Preload Responsiveness in Patients With Acute Respiratory Distress Syndrome Managed With Extracorporeal Membrane Oxygenation.

A restrictive fluid strategy is recommended in patients with acute respiratory distress syndrome (ARDS) managed with venovenous extracorporeal membrane oxygenation (VV ECMO). However, there are no established predictors for preload responsiveness in these patients. In 20 ARDS patients managed with VV ECMO, transesophageal echocardiography was used to repeatedly evaluate dynamic parameters of the left (velocity and stroke volume variation) and right ventricular outflow tract (velocity [respiratory variations of the maximal Doppler velocity in the truncus pulmonalis {ΔV max TP}] and velocity time integral [respiratory variation of the velocity time integral measured in the truncus pulmonalis {ΔVTI_TP}] variation in the truncus pulmonalis), the diameter variation in the superior and inferior vena cava and stroke volume variation measured by pulse contour analysis (SVV_PCA). Patients were categorized as responders and nonresponders according to an increase in stroke volume measured by echocardiography during a Passive Leg Raise Test with a cutoff value ≥10%. The final analysis includes 86 measurements. Predictive values for preload responsiveness were found for ΔV max TP (area under the curve [AUC] of 0.64), ΔVTI_TP (AUC 0.67), and SVV_PCA (AUC 0.74). In conclusion, SVV_PCA and, to a lesser extent, ΔV max TP and ΔVTI_TP are the most accurate parameters to predict preload responsiveness in ARDS patients managed with VV ECMO. Transesophageal echocardiography offers no advantages over pulse contour analysis for predicting preload responsiveness and provides only intermittent monitoring and assessment.

Ground truth labels challenge the validity of sepsis consensus definitions in critical illness.

BACKGROUND: Sepsis is the leading cause of death in the intensive care unit (ICU). Expediting its diagnosis, largely determined by clinical assessment, improves survival. Predictive and explanatory modelling of sepsis in the critically ill commonly bases both outcome definition and predictions on clinical criteria for consensus definitions of sepsis, leading to circularity. As a remedy, we collected ground truth labels for sepsis. METHODS: In the Ground Truth for Sepsis Questionnaire (GTSQ), senior attending physicians in the ICU documented daily their opinion on each patient's condition regarding sepsis as a five-category working diagnosis and nine related items. Working diagnosis groups were described and compared and their SOFA-scores analyzed with a generalized linear mixed model. Agreement and discriminatory performance measures for clinical criteria of sepsis and GTSQ labels as reference class were derived. RESULTS: We analyzed 7291 questionnaires and 761 complete encounters from the first survey year. Editing rates for all items were > 90%, and responses were consistent with current understanding of critical illness pathophysiology, including sepsis pathogenesis. Interrater agreement for presence and absence of sepsis was almost perfect but only slight for suspected infection. ICU mortality was 19.5% in encounters with SIRS as the "worst" working diagnosis compared to 5.9% with sepsis and 5.9% with severe sepsis without differences in admission and maximum SOFA. Compared to sepsis, proportions of GTSQs with SIRS plus acute organ dysfunction were equal and macrocirculatory abnormalities higher (p < 0.0001). SIRS proportionally ranked above sepsis in daily assessment of illness severity (p < 0.0001). Separate analyses of neurosurgical referrals revealed similar differences. Discriminatory performance of Sepsis-1/2 and Sepsis-3 compared to GTSQ labels was similar with sensitivities around 70% and specificities 92%. Essentially no difference between the prevalence of SIRS and SOFA ≥ 2 yielded sensitivities and specificities for detecting sepsis onset close to 55% and 83%, respectively. CONCLUSIONS: GTSQ labels are a valid measure of sepsis in the ICU. They reveal suspicion of infection as an unclear clinical concept and refute an illness severity hierarchy in the SIRS-sepsis-severe sepsis spectrum. Ground truth challenges the accuracy of Sepsis-1/2 and Sepsis-3 in detecting sepsis onset. It is an indispensable intermediate step towards advancing diagnosis and therapy in the ICU and, potentially, other health care settings.

Maintaining oxygen delivery is crucial to prevent intestinal ischemia in critical ill patients.

