influx, tissue necrosis and inflammation in patient´s biopsies were determined using immunohistochemistry. SpeB secretion and activity by GAS post infections or challenges with reactive agents were determined via Western blot or casein agar and proteolytic activity assays, respectively. Proteome of GAS single colonies and neutrophil secretome were profiled, using mass spectrometry. Results Here, we identify another strategy resulting in SpeB-negative variants, namely reversible abrog...
Purpose: To assess long-term outcomes of restrictive versus standard intravenous (IV) fluid thera... more Purpose: To assess long-term outcomes of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock included in the European Conservative versus Liberal Approach to Fluid Therapy in Septic Shock in Intensive Care (CLASSIC) trial. Methods: We conducted the pre-planned analyses of mortality, health-related quality of life (HRQoL) using EuroQol (EQ)-5D-5L index values and EQ visual analogue scale (VAS), and cognitive function using Mini Montreal Cognitive Assessment (Mini MoCA) test at 1 year. Deceased patients were assigned numerical zero for HRQoL as a state equal to death and zero for cognitive function outcomes as worst possible score, and we used multiple imputation for missing data on HRQoL and cognitive function. Results: Among 1554 randomized patients, we obtained 1-year data on mortality in 97.9% of patients, HRQoL in 91.3%, and cognitive function in 86.3%. One-year mortality was 385/746 (51.3%) in the restrictive-fluid group versus 383/767 (49.9%) in the standard-fluid group, absolute risk difference 1.5%-points [99% confidence interval (CI) − 4.8 to
IntroductionDifferent outcomes are reported in randomised clinical trials (RCTs) in intensive car... more IntroductionDifferent outcomes are reported in randomised clinical trials (RCTs) in intensive care unit (ICU) patients, and no core outcome set (COS) is available for ICU patients in general. Accordingly, we aim to develop a COS for ICU patients in general.MethodsThe COS will be developed in accordance with the Core Outcome Measures in Effectiveness Trials (COMET) Handbook, using a modified Delphi consensus process and semi‐structured interviews involving adults who have survived acute admission to an ICU, family members, clinicians, researchers and other stakeholders. The modified Delphi process will include two steps. Step 1: conduction of a modified Delphi survey, developed and informed by combining the outputs of a literature search of outcomes in previous COSs and semi‐structured interviews with key stakeholders. We plan at least two survey rounds to obtain consensus and refine the COS. Step 2: a consensus process regarding instruments or definitions to be recommended for the m...
Go to publication entry in University of Southern Denmark's Research Portal Terms of use This wor... more Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim.
Necrotising soft-tissue infections (NSTI) are characterised by necrosis, fast progression, and hi... more Necrotising soft-tissue infections (NSTI) are characterised by necrosis, fast progression, and high rates of morbidity and mortality, but our knowledge is primarily derived from small prospective studies and retrospective studies. Methods: We performed an international, multicentre, prospective cohort study of adults with NSTI describing patient's characteristics and associations between baseline variables and microbiological findings, amputation, and 90-day mortality. Results: We included 409 patients with NSTI; 402 were admitted to the ICU. Cardiovascular disease [169 patients (41%)] and diabetes [98 (24%)] were the most common comorbidities; 122 patients (30%) had no comorbidity. Before surgery, bruising of the skin [210 patients (51%)] and pain requiring opioids [172 (42%)] were common. The sites most commonly affected were the abdomen/ano-genital area [140 patients (34%)] and lower extremities [126 (31%)]. Monomicrobial infection was seen in 179 patients (44%). NSTI of the upper or lower extremities was associated with monomicrobial group A streptococcus (GAS) infection, and NSTI located to the abdomen/ano-genital area was associated with polymicrobial infection. Septic shock [202 patients (50%)] and acute kidney injury [82 (20%)] were common. Amputation occurred in 22% of patients with NSTI of an extremity and was associated with higher lactate level. All-cause 90-day mortality was 18% (95% CI 14-22); age and higher lactate levels were associated with increased mortality and GAS aetiology with decreased mortality. Conclusions: Patients with NSTI were heterogeneous regarding co-morbidities, initial symptoms, infectious localisation, and microbiological findings. Higher age and lactate levels were associated with increased mortality, and GAS infection with decreased mortality.
