Molecular profiling of NSCLC is essential for optimising treatment decisions, but often incomplete. We assessed the efficacy of protocolised molecular profiling in the current standard-of-care (SoC) ...in a prospective observational study in the Netherlands and measured the effect of providing standardised diagnostic procedures. We also explored the potential of plasma-based molecular profiling in the primary diagnostic setting. This multi-centre prospective study was designed to explore the performance of current clinical practice during the run-in phase using local SoC tissue profiling procedures. The subsequent phase was designed to investigate the extent to which comprehensive molecular profiling (CMP) can be maximized by protocolising tumour profiling. Successful molecular profiling was defined as completion of at least EGFR and ALK testing. Additionally, PD-L1 tumour proportions scores were explored. Lastly, the additional value of centralised plasma-based testing for EGFR and KRAS mutations using droplet digital PCR was evaluated. Total accrual was 878 patients, 22.0% had squamous cell carcinoma and 78.0% had non-squamous NSCLC. Stage I-III was seen in 54.0%, stage IV in 46.0%. Profiling of EGFR and ALK was performed in 69.9% of 136 patients included in the run-in phase, significantly more than real-world data estimates of 55% (p<0.001). Protocolised molecular profiling increased the rate to 77.0% (p = 0.049). EGFR and ALK profiling rates increased from 77.9% to 82.1% in non-squamous NSCLC and from 43.8% to 57.5% in squamous NSCLC. Plasma-based testing was feasible in 98.4% and identified oncogenic driver mutations in 7.1% of patients for whom tissue profiling was unfeasible. This study shows a high success rate of tissue-based molecular profiling that was significantly improved by a protocolised approach. Tissue-based profiling remains unfeasible for a substantial proportion of patients. Combined analysis of tumour tissue and circulating tumour DNA is a promising approach to allow adequate molecular profiling of more patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background & Aims The prevalence of non-alcoholic fatty liver disease (NAFLD) appears to increase with age. However, limited data are available concerning the prevalence of NAFLD in the elderly. Our ...aim was to determine the prevalence and risk factors of NAFLD in an elderly population. Methods This study was based on participants in the population-based Rotterdam Study. Each participant was interviewed and had a clinical examination at the research center, including a fasting blood collection, liver ultrasonography, and anthropometric assessment. Ordinal and logistic regression analysis was used to assess associations between covariables and (severity of) NAFLD. Results Data from 2811 participants (mean age 76.4 ± 6.0 years) were analyzed. The prevalence of NAFLD was 35.1%. The prevalence of NAFLD decreased with advancing age ( p <0.001). In logistic regression analysis, age (OR 0.97; 95% CI 0.95–0.99; p <0.001), total physical activity level (OR 0.98, 95% CI 0.96–0.99; p = 0.005), pack years of smoking (OR 1.01, 95% CI 1.00–1.01; p = 0.02), waist circumference >88 cm for women and >102 cm for men (OR 4.89; CI 4.00–5.96; p <0.001), fasting glucose ⩾100 mg/dl or drug treatment for elevated blood glucose (OR 2.11, 95% CI 1.72–2.59; p <0.001), blood pressure ⩾130/85 mmHg or drug treatment for elevated blood pressure (OR 1.80, 95% CI 1.08–3.01; p = 0.03), and triglycerides ⩾150 mg/dl or treatment with serum lipid reducing agents (OR 1.56, 95% CI 1.28–1.91; p <0.001) were associated with NAFLD. Conclusions NAFLD is common in the elderly, although the prevalence decreases with advancing age. Further studies are warranted exploring potential factors contributing to this apparent positive selection effect in the elderly.
Summary
In this small cross-sectional study of predominantly well-treated participants with relatively short-term type 2 diabetes duration, HbA1c > 7% (53 mmol/mol) was associated with lower cortical ...density and thickness and higher cortical porosity at the distal radius, lower trabecular thickness at the distal tibia, and higher trabecular number at both sites.
Introduction
To examine the association between diabetes status and volumetric bone mineral density (vBMD), bone microarchitecture and strength of the distal radius and tibia as assessed with HR-pQCT. Additionally—in participants with type 2 diabetes (T2DM), to examine the association between HbA1c, diabetes duration, and microvascular disease (MVD) and bone parameters.
Methods
Cross-sectional data from 410 (radius) and 198 (tibia) participants of The Maastricht Study (mean age 58 year, 51% female). Diabetes status (normal glucose metabolism, prediabetes, or T2DM) was based on an oral glucose tolerance test and medication history.