BACKGROUND: Intestinal ischemia is a common complication with obscure pathophysiology in critically ill patients. Since insufficient delivery of oxygen is discussed, we investigated the influence of oxygen delivery, hemoglobin, arterial oxygen saturation, cardiac index and the systemic vascular resistance index on the development of intestinal ischemia. Furthermore, we evaluated the predictive power of elevated lactate levels for the diagnosis of intestinal ischemia. METHODS: In a retrospective case-control study data (mean oxygen delivery, minimum oxygen delivery, systemic vascular resistance index) of critical ill patients from 02/2009-07/2017 were analyzed using a proportional hazard model. General model fit and linearity were tested by likelihood ratio tests. The components of oxygen delivery (hemoglobin, arterial oxygen saturation and cardiac index) were individually tested in models. RESULTS: 59 out of 874 patients developed intestinal ischemia. A mean oxygen delivery less than 250ml/min/m2 (LRT vs. null model: p = 0.018; LRT for non-linearity: p = 0.012) as well as a minimum oxygen delivery less than 400ml/min/m2 (LRT vs null model: p = 0.016; LRT for linearity: p = 0.019) were associated with increased risk of the development of intestinal ischemia. We found no significant influence of hemoglobin, arterial oxygen saturation, cardiac index or systemic vascular resistance index. Receiver operating characteristics analysis for elevated lactate levels, pH, CO2 and central venous saturation was poor with an area under the receiver operating characteristic of 0.5324, 0.52, 0.6017 and 0.6786. CONCLUSION: There was a significant correlation for mean and minimum oxygen delivery with the incidence of intestinal ischemia for values below 250ml/min/m2 respectively 400ml/min/m2. Neither hemoglobin, arterial oxygen saturation, cardiac index, systemic vascular resistance index nor elevated lactate levels could be identified as individual risk factors.

A quantitative CT parameter for the assessment of pulmonary oedema in patients with acute respiratory distress syndrome.

OBJECTIVES: The aim of this study was to establish quantitative CT (qCT) parameters for pathophysiological understanding and clinical use in patients with acute respiratory distress syndrome (ARDS). The most promising parameter is introduced. MATERIALS AND METHODS: 28 intubated patients with ARDS obtained a conventional CT scan in end-expiratory breathhold within the first 48 hours after admission to intensive care unit (ICU). Following manual segmentation, 137 volume- and lung weight-associated qCT parameters were correlated with 71 clinical parameters such as blood gases, applied ventilation pressures, pulse contour cardiac output measurements and established status and prognosis scores (SOFA, SAPS II). RESULTS: Of all examined qCT parameters, excess lung weight (ELW), i.e. the difference between a patient's current lung weight and the virtual lung weight of a healthy person at the same height, displayed the most significant results. ELW correlated significantly with the amount of inflated lung tissue [%] (p<0.0001; r = -0.66) and was closely associated with the amount of extravascular lung water (EVLW) (p<0.0001; r = 0.72). More substantially than the oxygenation index (PaO2/FiO2) or any other clinical parameter it correlated with the patients' mean SOFA- (p<0.0001, r = 0.69) and SAPS II-Score (p = 0.0005, r = 0.62). Patients who did not survive intensive care treatment displayed higher values of ELW in the initial CT scans. CONCLUSIONS: ELW could serve as a non-invasive method to quantify the amount of pulmonary oedema. It might serve as an early radiological marker of severity in patients with ARDS.

Pull-out forces of headless compression screws in variations of synthetic bone models imitating different types of scaphoid fractures in good bone quality.

Screw osteosynthesis using headless compression screws has become the accepted gold standard for the surgical treatment of scaphoid fractures. Optimal screw specifications remain controversially discussed. We aimed to investigate the influence of bone model composition on screw stability tests using headless compression screws in different scaphoid fracture models. We conducted pull-out tests using Acutrak2®mini, HCS®, HKS®, HBS®, Herbert/Whipple® and Twinfix® screws. To imitate cortical and cancellous bone, two-layer polyurethane (PU) models with two distinct densities were produced. The cylinders were cut at different positions to replicate fracture localisations at increasing distances. The maximum pull-out force required to achieve up to 1 mm of pull-out distance (Nto 1 mm) was measured. Acutrak2®mini and HCS® followed by Twinfix® showed the greatest average pull-out forces. Nto 1 mm was, on average, greater in the cortico-cancellous model than in the cancellous cylinder with the Acutrak2®mini and the Herbert/Whipple® screws, while it was the least with the HBS® and the Twinfix® screws; there were also differences between the HCS® and HKS®. There were no differences between the different fracture simulations in the synthesis strength using either the HKS® or HBS®. The pull-out forces of the HCS® and Twinfix® remained high also in simulations with the smaller screw base fragments. Varying imitations of cancellous and cortico-cancellous bone and fracture localisation reveal important information about the ex vivo strength of screw syntheses. The grip of the cortical structure should be used with the screws that fit more firmly in cortico-cancellous bone.