Patients in the intensive care unit (ICU) are often transfused with red blood cells (RBC). During... more Patients in the intensive care unit (ICU) are often transfused with red blood cells (RBC). During storage, the RBCs and storage medium undergo changes, which may have clinical consequences. Several trials now have assessed these consequences, and we reviewed the present evidence on the effects of shorter versus longer storage time of transfused RBCs on outcomes in ICU patients. We conducted a systematic review with meta-analyses and trial sequential analyses (TSA) of randomised clinical trials including adult ICU patients transfused with fresher versus older or standard issue blood. We included seven trials with a total of 18,283 randomised ICU patients; two trials of 7504 patients were judged to have low risk of bias. We observed no effects of fresher versus older blood on death (relative risk 1.04, 95% confidence interval (CI) 0.97-1.11; 7349 patients; TSA-adjusted CI 0.93-1.15), adverse events (1.26, 0.76-2.09; 7332 patients; TSA-adjusted CI 0.16-9.87) or post-transfusion infecti...
We assessed the effects of early goal-directed nutrition (EGDN) vs. standard nutritional care in ... more We assessed the effects of early goal-directed nutrition (EGDN) vs. standard nutritional care in adult intensive care unit (ICU) patients. Methods: We randomised acutely admitted, mechanically ventilated ICU patients expected to stay longer than 3 days in the ICU. In the EGDN group we estimated nutritional requirements by indirect calorimetry and 24-h urinary urea aiming at covering 100% of requirements from the first full trial day using enteral and parenteral nutrition. In the standard of care group we aimed at providing 25 kcal/kg/day by enteral nutrition. If this was not met by day 7, patients were supplemented with parenteral nutrition. The primary outcome was physical component summary (PCS) score of SF-36 at 6 months. We performed multiple imputation for data of the non-responders. Results: We randomised 203 patients and included 199 in the intention-to-treat analyses; baseline variables were reasonably balanced between the two groups. The EGDN group had less negative energy (p < 0.001) and protein (p < 0.001) balances in the ICU as compared to the standard of care group. The PCS score at 6 months did not differ between the two groups (mean difference 0.0, 95% CI −5.9 to 5.8, p = 0.99); neither did mortality, rates of organ failures, serious adverse reactions or infections in the ICU, length of ICU or hospital stay, or days alive without life support at 90 days. Conclusions: EGDN did not appear to affect physical quality of life at 6 months or other important outcomes as compared to standard nutrition care in acutely admitted, mechanically ventilated, adult ICU patients. Clinicaltrials.gov identifier no. NCT01372176.
APS Bulletin of the American Physical Society. 38th Annual Meeting of the Division of Atomic, Mol... more APS Bulletin of the American Physical Society. 38th Annual Meeting of the Division of Atomic, Molecular, and Optical Physics Volume 52, Number 7. TuesdaySaturday, June 59, 2007; Calgary, Alberta, Canada. ...
These infections are infrequent, but are associated with a significant health burden due to high ... more These infections are infrequent, but are associated with a significant health burden due to high mortality and risk of severe long-term disability as a consequence of extensive tissue loss or amputations (3-5). The progression of the disease is rapid, and early identification is therefore pivotal for improving the prognosis of affected patients. Currently, the initial diagnosis of NSTI is challenging due to the often vague symptoms during early stages, a heterogeneous patient group, and lack of specific diagnostic tools (6), which lead to misdiagnoses of NSTI in many cases (7). Still, doctors are advised that in case of NSTI suspicion, patients should be referred to surgical evaluation immediately (8). Previous efforts to improve the diagnosis of NSTIs led to the proposal of the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) CONCLUSIONS. This study identifies predictive biomarkers for NSTI clinical phenotypes of potential value for diagnostic, prognostic, and therapeutic approaches in NSTIs. TRIAL REGISTRATION. ClinicalTrials.gov NCT01790698.
