Effects of hyperoxemia in patients with sepsis - A post-hoc analysis of a multicentre randomized clinical trial.

BACKGROUND: Administration of supplemental oxygen is a life-saving treatment in critically ill patients. Still, optimal dosing remains unclear during sepsis. The aim of this post-hoc analysis was to assess the association between hyperoxemia and 90-day mortality in a large cohort of septic patients. METHODS: This is a post-hoc analysis of the Albumin Italian Outcome Sepsis (ALBIOS) randomized controlled trial (RCT). Patients with sepsis who survived the first 48 h since randomization were included and stratified into two groups according to their average PaO2 levels during the first 48 h (PaO2 0-48 h). The cut-off value was established at 100 mmHg (average PaO2 0-48 h >100 mmHg: hyperoxemia group; PaO2 0-48h≤100: normoxemia group). The primary outcome was 90-day mortality. RESULTS: 1632 patients were included in this analysis (661 patients in the hyperoxemia group, 971 patients in the normoxemia group). Concerning the primary outcome, 344 (35.4%) patients in the hyperoxemia group vs. 236 (35.7%) in the normoxemia group had died within 90 days from randomization (p = 0.909). No association was found after adjusting for confounders (HR 0.87; CI [95%] 0.736-1.028, p = 0.102) or after excluding patients with hypoxemia at enrollment, patients with lung infection or including post-surgical patients only. Conversely, we found an association between lower risk of 90-day mortality and hyperoxemia in the subgroup including patients who had the lung as primary site of infection (HR 0.72; CI [95%] 0.565-0.918). Mortality at 28 days, ICU mortality, incidence of acute kidney injury, use of renal replacement therapy, days to suspension of vasopressor or inotropic agents, and resolution of primary and secondary infections did not differ significantly. Duration of mechanical ventilation and length of stay in ICU were significantly longer in patients with hyperoxemia. CONCLUSIONS: In a post-hoc analysis of a RCT enrolling septic patients, hyperoxemia as average PaO2>100 mmHg during the first 48 h was not associated with patients' survival.

PCSK9 is associated with mortality in patients with septic shock: data from the ALBIOS study.

BACKGROUND: Pro-protein convertase subtilisin/kexin 9 (PCSK9) is a proenzyme primarily known to regulate low-density lipoprotein receptor re-uptake on hepatocytes. Whether PCSK9 can concurrently trigger inflammation or not remains unclear. Here, we investigated the potential association between circulating levels of PCSK9 and mortality in patients with severe sepsis or septic shock. METHODS: Plasma PCSK9 levels at days 1, 2 and 7 were measured in 958 patients with severe sepsis or septic shock previously enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) trial. Correlations between levels of PCSK9 and pentraxin 3 (PTX3), a biomarker of disease severity, were evaluated with ranked Spearman's coefficients. Cox proportional hazards models were used to assess the association of PCSK9 levels at day 1 with 28- and 90-day mortality. RESULTS: Median plasma PCSK9 levels were 278 [182-452] ng mL-1 on day 1. PCSK9 correlated positively with PTX3 at the three time-points, and patients with septic shock within the first quartile of PCSK9 showed higher levels of PTX3. Similar mortality rates were observed in patients with severe sepsis across PCSK9 quartiles. Patients with septic shock with lower PCSK9 levels on day 1 (within the first quartile) showed the highest 28- and 90-day mortality rate as compared to other quartiles. CONCLUSION: In our sub-analysis of the ALBIOS trial, we found that patients with septic shock presenting with lower plasma PCSK9 levels experienced higher mortality rate. Further studies are warranted to better evaluate the pathophysiological role of PCSK9 in sepsis.

Serum fatty acid chain length associates with prevalent symptomatic end-stage osteoarthritis, independent of BMI.