Wrist movements induce torque and lever force in the scaphoid: an ex vivo study.

PURPOSE: We hypothesised that intercarpal K-wire fixation of adjacent carpal bones would reduce torque and lever force within a fractured scaphoid bone. METHODS: In eight cadaver wrists, a scaphoid osteotomy was stabilised using a locking nail, which also functioned as a sensor to measure isometric torque and lever forces between the fragments. The wrist was moved through 80% of full range of motion (ROM) to generate torque and force within the scaphoid. Testing was performed with and without loading of the wrist and K-wire stabilisation of the adjacent carpal bones. RESULTS: Average torque and lever force values were 49.6 ± 25.1 Nmm and 3.5 ± 0.9 N during extension and 41 ± 26.7 Nmm and 8.1 ± 2.8 N during flexion. Torque and lever force did not depend on scaphoid size, individual wrist ROM, or deviations of the sensor versus the anatomic axis. K-wire fixation did not produce significant changes in average torque and lever force values except with wrist radial abduction (P = 0.0485). Other than wrist extension, torque direction was not predictable. CONCLUSION: In unstable scaphoid fractures, we suggest securing rotational stability with selected implants for functional postoperative care. Wrist ROM within 20% extension and radial abduction to 50% flexion limit torque and lever force exacerbation between scaphoid fragments.

Impact of different consensus definition criteria on sepsis diagnosis in a cohort of critically ill patients-Insights from a new mathematical probabilistic approach to mortality-based validation of sepsis criteria.

BACKGROUND: Sepsis-3 definition uses SOFA score to discriminate sepsis from uncomplicated infection, replacing SIRS criteria that were criticized for being inaccurate. Eligibility of sepsis-3 criteria for sepsis diagnosis and the applied validation methodology using mortality as endpoint are topic of ongoing debate. We assessed the impact of different criteria on sepsis diagnosis in our ICU and devised a mathematical approach for mortality-based validation of sepsis criteria. As infectious status is often unclear at clinical deterioration, we integrated non-infected patients into analysis. METHODS: Suspected infection, SOFA and SIRS were captured for an ICU cohort of a university center over one year. For raw scores (SIRS/SOFA) and sepsis criteria (SIRS≥2/SOFA≥2/SOFA_change≥2) frequencies and associations with in-hospital mortality were assessed. Using a mathematical approach, we estimated the correlation between sepsis and in-hospital mortality serving as reference for evaluation of observed mortality correlations of sepsis criteria. RESULTS: Of 791 patients, 369 (47%) were infected and 422 (53%) non-infected, with an in-hospital mortality of 39% and 15%. SIRS≥2 indicated sepsis in 90% of infected patients, SOFA≥2 in 99% and SOFA_change≥2 in 77%. In non-infected patients, SIRS, SOFA and SOFA_change were ≥2 in 78%, 88% and 58%. In AUROC analyses neither SOFA nor SIRS displayed superior mortality discrimination in infected compared to non-infected patients. The mathematically estimated correlation of sepsis and in-hospital mortality was 0.10 in infected and 0 in non-infected patients. Among sepsis criteria, solely SIRS≥2 agreed with expected correlations in both subgroups (infected: r = 0.19; non-infected: r = 0.02). CONCLUSIONS: SOFA≥2 yielded a more liberal sepsis diagnosis than SIRS≥2. None of the criteria showed an infection specific occurrence that would be essential for reliable sepsis detection. However, SIRS≥2 matched the mortality association pattern of a valid sepsis criterion, whereas SOFA-based criteria did not. With this study, we establish a mathematical approach to mortality-based evaluation of sepsis criteria.

Does the choice of intraoperative fluid modify abdominal aneurysm repair outcomes?: A cohort analysis.