Posesivni pridev u jeziku, ili jezicima Srba, Hrvata, Bošnjaka i Crnogoraca, pojava je, koja priv... more Posesivni pridev u jeziku, ili jezicima Srba, Hrvata, Bošnjaka i Crnogoraca, pojava je, koja privlači pažnju uglavnom zato što se ta vrsta prideva često pojavljuje, a i zato što je njihova upotreba nešto šira nego što bi se na prvi pogled očekivalo od jezičke po-jave sa tim nazivom. Ovde mislim na posesivne prideve upotreblje-ne kao u sledećim primerima: Knez Mihailova ulica, Trumanova jaja, Gordijev čvor, Venerin breg, Avalin vrh, Politikin zabavnik, vladin list, Jupiterovi mjeseci, sunčevi zraci, kućni prag, ružin miris, hrastova krošnja, lipova daščica, kaljeva peć, Tubakovi, Hercfeldova. Ovamo mogu ići i primeri kao: autorov stav, majčina tuga, paukova mreža, kada se u izrazu ne misli na određenog autora, majku ili pauka, tj. kada stav nije stav jednog određenog autora, kada tuga nije tuga jedne određene majke i kada mreža nije mreža jednog određenog pauka. Dakle, cilj ispitivanja jeste da se precizira u kojoj se meri pojavljuju formalno posesivni, a u kojoj meri semantički nepo...
Background Necrotising soft tissue infections (NSTIs) are rapidly progressing bacterial infecti... more Background Necrotising soft tissue infections (NSTIs) are rapidly progressing bacterial infections usually caused by either several pathogens in unison (polymicrobial infections) or Streptococcus pyogenes (mono-microbial infection). These infections are rare and are associated with high mortality rates. However, the underlying pathogenic mechanisms in this heterogeneous group remain elusive. Methods In this study, we built interactomes at both the population and individual levels consisting of host-pathogen interactions inferred from dual RNA-Seq gene transcriptomic profiles of the biopsies from NSTI patients. Results NSTI type-specific responses in the host were uncovered. The S. pyogenes mono-microbial subnetwork was enriched with host genes annotated with involved in cytokine production and regulation of response to stress. The polymicrobial network consisted of several significant associations between different species (S. pyogenes, Porphyromonas asaccharolytica and Escherichi...
Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differe... more Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ’s ability to activate target genes in a cellular context is currently poorly understood. Here we take advantage of two previously uncharacterized lipodystrophy mutations, R212Q and E379K, that are predicted to interfere with the interaction of the hinge of PPARγ with DNA and with the interaction of PPARγ ligand binding domain (LBD) with the DNA-binding domain (DBD) of the retinoid X receptor, respectively. Using biochemical and genome-wide approaches we show that these mutations impair PPARγ function on an overlapping subset of target enhancers. The hinge region-DNA interaction appears mostly important for binding and remodelling o...
Background: Necrotizing soft-tissue infection (NSTI) is a severe and fast-progressing bacterial i... more Background: Necrotizing soft-tissue infection (NSTI) is a severe and fast-progressing bacterial infection. Prognostic biomarkers may provide valuable information in treatment guidance and decision-making, but none have provided sufficient robustness to have a clinical impact. YKL-40 may reflect the ongoing pathological inflammatory processes more accurately than traditional biomarkers as it is secreted by the activated immune cells, but its prognostic yields in NSTI remains unknown. For this purpose, we investigated the association between plasma YKL-40 and 30-day mortality in patients with NSTI, and assessed its value as a marker of disease severity. We determined plasma YKL-40 levels in patients with NSTI (n = 161) and age-sex matched controls (n = 65) upon admission and at day 1, 2 and 3. Results: Baseline plasma YKL-40 was 1191 ng/mL in patients with NSTI compared with 40 ng/mL in controls (p < 0.001). YKL-40 was found to be significantly higher in patients with septic shock (1942 vs. 720 ng/mL, p < 0.001), and in patients receiving renal-replacement therapy (2382 vs. 1041 ng/mL, p < 0.001). YKL-40 correlated with Simplified Acute Physiology Score II (Rho 0.33, p < 0.001). Baseline YKL-40 above 1840 ng/mL was associated with increased risk of 30-day mortality in age-sex-comorbidity adjusted analysis (OR 3.77, 95% CI; 1.59-9.24, p = 0.003), but after further adjustment for Simplified Acute Physiology Score II no association was found between YKL-40 and early mortality. High plasma YKL-40 to be associated with disease severity, renal-replacement therapy and risk of death in patients with NSTI. However, YKL-40 is not an independent predictor of 30-day mortality.