Higher body mass index (BMI) is associated with osteoarthritis (OA) in both weight-bearing and non-weight-bearing joints, suggesting a link between OA and poor metabolic health beyond mechanical loading. This risk may be influenced by systemic factors accompanying BMI. Fluctuations in concentrations of metabolites may mark or even contribute to development of OA. This study explores the association of metabolites with radiographic knee/hip OA prevalence and progression. A 1H-NMR-metabolomics assay was performed on plasma samples of 1564 cases for prevalent OA and 2,125 controls collected from the Rotterdam Study, CHECK, GARP/NORREF and LUMC-arthroplasty cohorts. OA prevalence and 5 to 10 year progression was assessed by means of Kellgren-Lawrence (KL) score and the OARSI-atlas. End-stage knee/hip OA (TJA) was defined as indication for arthroplasty surgery. Controls did not have OA at baseline or follow-up. Principal component analysis of 227 metabolites demonstrated 23 factors, of which 19 remained interpretable after quality-control. Associations of factor scores with OA definitions were investigated with logistic regression. Fatty acids chain length (FALen), which was included in two factors which associated with TJA, was individually associated with both overall OA as well as TJA. Increased Fatty Acid chain Length is associated with OA.

Physical activity in patients with systemic sclerosis.

OBJECTIVES: To compare self-reported levels of physical activity (PA) of systemic sclerosis (SSc) patients with the general population. To evaluate in SSc patients factors associated with PA levels and needs and preferences regarding PA. METHODS: Fifty nine SSc patients completed the Short QUestionnaire to ASsess Health-Enhancing PA. The proportion of patients meeting the Dutch Recommendation for PA (= moderate PA for 30 min on ≥ 5 days/week) and total minutes of PA per week were calculated and compared with similar data from the Dutch population. Characteristics were univariately and multivariately compared between patients with low and high PA levels (either ≤ or > mean minutes/week of the Dutch population). Needs and preferences regarding PA promotion and guidance related to exercise were assessed by questionnaires. RESULTS: Stratified for age (< 55 or ≥ 55 years) and gender, the proportion SSc patients meeting the Dutch recommendation for PA was not significantly different from the Dutch population. The total minutes of PA per week was significantly lower among SSc patients (1704 vs. 2614, P < 0.001). Multivariable analyses showed that in SSc patients the male gender, scleroderma health assessment questionnaire (SHAQ) and lack of energy were significantly associated with lower PA levels (P = 0.007; P = 0.042; P = 0.025). Two-third of patients required more information about PA. CONCLUSION: In SSc patients, the total minutes of PA per week are significantly lower compared to the general population. The male gender, functional ability as reflected by SHAQ and lack of energy seem to interfere with PA. These results might guide health professionals in providing their patients with appropriate information on PA.

[Increased mortality in metal-on-metal versus non-metal-on-metal primary total hip arthroplasty at 10 years and longer follow-up: a systematic review and meta-analysis]. / Verhoogde mortaliteit bij patiënten met een metaal-op-metaal heupprothese.

OBJECTIVE: To determine the mortality and the morbidity in patients with metal-on-metal articulations (MOM THA) when compared to patients with non-metal-on-metal articulations (non-MOM THA) after primary total hip arthroplasty. DESIGN: Systematic review, meta-analyses and meta-regression (registration: PROSPERO 2014:CRD42014007417). METHOD: Search of PubMed, MEDLINE, EMBASE, Web of Science, Cochrane, CINAHL, AcademicSearchPremier, ScienceDirect, Wiley and clinical trial registers. We included randomised controlled trials and observational studies of primary total hip arthroplasty comparing MOM THA with non-MOM THA. We used meta-regression to identify and evaluate potential modifying variables such as follow-up duration. RESULTS: Forty-seven studies were included, comprising over 4,000 THA in randomised trials and over 500,000 THA in observational studies. For mortality, random effects analysis revealed a higher pooled risk difference (RD) of 0.7% (95%-CI: 0.0-2.3%; I-square 42%); the heterogeneity was explained by differences in follow-up. When restricted to studies with long term follow-up (i.e. 10 years or more), the RD for mortality was 8,5% (95%-CI: 5,8-11,2). Further subgroup analyses and meta-regression random effects models revealed no evidence for other modifying variables (study level covariates, e.g. resurfacing vs. non-resurfacing MOM) than follow-up duration. CONCLUSION: Meta-analysis suggests there may be an increased long-term risk of mortality associated with MOM THA compared to patients with non-MOM THA.

Patients who underwent total hip or knee arthroplasty are more physically active than the general Dutch population.