Intraoperatively administered hydroxyethyl starch could be a risk indicator for postoperative acute kidney injury (AKI) in vascular surgical patients.In a single-center retrospective cohort analysis, we assessed the impact of hydroxyethyl starch and other risk indicators on AKI and mortality in 1095 patients undergoing elective open abdominal aneurysm repair (AAA-OR) or endovascular aortic repair (EVAR). We established logistic regression models to determine the effect of various risk indicators, including hydroxyethyl starch, on AKI, as well as Cox proportional hazard models to assess the effect on mortality.The use of intravenous hydroxyethyl starch was not associated with an increased risk of AKI or mortality. Patients undergoing EVAR were less likely to develop AKI (4% vs 18%). Multivariate risk indicators associated for AKI included suprarenal or pararenal aortic cross-clamp [odds ratio (OR), 4.44; 95% confidence interval (95% CI), 2.538-7.784; P < .001] and procedure length (OR, 1.005; 95% CI, 1.003-1.007; P < .001), and favored EVAR (OR, 0.351; 95% CI, 0.118-0.654; P < .01). Main multivariate risk indicators associated with mortality included patients needing an urgent procedure [hazard ratio (HR), 2.294; 95% CI, 1.541-3.413; P < .001], those with suprarenal or pararenal aortic cross-clamp (HR, 1.756; 95% CI, 1.247-2.472; P < .01), and patients undergoing EVAR (HR, 1.654; 95% CI, 1.292-2.118; P < .001).We found neither a benefit nor a negative effect of hydroxyethyl starch on the risk of AKI or mortality. Instead, other variables and comorbidities were found to be relevant for the development of postoperative AKI and survival. Nevertheless, clinicians should be aware of the high risk of postoperative AKI, particularly among those undergoing AAA-OR procedures.

Is antibacterial treatment intensity lower in elderly patients? A retrospective cohort study in a German surgical intensive care unit.

BACKGROUND: Demographic change concurrent with medical progress leads to an increasing number of elderly patients in intensive care units (ICUs). Antibacterial treatment is an important, often life-saving, aspect of intensive care but burdened by the associated antimicrobial resistance risk. Elderly patients are simultaneously at greater risk of infections and may be more restrictively treated because, generally, treatment intensity declines with age. We therefore described utilization of antibacterials in ICU patients older and younger than 80 years and examined differences in the intensity of antibacterial therapy between both groups. METHODS: We analysed 17,464 valid admissions from the electronic patient data management system of our surgical ICU from April 2006 - October 2013. Antibacterial treatment rates were defined as days of treatment (exposed patient days) relative to patient days of ICU stay and calculated for old and young patients. Rates were compared in zero-inflated Poisson regression models adjusted for patients' sex, mean SAPS II- and TISS-scores, and calendar years yielding adjusted rate ratios (aRRs). Rate ratios exceeding 1 represent higher rates in old patients reflecting greater treatment intensity in old compared to younger patients. RESULTS: Observed antibacterial treatment rates were lower in patients 80 years and older compared to younger patients (30.97 and 39.73 exposed patient days per 100 patient days in the ICU, respectively). No difference in treatment intensity, however, was found from zero-inflated Poisson regression models permitting more adequate consideration of patient days with low treatment probability: for all antibacterials the adjusted rate ratio (aRR) was 1.02 (95%CI: 0.98-1.07). Treatment intensities were higher in elderly patients for penicillins (aRR 1.37 (95%CI: 1.26-1.48)), cephalosporins (aRR 1.20 (95%CI: 1.09-1.31)), carbapenems (aRR 1.35 (95%CI: 1.20-1.50)), fluoroquinolones (aRR 1.17 (95%CI: 1.05-1.30), and imidazoles (aRR 1.34 (95%CI: 1.23-1.46)). CONCLUSIONS: Elderly patients were generally less likely to be treated with antibacterials. This observation, however, did not persist in patients with comparable treatment probability. In these, antibacterial treatment intensity did not differ between younger and older ICU patients, for some antibacterial classes treatment intensity was even higher in the latter. Patient-level covariates are instrumental for a nuanced evaluation of age-effects in antibacterial treatment in the ICU.

Impact of CPAP on Forehead Near-infrared Spectroscopy Measurements in Patients With Acute Respiratory Failure: Truth or Illusion.