Acute Physiology Score II was included in the analysis [hazard ratio 3.16 (95% confidence interva... more Acute Physiology Score II was included in the analysis [hazard ratio 3.16 (95% confidence interval 1.03-9.73), p = 0.045]. Conclusions: All PRMs were significantly lower in patients with NSTI than in controls. Only baseline Ficolin-2 was associated with short-and long-term mortality. A high baseline Ficolin-2 level indicated a 94% chance of surviving the first 28 days after admission.
Objectives Application of hyperbaric oxygen (HBO 2 ) treatment in the multidisciplinary setting o... more Objectives Application of hyperbaric oxygen (HBO 2 ) treatment in the multidisciplinary setting of necrotising soft-tissue infection (NSTI) is debated as a considerable number of studies are of low quality with marked prognostication bias due to inadequately addressing disease severity. The objective of this study was to associate HBO 2 treatment with mortality in patients with NSTI including disease severity as a prognostic variable. Design Nationwide population-based register study. Setting Denmark. Participants Danish residents with NSTI patients between January 2011 and June 2016. Primary and secondary outcome measures Thirtyday mortality was compared between patients receiving and patients not receiving HBO 2 treatment using inverse probability of treatment weighting and propensity-score matching with predetermined variables (age, sex and weighted Charlson comorbidity score, presence of septic shock and Simplified Acute Physiology Score II (SAPS II)). Results A total of 671 NSTI patients were included with a median age of 63 (52-71), 61% male sex, 30% had septic shock and a median SAPS II of 46 (34-58). Patients who received HBO 2 treatment (n=266) were younger and had lower SAPS II, but a larger fraction had septic shock compared with patients not receiving HBO 2 treatment. Overall, all-cause 30-day mortality was 19% (95% CI 17% to 23%). The statistical models were in general acceptably balanced with covariates reaching <0.1 absolute standardised mean differences and patients receiving HBO 2 treatment were associated with lower 30-day mortality (OR 0.40, 95% CI 0.30 to 0.53, p<0.001). Conclusions In analyses using inverse probability of treatment weighting and propensity score analysis, patients treated with HBO 2 treatment were associated with improved 30-day survival.
Background: New biomarkers are needed to assess the severity of necrotizing soft tissue infection... more Background: New biomarkers are needed to assess the severity of necrotizing soft tissue infection (NSTI) at an early stage and to individualize treatment strategies. We assessed pentraxin-3 (PTX3) as a marker of disease severity and risk of death in patients with NSTI. Methods: We conducted a prospective, observational study in the intensive care unit at Copenhagen University Hospital, where treatment of NSTI is centralized at a national level. We compared PTX3, procalcitonin and C-reactive protein in septic shock versus nonshock patients and in amputated versus nonamputated patients using the Mann-Whitney U test. The prognostic value of the markers for 180-day mortality was assessed using Cox regression analyses. Results: Patients with NSTI (n = 135) were included over 25 months with up to 2.5-year follow-up; 71 % had septic shock, amputation was undertaken in 20 % and the 180-day mortality was 27 %. Baseline plasma PTX3 level was significantly higher in patients with septic shock (67.3 versus 24.6 ng/mL, p < 0.0001) and in patients who underwent amputation (118.6 versus 43.6 ng/mL, p = 0.019). No significant differences in baseline procalcitonin or C-reactive protein levels were found according to amputation (25.2 versus 7.0 μg/L, p = 0.060 and 202 versus 225 mg/L, p = 0.123), respectively. Baseline PTX3 level above the median was associated with death (p = 0.009, log-rank test) and the univariate Cox regression analysis revealed a significant association between PTX3 level upon admission and 180-day mortality (hazard ratio 2.60 (95 % confidence interval 1.28-5.29), p = 0.008). When adjusted for age, sex, chronic disease and Simplified Acute Physiology Score II, no significant association was found. Conclusions: High PTX3 level is associated with septic shock, amputation and risk of death in patients with NSTI, but it is not an independent predictor of 180-day mortality in this patient group.