Total hip arthroplasty (THA) and total knee arthroplasty (TKA) bring relief of pain and functional disability to patients with end-stage osteoarthritis, and however, the literature on their impact on patients' level of physical activity (PA) is scarce. Cross-sectional study in patients who underwent THA/TKA surgery in the preceding 6-22 months and a random sample of persons aged >40 years from the Dutch general population, participating in a national survey. PA in minutes per week (min/week) and adherence to the Dutch recommendation for PA (NNGB yes/no) were measured by the short questionnaire to assess health-enhancing PA. Multivariable linear (total min/week) and logistic regression analyses (meeting recommendations PA), adjusting for confounders, were performed for THA and TKA separately. In total, 258 THA [62.3% female, aged 69.4 (9.1)] and 221 TKA [65.7% female, aged 69.5 (8.9)] patients and 4373 persons from the Dutch general population [51.4% female, aged 58.9 (11.6)] were included. The presence of THA was associated after adjusting for age, sex, BMI education and musculoskeletal comorbidities, with more total min/week spent on PA (THA 13.8% increase, 95% CI 1.6-27.6%), whilst both TJA groups were associated with adhering to NNGB (THA: OR 1.79, 95% CI 1.26-2.56; TKA: OR 1.73, 95% CI 1.20-2.51). As this study used questionnaires to compare the PA of THA/TKA patients to the general population, some recall and selection bias might have been induced. After surgery, overall, TJA patients are more likely to adhere NNGB than a representative sample of persons >40 years from the Dutch general population.

Increased Mortality in Metal-on-Metal versus Non-Metal-on-Metal Primary Total Hip Arthroplasty at 10 Years and Longer Follow-Up: A Systematic Review and Meta-Analysis.

IMPORTANCE: There are concerns about increased mortality in patients with metal-on-metal bearings in total hip arthroplasty (THA). OBJECTIVE: To determine the mortality and the morbidity in patients with metal-on-metal articulations (MOM THA) compared to patients with non-metal-on-metal articulations (non-MOM THA) after primary total hip arthroplasty. DATA SOURCES: Search of PubMed, MEDLINE, EMBASE, Web of Science, Cochrane, CINAHL, AcademicSearchPremier, ScienceDirect, Wiley and clinical trial registers through March 2015, augmented by a hand search of references from the included articles. No language restrictions were applied. STUDY SELECTION: Two reviewers screened and identified randomised controlled trials and observational studies of primary total hip arthroplasty comparing MOM THA with non-MOM THA. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted study data and assessed risk of bias. Risk differences (RD) were calculated with random effect models. Meta-regression was used to explore modifying factors. MAIN OUTCOMES AND MEASURES: Difference in mortality and difference in morbidity expressed as revisions and medical complications between patients with MOM THA and non-MOM THA. RESULTS: Forty-seven studies were included, comprising 4,000 THA in randomised trials and over 500,000 THA in observational studies. For mortality, random effects analysis revealed a higher pooled RD of 0.7%, 95%, confidence interval (CI) [0.0%, 2.3%], I-square 42%; the heterogeneity was explained by differences in follow-up. When restricted to studies with long term follow-up (i.e. 10 years or more), the RD for mortality was 8.5%, 95%, CI [5.8%, 11.2%]; number needed to treat was 12. Further subgroup analyses and meta-regression random effects models revealed no evidence for other moderator variables (study level covariates, e.g. resurfacing vs. non-resurfacing MOM) than follow-up duration. The quality of the evidence presented in this meta-analysis was characterized as moderate according to the CLEAR-NPT (for non-pharmacological trials) and Cochrane risk of bias Table. CONCLUSIONS AND RELEVANCE: Meta-analysis suggests there may be an increased long-term risk of mortality and revision surgery for patients with MOM THA compared to patients with non-MOM THA. REGISTRATION: PROSPERO 2014:CRD42014007417.

Sub-50 nm metrology on extreme ultra violet chemically amplified resist--A systematic assessment.