BACKGROUND: Critically ill patients with acute respiratory failure admitted to an intensive care unit are at high risk for cerebral hypoxia. We investigated the impact of continuous positive airway pressure (CPAP) therapy on regional cerebral tissue oxygenation (rSO2). MATERIALS AND METHODS: In total, 40 extubated surgical intensive care unit patients requiring classic oxygen therapy (COT) for acute respiratory failure were examined. Near-infrared spectroscopy (INVOS 5100C, Covidien) was used for 30 minutes to detect bilateral rSO2 during COT via facemask (6 L/min) and CPAP therapy (40% fraction of inspired oxygen, 8 cm H2O CPAP) using a randomized crossover study design. Patients served as their own control. Continuous hemodynamic routine monitoring and blood gas analysis were performed. The effect of CPAP therapy on rSO2 and influence of assessed covariables were investigated using a mixed linear model. RESULTS: Median rSO2 increased from 57.9% (95% confidence interval [CI], 54.2-61.5) during COT to 62.8% (95% CI, 59.2-66.5) during CPAP therapy (P<0.0001). The estimated difference from the mixed model between COT and CPAP is -5.0 (95% CI, -6.3 to -3.7). Median arterial partial pressure of carbon dioxide decreased from 47.8±5.1 mm Hg during COT to 43.1±5 mm Hg during CPAP (P<0.001), whereas arterial partial pressure of oxygen remained unchanged (P=0.329). In total, 23% of patients had SO2 levels <50%, with a higher prevalence under COT. CONCLUSIONS: Our results reveal that CPAP therapy compared with COT may influence rSO2 in patients with acute respiratory failure. However, the cause of the rSO2 increase following CPAP application remains to be elucidated, and the accuracy of cerebral oximetry during CPAP therapy in patients with acute respiratory failure remains questionable.

Positive end-expiratory pressure titrated according to respiratory system mechanics or to ARDSNetwork table did not guarantee positive end-expiratory transpulmonary pressure in acute respiratory distress syndrome.

PURPOSE: Pulmonary recruitment and positive end-expiratory pressure (PEEP) titrated according to minimal static elastance of the respiratory system (PEEPEstat,RS) compared to PEEP set according to the ARDSNetwork table (PEEPARDSNetwork) as a strategy to prevent ventilator-associated lung injury (VALI) in patients with acute respiratory distress syndrome (ARDS) increases mortality. Alternatively, avoiding negative end-expiratory transpulmonary pressure has been discussed as superior PEEP titration strategy. Therefore, we tested whether PEEPEstat,RS or PEEPARDSNetwork prevent negative end-expiratory transpulmonary pressure in ARDS patients. MATERIAL AND METHODS: Thirteen patients with moderate to severe ARDS were studied at PEEPARDSNetwork versus PEEPEstat,RS. Patients were then grouped post hoc according to the end-expiratory transpulmonary pressure (positive or negative). RESULTS: 7 out of 13 patients showed negative end-expiratory transpulmonary pressures (Ptp-) with both strategies (PEEPARDSNetwork: - 5.4 ±â€¯3.5 vs. 2.2 ±â€¯3.7 cm H2O, p = .005; PEEPEstat,RS: - 3.6 ±â€¯1.5 vs. 3.5 ±â€¯3.3 cm H2O, p < .001). Ptp- was associated with higher intra-abdominal pressure and lower end-expiratory lung volume with both PEEP strategies. CONCLUSIONS: In patients with moderate-to-severe ARDS, PEEP titrated according to the minimal static elastance of the respiratory system or according to the ARDSNetwork table did not prevent negative end-expiratory transpulmonary pressure.

Quality of life and functional assessment of facial palsy patients: A questionnaire study.

BACKGROUND: Facial palsy leads to functional and aesthetic deficits, which impair the quality of life of affected patients. General health-related and disease-specific questionnaires are available for quality of life assessment. In this study, observer-based analysis of facial function (Sunnybrook Facial Grading Scale) was compared patient-based to facial palsy-specific gradings (Facial Clinimetric Evaluation Scale and Facial Disability Index), and general health-related quality of life questionnaires (SF-36). We hypothesized that only facial palsy-specific instruments capture functional and social impairments of affected patients. METHODS: Thirty facial palsy patients treated at a tertiary referral centre were included in this study. Inclusion criteria were unilateral facial palsy with stable facial function, age over 18 years and fluency in German. Facial function was assessed with general and disease-specific patient-reported outcome measures and subsequently evaluated by the treating facial plastic surgeon. Statistical analysis included descriptive statistics for all assessed measurements. Correlations were calculated to compare general and facial palsy-specific instruments, as well as observer-based grading. RESULTS: Observer-based evaluation of facial function correlated well to the patients-based assessment of physical function, however social subscores did not correlate demonstrating the limited correlation of patient distress and facial nerve impairment. Physical function scores of disease-specific instruments did not correlate with general health assessment scores, while social function scores showed moderate to good correlations. CONCLUSION: Validated disease-specific instruments are essential for the assessment of facial palsy patients. Patient-reported outcome measures like the FaCE Scale and the Facial Disability Index should be applied in addition to standardized observer-based ratings to capture the patients' perspective on functional and social impairments associated with facial palsy to fully assess the burden of disease.