Background Streptococcus pyogenes (group A streptococci; GAS) is the main causative pathogen of m... more Background Streptococcus pyogenes (group A streptococci; GAS) is the main causative pathogen of monomicrobial necrotizing soft tissue infections (NSTIs). To resist immuno-clearance, GAS adapt their genetic information and/or phenotype to the surrounding environment. Hyper-virulent streptococcal pyrogenic exotoxin B (SpeB) negative variants caused by covRS mutations are enriched during infection. A key driving force for this process is the bacterial Sda1 DNase. Methods Bacterial infiltration, immune cell influx, tissue necrosis and inflammation in patient´s biopsies were determined using immunohistochemistry. SpeB secretion and activity by GAS post infections or challenges with reactive agents were determined via Western blot or casein agar and proteolytic activity assays, respectively. Proteome of GAS single colonies and neutrophil secretome were profiled, using mass spectrometry. Results Here, we identify another strategy resulting in SpeB-negative variants, namely reversible abrog...
Purpose: To assess long-term outcomes of restrictive versus standard intravenous (IV) fluid thera... more Purpose: To assess long-term outcomes of restrictive versus standard intravenous (IV) fluid therapy in adult intensive care unit (ICU) patients with septic shock included in the European Conservative versus Liberal Approach to Fluid Therapy in Septic Shock in Intensive Care (CLASSIC) trial. Methods: We conducted the pre-planned analyses of mortality, health-related quality of life (HRQoL) using EuroQol (EQ)-5D-5L index values and EQ visual analogue scale (VAS), and cognitive function using Mini Montreal Cognitive Assessment (Mini MoCA) test at 1 year. Deceased patients were assigned numerical zero for HRQoL as a state equal to death and zero for cognitive function outcomes as worst possible score, and we used multiple imputation for missing data on HRQoL and cognitive function. Results: Among 1554 randomized patients, we obtained 1-year data on mortality in 97.9% of patients, HRQoL in 91.3%, and cognitive function in 86.3%. One-year mortality was 385/746 (51.3%) in the restrictive-fluid group versus 383/767 (49.9%) in the standard-fluid group, absolute risk difference 1.5%-points [99% confidence interval (CI) − 4.8 to
IntroductionDifferent outcomes are reported in randomised clinical trials (RCTs) in intensive car... more IntroductionDifferent outcomes are reported in randomised clinical trials (RCTs) in intensive care unit (ICU) patients, and no core outcome set (COS) is available for ICU patients in general. Accordingly, we aim to develop a COS for ICU patients in general.MethodsThe COS will be developed in accordance with the Core Outcome Measures in Effectiveness Trials (COMET) Handbook, using a modified Delphi consensus process and semi‐structured interviews involving adults who have survived acute admission to an ICU, family members, clinicians, researchers and other stakeholders. The modified Delphi process will include two steps. Step 1: conduction of a modified Delphi survey, developed and informed by combining the outputs of a literature search of outcomes in previous COSs and semi‐structured interviews with key stakeholders. We plan at least two survey rounds to obtain consensus and refine the COS. Step 2: a consensus process regarding instruments or definitions to be recommended for the m...
Go to publication entry in University of Southern Denmark's Research Portal Terms of use This wor... more Go to publication entry in University of Southern Denmark's Research Portal Terms of use This work is brought to you by the University of Southern Denmark. Unless otherwise specified it has been shared according to the terms for self-archiving. If no other license is stated, these terms apply: • You may download this work for personal use only. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying this open access version If you believe that this document breaches copyright please contact us providing details and we will investigate your claim.