With lithographic patterning dimensions decreasing well below 50 nm, it is of high importance to understand metrology at such small scales. This paper presents results obtained from dense arrays of contact holes (CHs) with various Critical Dimension (CD) between 15 and 50 nm, as patterned in a chemically amplified resist using an ASML EUV scanner and measured at ASML and TNO. To determine the differences between various (local) CD metrology techniques, we conducted an experiment using optical scatterometry, CD-Scanning Electron Microscopy (CD-SEM), Helium ion Microscopy (HIM), and Atomic Force Microscopy (AFM). CD-SEM requires advanced beam scan strategies to mitigate sample charging; the other tools did not need that. We discuss the observed main similarities and differences between the various techniques. To this end, we assessed the spatial frequency content in the raw images for SEM, HIM, and AFM. HIM and AFM resolve the highest spatial frequencies, which are attributed to the more localized probe-sample interaction for these techniques. Furthermore, the SEM, HIM, and AFM waveforms are analyzed in detail. All techniques show good mutual correlation, albeit the reported CD values systematically differ significantly. HIM systematically reports a 25% higher CD uniformity number than CD-SEM for the same arrays of CHs, probably because HIM has a higher resolution than the CD-SEM used in this assessment. A significant speed boost for HIM and AFM is required before these techniques are to serve the demanding industrial metrology applications like optical critical dimension and CD-SEM do nowadays.

Resistance of the Lichen Buellia frigida to Simulated Space Conditions during the Preflight Tests for BIOMEX--Viability Assay and Morphological Stability.

Samples of the extremotolerant Antarctic endemite lichen Buellia frigida are currently exposed to low-Earth orbit-space and simulated Mars conditions at the Biology and Mars Experiment (BIOMEX), which is part of the ESA mission EXPOSE-R2 on the International Space Station and was launched on 23 July 2014. In preparation for the mission, several preflight tests (Experimental and Scientific Verification Tests, EVT and SVT) assessed the sample preparation and hardware integration procedures as well as the resistance of the candidate organism toward the abiotic stressors experienced under space and Mars conditions. Therefore, we quantified the post-exposure viability with a live/dead staining technique utilizing FUN-1 and confocal laser scanning microscopy (CLSM). In addition, we used scanning electron microscopy (SEM) to investigate putative patterns of morphological-anatomical damage that lichens may suffer under the extreme exposure conditions. The present results demonstrate that Buellia frigida is capable of surviving the conditions tested in EVT and SVT. The mycobiont showed lower average impairment of its viability than the photobiont (viability rates of >83% and >69%, respectively), and the lichen thallus suffered no significant damage in terms of thalline integrity and symbiotic contact. These results will become essential to substantiate and validate the results prospectively obtained from the returning space mission. Moreover, they will help assess the limits and limitations of terrestrial organisms under space and Mars conditions as well as characterize the adaptive traits that confer lichen extremotolerance.

Extremotolerance and resistance of lichens: comparative studies on five species used in astrobiological research II. Secondary lichen compounds.

Lichens, which are symbioses of a fungus and one or two photoautotrophs, frequently tolerate extreme environmental conditions. This makes them valuable model systems in astrobiological research to fathom the limits and limitations of eukaryotic symbioses. Various studies demonstrated the high resistance of selected extremotolerant lichens towards extreme, non-terrestrial abiotic factors including space exposure, hypervelocity impact simulations as well as space and Martian parameter simulations. This study focusses on the diverse set of secondary lichen compounds (SLCs) that act as photo- and UVR-protective substances. Five lichen species used in present-day astrobiological research were compared: Buellia frigida, Circinaria gyrosa, Rhizocarpon geographicum, Xanthoria elegans, and Pleopsidium chlorophanum. Detailed investigation of secondary substances including photosynthetic pigments was performed for whole lichen thalli but also for axenically cultivated mycobionts and photobionts by methods of UV/VIS-spectrophotometry and two types of high performance liquid chromatography (HPLC). Additionally, a set of chemical tests is presented to confirm the formation of melanic compounds in lichen and mycobiont samples. All investigated lichens reveal various sets of SLCs, except C. gyrosa where only melanin was putatively identified. Such studies will help to assess the contribution of SLCs on lichen extremotolerance, to understand the adaptation of lichens to prevalent abiotic stressors of the respective habitat, and to form a basis for interpreting recent and future astrobiological experiments. As most of the identified SLCs demonstrated a high capacity in absorbing UVR, they may also explain the high resistance of lichens towards non-terrestrial UVR.

Extremotolerance and resistance of lichens: comparative studies on five species used in astrobiological research I. Morphological and anatomical characteristics.