Detection of inspiratory recruitment of atelectasis by automated lung sound analysis as compared to four-dimensional computed tomography in a porcine lung injury model.

BACKGROUND: Cyclic recruitment and de-recruitment of atelectasis (c-R/D) is a contributor to ventilator-induced lung injury (VILI). Bedside detection of this dynamic process could improve ventilator management. This study investigated the potential of automated lung sound analysis to detect c-R/D as compared to four-dimensional computed tomography (4DCT). METHODS: In ten piglets (25 ± 2 kg), acoustic measurements from 34 thoracic piezoelectric sensors (Meditron ASA, Norway) were performed, time synchronized to 4DCT scans, at positive end-expiratory pressures of 0, 5, 10, and 15 cmH2O during mechanical ventilation, before and after induction of c-R/D by surfactant washout. 4DCT was post-processed for within-breath variation in atelectatic volume (Δ atelectasis) as a measure of c-R/D. Sound waveforms were evaluated for: 1) dynamic crackle energy (dCE): filtered crackle sounds (600-700 Hz); 2) fast Fourier transform area (FFT area): spectral content above 500 Hz in frequency and above -70 dB in amplitude in proportion to the total amount of sound above -70 dB amplitude; and 3) dynamic spectral coherence (dSC): variation in acoustical homogeneity over time. Parameters were analyzed for global, nondependent, central, and dependent lung areas. RESULTS: In healthy lungs, negligible values of Δ atelectasis, dCE, and FFT area occurred. In lavage lung injury, the novel dCE parameter showed the best correlation to Δ atelectasis in dependent lung areas (R2 = 0.88) where c-R/D took place. dCE was superior to FFT area analysis for each lung region examined. The analysis of dSC could predict the lung regions where c-R/D originated. CONCLUSIONS: c-R/D is associated with the occurrence of fine crackle sounds as demonstrated by dCE analysis. Standardized computer-assisted analysis of dCE and dSC seems to be a promising method for depicting c-R/D.

Bayesian and frequentist analysis of an Austrian genome-wide association study of colorectal cancer and advanced adenomas.

Most genome-wide association studies (GWAS) were analyzed using single marker tests in combination with stringent correction procedures for multiple testing. Thus, a substantial proportion of associated single nucleotide polymorphisms (SNPs) remained undetected and may account for missing heritability in complex traits. Model selection procedures present a powerful alternative to identify associated SNPs in high-dimensional settings. In this GWAS including 1060 colorectal cancer cases, 689 cases of advanced colorectal adenomas and 4367 controls we pursued a dual approach to investigate genome-wide associations with disease risk applying both, single marker analysis and model selection based on the modified Bayesian information criterion, mBIC2, implemented in the software package MOSGWA. For different case-control comparisons, we report models including between 1-14 candidate SNPs. A genome-wide significant association of rs17659990 (P=5.43×10-9, DOCK3, chromosome 3p21.2) with colorectal cancer risk was observed. Furthermore, 56 SNPs known to influence susceptibility to colorectal cancer and advanced adenoma were tested in a hypothesis-driven approach and several of them were found to be relevant in our Austrian cohort. After correction for multiple testing (α=8.9×10-4), the most significant associations were observed for SNPs rs10505477 (P=6.08×10-4) and rs6983267 (P=7.35×10-4) of CASC8, rs3802842 (P=8.98×10-5, COLCA1,2), and rs12953717 (P=4.64×10-4, SMAD7). All previously unreported SNPs demand replication in additional samples. Reanalysis of existing GWAS datasets using model selection as tool to detect SNPs associated with a complex trait may present a promising resource to identify further genetic risk variants not only for colorectal cancer.

Retinal pigment epithelial features indicative of neovascular progression in age-related macular degeneration.