Necrotising soft-tissue infections (NSTI) are characterised by necrosis, fast progression, and hi... more Necrotising soft-tissue infections (NSTI) are characterised by necrosis, fast progression, and high rates of morbidity and mortality, but our knowledge is primarily derived from small prospective studies and retrospective studies. Methods: We performed an international, multicentre, prospective cohort study of adults with NSTI describing patient's characteristics and associations between baseline variables and microbiological findings, amputation, and 90-day mortality. Results: We included 409 patients with NSTI; 402 were admitted to the ICU. Cardiovascular disease [169 patients (41%)] and diabetes [98 (24%)] were the most common comorbidities; 122 patients (30%) had no comorbidity. Before surgery, bruising of the skin [210 patients (51%)] and pain requiring opioids [172 (42%)] were common. The sites most commonly affected were the abdomen/ano-genital area [140 patients (34%)] and lower extremities [126 (31%)]. Monomicrobial infection was seen in 179 patients (44%). NSTI of the upper or lower extremities was associated with monomicrobial group A streptococcus (GAS) infection, and NSTI located to the abdomen/ano-genital area was associated with polymicrobial infection. Septic shock [202 patients (50%)] and acute kidney injury [82 (20%)] were common. Amputation occurred in 22% of patients with NSTI of an extremity and was associated with higher lactate level. All-cause 90-day mortality was 18% (95% CI 14-22); age and higher lactate levels were associated with increased mortality and GAS aetiology with decreased mortality. Conclusions: Patients with NSTI were heterogeneous regarding co-morbidities, initial symptoms, infectious localisation, and microbiological findings. Higher age and lactate levels were associated with increased mortality, and GAS infection with decreased mortality.
Patients in the intensive care unit (ICU) are often transfused with red blood cells (RBC). During... more Patients in the intensive care unit (ICU) are often transfused with red blood cells (RBC). During storage, the RBCs and storage medium undergo changes, which may have clinical consequences. Several trials now have assessed these consequences, and we reviewed the present evidence on the effects of shorter versus longer storage time of transfused RBCs on outcomes in ICU patients. We conducted a systematic review with meta-analyses and trial sequential analyses (TSA) of randomised clinical trials including adult ICU patients transfused with fresher versus older or standard issue blood. We included seven trials with a total of 18,283 randomised ICU patients; two trials of 7504 patients were judged to have low risk of bias. We observed no effects of fresher versus older blood on death (relative risk 1.04, 95% confidence interval (CI) 0.97-1.11; 7349 patients; TSA-adjusted CI 0.93-1.15), adverse events (1.26, 0.76-2.09; 7332 patients; TSA-adjusted CI 0.16-9.87) or post-transfusion infecti...
We assessed the effects of early goal-directed nutrition (EGDN) vs. standard nutritional care in ... more We assessed the effects of early goal-directed nutrition (EGDN) vs. standard nutritional care in adult intensive care unit (ICU) patients. Methods: We randomised acutely admitted, mechanically ventilated ICU patients expected to stay longer than 3 days in the ICU. In the EGDN group we estimated nutritional requirements by indirect calorimetry and 24-h urinary urea aiming at covering 100% of requirements from the first full trial day using enteral and parenteral nutrition. In the standard of care group we aimed at providing 25 kcal/kg/day by enteral nutrition. If this was not met by day 7, patients were supplemented with parenteral nutrition. The primary outcome was physical component summary (PCS) score of SF-36 at 6 months. We performed multiple imputation for data of the non-responders. Results: We randomised 203 patients and included 199 in the intention-to-treat analyses; baseline variables were reasonably balanced between the two groups. The EGDN group had less negative energy (p < 0.001) and protein (p < 0.001) balances in the ICU as compared to the standard of care group. The PCS score at 6 months did not differ between the two groups (mean difference 0.0, 95% CI −5.9 to 5.8, p = 0.99); neither did mortality, rates of organ failures, serious adverse reactions or infections in the ICU, length of ICU or hospital stay, or days alive without life support at 90 days. Conclusions: EGDN did not appear to affect physical quality of life at 6 months or other important outcomes as compared to standard nutrition care in acutely admitted, mechanically ventilated, adult ICU patients. Clinicaltrials.gov identifier no. NCT01372176.