Lichens are symbioses of two organisms, a fungal mycobiont and a photoautotrophic photobiont. In nature, many lichens tolerate extreme environmental conditions and thus became valuable models in astrobiological research to fathom biological resistance towards non-terrestrial conditions; including space exposure, hypervelocity impact simulations as well as space and Martian parameter simulations. All studies demonstrated the high resistance towards non-terrestrial abiotic factors of selected extremotolerant lichens. Besides other adaptations, this study focuses on the morphological and anatomical traits by comparing five lichen species-Circinaria gyrosa, Rhizocarpon geographicum, Xanthoria elegans, Buellia frigida, Pleopsidium chlorophanum-used in present-day astrobiological research. Detailed investigation of thallus organization by microscopy methods allows to study the effect of morphology on lichen resistance and forms a basis for interpreting data of recent and future experiments. All investigated lichens reveal a common heteromerous thallus structure but diverging sets of morphological-anatomical traits, as intra-/extra-thalline mucilage matrices, cortices, algal arrangements, and hyphal strands. In B. frigida, R. geographicum, and X. elegans the combination of pigmented cortex, algal arrangement, and mucilage seems to enhance resistance, while subcortex and algal clustering seem to be crucial in C. gyrosa, as well as pigmented cortices and basal thallus protrusions in P. chlorophanum. Thus, generalizations on morphologically conferred resistance have to be avoided. Such differences might reflect the diverging evolutionary histories and are advantageous by adapting lichens to prevalent abiotic stressors. The peculiar lichen morphology demonstrates its remarkable stake in resisting extreme terrestrial conditions and may explain the high resistance of lichens found in astrobiological research.

[Anorectal anaplastic cancer (neuroendocrine)]. / Cancer anaplasique (neuro-endocrinien) anorectal.

An extensive case of undifferentiated neuroendocrine carcinoma with small cells of the anorectal region is reported. The carcinoma is related to pulmonary anaplasia and quite rare in the colonic and rectal region. Its aggressivity is considerable with a strong propensity for hematogenous and lymphatic metastases and with a disastrous prognosis: 0% survival over 1 year. The incidence, the characteristic features, the histogenesis, and the anatomical pathology of this rare neoplasm are mentioned. Furthermore, the case illustrates a radiological pattern typical for major lymphatic dissemination with an intra- and extraparietal component. The mechanism of dissemination is explained by the "lymphatic block" theory. The absolute necessity of obtaining an histology in radiologically unusual and/or extensive cases is mentioned.

Pharmacokinetics of sulfamethoxazole--trimethoprim combination during chronic peritoneal dialysis: effect of peritonitis.

The pharmacokinetics of the fixed combination trimethoprim sulfamethoxazole (TMP--SMZ), including peritoneal transfer, has been studied in patients with end-stage renal disease treated by peritoneal dialysis, intermittent in 18 cases and continuous ambulatory dialysis in 6 cases. After a single oral dose of TMP 4 mg and SMZ 20 mg per kg, peak serum levels of approximately 2.0 micrograms/ml TMP and 28 micrograms/ml SMZ were achieved at 4 hours for TMP, and at 6 hours for SMZ. The protein binding of TMP was 34.7 +/- 1.1% and its distribution volume was 2.2 +/- 0.51/kg. Total plasma clearance of TMP was 66.2 +/- 11.5 ml/min, peritoneal dialysance was 5.1 +/- 0.5 ml/min, and renal clearance was negligible. The protein binding of SMZ was 48.0 +/- 1.4% and the distribution volume was 0.55 +/- 0.071/kg. Total plasma clearance of SMZ was 26.2 +/- 5.7 ml/min, peritoneal dialysance was 1.2 +/- 0.2 ml/min, and renal clearance was negligible. The half lives of TMP and SMZ were 23.7 +/- 4.0 h and 18.1 +/- 3.5 h, respectively. The peritoneal dialysance both of TMP and SMZ after oral administration was very low. In contrast the absorption after intra-peritoneal administration is high. Peritoneal absorption was increased during peritonitis. In patients with peritonitis, the intra-peritoneal administration of TMP-SMZ resulted in an immediate high local concentration, and a serum concentration of both drugs in the therapeutic range within 6 to 12 h.