BACKGROUND/AIMS: To identify characteristic retinal pigment epithelium (RPE) changes in fellow eyes of patients with neovascular age-related macular degeneration (nAMD) using polarisation-sensitive optical coherence tomography (PS-OCT). METHODS: Thirty-one fellow eyes of 31 patients with unilateral nAMD were evaluated in this cohort study of a prospective interventional trial. PS-OCT as well as conventional imaging including spectral-domain (SD)-OCT and fluorescein angiography (FA) were performed using a standardised protocol. Monitoring visits were performed continuously at 1-month intervals. Morphological RPE features associated with the development of choroidal neovascularisation (CNV) were systematically analysed. RESULTS: Mean follow-up was 29 months (±17, SD). Thirteen (42%) of 31 eyes developed de novo CNV: 9 eyes type I CNV, 2 eyes type II CNV, 2 eyes a retinal angiomatous proliferation lesion. RPE thickening and reticular pseudodrusen (RPD) were observed significantly more often in eyes that developed CNV than in eyes without CNV development (p<0.01). Monthly increase in drusen volume was higher in the CNV group with a median increase of +2.2% in area and +2.9% in volume compared with +0.8% and +0.6% in the non-progressing group. RPE migration within the neurosensory retina and at the level of the RPE resulting in RPE thickening was seen topographically and chronologically associated with CNV development. CONCLUSIONS: Conversion to CNV is associated with RPE-related changes such as RPE migration, RPE thickening, drusen volume or the presence of RPD. Early detection of these features may allow more efficient screening in risk eyes and timely vision-preserving treatment in eyes developing neovascular disease.

The colonization with Candida species is more harmful in the second trimester of pregnancy.

PURPOSE: Vaginal colonization with Candida species (spp.) during pregnancy has been associated with impaired pregnancy outcomes. There is a reduction in spontaneous preterm birth among women with recurrent asymptomatic colonization of Candida who were treated with clotrimazole. This study aimed to evaluate the impact of the trimester of vulvovaginal colonization with Candida species. METHODS: Data from all women, who were tested positive for the vaginal colonization with Candida spp. during the first or second trimester of pregnancy, and who registered for a planned birth at our tertiary referral center between 2005 and 2014 were retrospectively analyzed. Their preterm birth rate served as the primary outcome variable. Secondary outcome variables were neonatal birthweight and Apgar score. RESULTS: Overall, 1066 women were eligible for the study. In 673 women (63%), who were diagnosed with Candida spp. during the first trimester of pregnancy, the rate of preterm birth was 10% (N = 64). In 393 women (37%), who were diagnosed with candidosis during the second trimester, the preterm birth rate was 18% (N = 71; p = 0.0002). Neonates of women, who presented with vulvovaginal candidosis during the first trimester, had a mean birthweight of 3243 g, compared to 2989 g in the group with a second trimester colonization (p < 0.0001). CONCLUSION: Women who are colonized with Candida spp. during the second trimester of pregnancy have higher rates of preterm birth and lower neonatal birthweight than those who are colonized during the first trimester of their pregnancy. Screening programs for asymptomatic Candida colonization should take this information into account.

Evaluation of the vaginal flora in pregnant women receiving opioid maintenance therapy: a matched case-control study.

BACKGROUND: Vaginal infections are a risk factor for preterm delivery. In this study, we sought to evaluate the vaginal flora of pregnant women receiving opioid maintenance therapy (OMT) in comparison to non-dependent, non-maintained controls. METHODS: A total of 3763 women with singleton pregnancies who underwent routine screening for asymptomatic vaginal infections between 10 + 0 and 16 + 0 gestational weeks were examined. Vaginal smears were Gram-stained, and microscopically evaluated for bacterial vaginosis, candidiasis, and trichomoniasis. In a retrospective manner, data of 132 women receiving OMT (cases) were matched for age, ethnicity, parity, education, previous preterm delivery, and smoking status to the data of 3631 controls. The vaginal flora at antenatal screening served as the primary outcome measure. Secondary outcome measures were gestational age and birth weight. RESULTS: In the OMT group, 62/132 (47 %) pregnant women received methadone, 39/132 (29.5 %) buprenorphine, and 31/132 (23.5 %) slow-release oral morphine. Normal or intermediate flora was found in 72/132 OMT women (54.5 %) and 2865/3631 controls [78.9 %; OR 0.49 (95 % CI, 0.33-0.71); p < 0.001]. Candidiasis occurred more frequently in OMT women than in controls [OR 2.11 (95 % CI, 1.26-3.27); p < 0.001]. Findings were inconclusive regarding bacterial vaginosis (± candidiasis) and trichomoniasis. Compared to infants of the control group, those of women with OMT had a lower mean birth weight [MD -165.3 g (95 % CI, -283.6 to -46.9); p = 0.006]. CONCLUSIONS: Pregnant women with OMT are at risk for asymptomatic vaginal infections. As recurrent candidiasis is associated with preterm delivery, the vulnerability of this patient population should lead to consequent antenatal infection screening at early gestation.