APS Bulletin of the American Physical Society. 38th Annual Meeting of the Division of Atomic, Mol... more APS Bulletin of the American Physical Society. 38th Annual Meeting of the Division of Atomic, Molecular, and Optical Physics Volume 52, Number 7. TuesdaySaturday, June 59, 2007; Calgary, Alberta, Canada. ...
These infections are infrequent, but are associated with a significant health burden due to high ... more These infections are infrequent, but are associated with a significant health burden due to high mortality and risk of severe long-term disability as a consequence of extensive tissue loss or amputations (3-5). The progression of the disease is rapid, and early identification is therefore pivotal for improving the prognosis of affected patients. Currently, the initial diagnosis of NSTI is challenging due to the often vague symptoms during early stages, a heterogeneous patient group, and lack of specific diagnostic tools (6), which lead to misdiagnoses of NSTI in many cases (7). Still, doctors are advised that in case of NSTI suspicion, patients should be referred to surgical evaluation immediately (8). Previous efforts to improve the diagnosis of NSTIs led to the proposal of the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) CONCLUSIONS. This study identifies predictive biomarkers for NSTI clinical phenotypes of potential value for diagnostic, prognostic, and therapeutic approaches in NSTIs. TRIAL REGISTRATION. ClinicalTrials.gov NCT01790698.
Posesivni pridev u jeziku, ili jezicima Srba, Hrvata, Bošnjaka i Crnogoraca, pojava je, koja priv... more Posesivni pridev u jeziku, ili jezicima Srba, Hrvata, Bošnjaka i Crnogoraca, pojava je, koja privlači pažnju uglavnom zato što se ta vrsta prideva često pojavljuje, a i zato što je njihova upotreba nešto šira nego što bi se na prvi pogled očekivalo od jezičke po-jave sa tim nazivom. Ovde mislim na posesivne prideve upotreblje-ne kao u sledećim primerima: Knez Mihailova ulica, Trumanova jaja, Gordijev čvor, Venerin breg, Avalin vrh, Politikin zabavnik, vladin list, Jupiterovi mjeseci, sunčevi zraci, kućni prag, ružin miris, hrastova krošnja, lipova daščica, kaljeva peć, Tubakovi, Hercfeldova. Ovamo mogu ići i primeri kao: autorov stav, majčina tuga, paukova mreža, kada se u izrazu ne misli na određenog autora, majku ili pauka, tj. kada stav nije stav jednog određenog autora, kada tuga nije tuga jedne određene majke i kada mreža nije mreža jednog određenog pauka. Dakle, cilj ispitivanja jeste da se precizira u kojoj se meri pojavljuju formalno posesivni, a u kojoj meri semantički nepo...
Background Necrotising soft tissue infections (NSTIs) are rapidly progressing bacterial infecti... more Background Necrotising soft tissue infections (NSTIs) are rapidly progressing bacterial infections usually caused by either several pathogens in unison (polymicrobial infections) or Streptococcus pyogenes (mono-microbial infection). These infections are rare and are associated with high mortality rates. However, the underlying pathogenic mechanisms in this heterogeneous group remain elusive. Methods In this study, we built interactomes at both the population and individual levels consisting of host-pathogen interactions inferred from dual RNA-Seq gene transcriptomic profiles of the biopsies from NSTI patients. Results NSTI type-specific responses in the host were uncovered. The S. pyogenes mono-microbial subnetwork was enriched with host genes annotated with involved in cytokine production and regulation of response to stress. The polymicrobial network consisted of several significant associations between different species (S. pyogenes, Porphyromonas asaccharolytica and Escherichi...
Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differe... more Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ’s ability to activate target genes in a cellular context is currently poorly understood. Here we take advantage of two previously uncharacterized lipodystrophy mutations, R212Q and E379K, that are predicted to interfere with the interaction of the hinge of PPARγ with DNA and with the interaction of PPARγ ligand binding domain (LBD) with the DNA-binding domain (DBD) of the retinoid X receptor, respectively. Using biochemical and genome-wide approaches we show that these mutations impair PPARγ function on an overlapping subset of target enhancers. The hinge region-DNA interaction appears mostly important for binding and remodelling o...
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Papers by Martin Madsen