Rotational Stability of Scaphoid Osteosyntheses: An In Vitro Comparison of Small Fragment Cannulated Screws to Novel Bone Screw Sets.

BACKGROUND: The current standard of care for operative repair of scaphoid fractures involves reduction and internal fixation with a single headless compression screw. However, a compression screw in isolation does not necessarily control rotational stability at a fracture or nonunion site. The single screw provides rotational control through friction and bone interdigitation from compression at the fracture site. We hypothesize that osteosyntheses with novel bone screw sets (BSS) equipped with anti-rotational elements provide improved rotational stability. METHODS: Stability of osteosynthesis under increasing cyclic torsional loading was investigated on osteotomized cadaveric scaphoids. Two novel prototype BSS, oblique type (BSS-obl.) and longitudinal type (BSS-long.) were compared to three conventional screws: Acutrak2®mini, HCS®3.0 and Twinfix®. Biomechanical tests were performed on scaphoids from single donors in paired comparison and analyzed by balanced incomplete random block design. Loading was increased by 50 mNm increments with 1,000 cycles per torque level and repeated until a rotational clearance of 10°. Primary outcome measure was the number of cycles to 10° clearance, secondary outcome measure was the maximum rotational clearance for each torque level. FINDINGS: BSS-obl. performed significantly better than Acutrak2®mini and HCS® (p = 0.015, p<0.0001). BSS-long. performed significantly better than HCS® (p = 0.010). No significant difference in performance between BSS-obl. and BSS-long. (p = 0.361), between BSS obl. and Twinfix® (p = 0.50) and BSS long. and Twinfix® (p = 0.667) was detected. Within the torque range up to 200 mNm, four of 21 (19%) BSS-long. and four of 21 (19%) BSS-obl. preparations showed early failure. The same loading led to early failure in four (29%) Twinfix®, seven (50%) Acutrak2®mini and 10 (71%) HCS® of 14 screw samples, respectively. CONCLUSIONS: For both BSS and to a lesser extent for Twinfix® (as dual-component screw), higher rotational stabilities were identified in comparison to single component headless compression screws.

Risk of Vaginal Infections at Early Gestation in Patients with Diabetic Conditions during Pregnancy: A Retrospective Cohort Study.

Pregnant women with gestational diabetes mellitus (GDM) are reported to be at increased risk for infections of the genital tract. This study aimed to compare the prevalence of asymptomatic bacterial vaginosis (BV) and Candida colonization at early gestation between pregnant women with and without diabetic conditions during pregnancy. We included data from 8, 486 singleton pregnancies that underwent an antenatal infection screen-and-treat programme at our department. All women with GDM or pre-existing diabetes were retrospectively assigned to the diabetic group (DIAB), whereas non-diabetic women served as controls (CON). Prevalence for BV and Candida colonization was 9% and 14% in the DIAB group, and 9% and 13% in the CON group, respectively (n.s.). No significant difference regarding stillbirth and preterm delivery (PTD), defined as a delivery earlier than 37 + 0 (37 weeks plus 0 days) weeks of gestation was found. We could not find an increased risk of colonization with vaginal pathogens at early gestation in pregnant women with diabetes, compared to non-diabetic women. Large prospective studies are needed to evaluate the long-term risk of colonization with vaginal pathogens during the course of pregnancy in these women.

Acetylic Salicylic Acid for the Treatment of Chronic Obstructive Pulmonary Disease: A Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the world. Current treatment options provide relief from symptoms rather than stop disease progress. Results from various preclinical experiments suggest a causal benefit of acetylic salicylic acid (ASA) in the treatment of COPD. Hence, this study set out to examine the clinical benefit of ASA in the treatment of COPD. COPD patients (Global Initiative for Chronic Obstructive Lung Disease II-III) received either once daily 500 mg of ASA or a matching placebo for 12 weeks in addition to their preexisting medication. Clinical response in terms of pulmonary function testing, symptomatic response and adverse events were assessed. After 40 subjects were included, the study was stopped and an interim analysis was performed. The addition of ASA to the treatment of subjects with COPD had no effect on clinical features or spirometry (forced expiratory volume in 1 s: F = 0.49, d.f.1 = 1, d.f.2 = 74, p = 0.486) and non-pulmonary markers. COPD represents a complex of different diseases, although currently classified mainly by markers of lung function. If future trials test the effects of anti-inflammatory therapies, COPD subpopulations should be predefined based on inflammatory features.