Results
After full adjustment, prediabetes and T2DM were not associated with vBMD, bone microarchitecture, and strength of the radius and tibia, except for lower trabecular number (Tb.N) of the tibia (− 4%) in prediabetes and smaller cross-sectional area of the tibia (− 7%) in T2DM. In T2DM, HbA1c > 7% was associated with lower cortical vBMD (− 5%), cortical thickness (− 16%), higher cortical porosity (+ 20%) and Tb.N (+ 9%) of the radius, and higher Tb.N (+ 9%) and lower trabecular thickness (− 13%) of the tibia. Diabetes duration > 5 years was associated with higher Tb.N (+ 6%) of the radius. The presence of MVD was not associated with any bone parameters.
Conclusions
In this study with predominantly well-treated T2DM participants with relatively short-term diabetes duration, inadequate blood glucose control was negatively associated with cortical bone measures of the radius. In contrast, trabecular number was increased at both sites. Studies of larger sample size are warranted for more detailed investigations of bone density and bone quality in patients with T2DM.
Recent studies have revealed that, in critically ill patients, lung microbiota are altered and correlate with alveolar inflammation. The clinical significance of altered lung bacteria in critical ...illness is unknown.
To determine if clinical outcomes of critically ill patients are predicted by features of the lung microbiome at the time of admission.
We performed a prospective, observational cohort study in an ICU at a university hospital. Lung microbiota were quantified and characterized using droplet digital PCR and bacterial 16S ribosomal RNA gene quantification and sequencing. Primary predictors were the bacterial burden, community diversity, and community composition of lung microbiota. The primary outcome was ventilator-free days, determined at 28 days after admission.
Lungs of 91 critically ill patients were sampled using miniature BAL within 24 hours of ICU admission. Patients with increased lung bacterial burden had fewer ventilator-free days (hazard ratio, 0.43; 95% confidence interval, 0.21-0.88), which remained significant when the analysis was controlled for pneumonia and severity of illness. The community composition of lung bacteria predicted ventilator-free days (
= 0.003), driven by the presence of gut-associated bacteria (e.g., species of the Lachnospiraceae and Enterobacteriaceae families). Detection of gut-associated bacteria was also associated with the presence of acute respiratory distress syndrome.
Key features of the lung microbiome (bacterial burden and enrichment with gut-associated bacteria) predict outcomes in critically ill patients. The lung microbiome is an understudied source of clinical variation in critical illness and represents a novel therapeutic target for the prevention and treatment of acute respiratory failure.
Coastal food webs can be supported by local benthic or pelagic primary producers and by the import of organic matter. Distinguishing between these energy sources is essential for our understanding of ...ecosystem functioning. However, the relative contribution of these components to the food web at the landscape scale is often unclear, as many studies lack good taxonomic and spatial resolution across large areas. Here, using stable carbon isotopes, we report on the primary carbon sources for consumers and their spatial variability across one of the world's largest intertidal ecosystems (Dutch Wadden Sea; 1460 km2 intertidal surface area), at an exceptionally high taxonomic (178 species) and spatial resolution (9,165 samples from 839 locations). The absence of overlap in δ13C values between consumers and terrestrial organic matter suggests that benthic and pelagic producers dominate carbon input into this food web. In combination with the consistent enrichment of benthic primary producers (δ13C –16.3‰) relative to pelagic primary producers (δ13C –18.8) across the landscape, this allowed the use of a two-food-source isotope-mixing model. This spatially resolved modelling revealed that benthic primary producers (microphytobenthos) are the most important energy source for the majority of consumers at higher trophic levels (worms, molluscs, crustaceans, fish, and birds), and thus to the whole food web. In addition, we found large spatial heterogeneity in the δ13C values of benthic primary producers (δ13C –19.2 to –11.5‰) and primary consumers (δ13C –25.5 to –9.9‰), emphasizing the need for spatially explicit sampling of benthic and pelagic primary producers in coastal ecosystems. Our findings have important implications for our understanding of the functioning of ecological networks and for the management of coastal ecosystems.
We report on 6 infants who underwent elective surgery and developed postoperative encephalopathy, which had features most consistent with intraoperative cerebral hypoperfusion. All infants were <48 ...weeks' postmenstrual age and underwent procedures lasting 120 to 185 minutes. Intraoperative records revealed that most of the measured systolic blood pressure (SBP) values were <60 mm Hg (the threshold for hypotension in awake infants according to the Pediatric Advanced Life Support guidelines) but that only 11% of the measured SBP values were <1 SD of the mean definition of hypotension (<45 mm Hg) as reported in a survey of members of the Society for Pediatric Anesthesia in 2009. Four infants also exhibited prolonged periods of mild hypocapnia (<35 mm Hg). One infant did not receive intraoperative dextrose. All infants developed new-onset seizures within 25 hours of administration of the anesthetic, with a predominant cerebral pathology of supratentorial watershed infarction in the border zone between the anterior, middle, and posterior cerebral arteries. Follow-up of these infants found that 1 died, 1 had profound developmental delays, 1 had minor motor delays, 2 were normal, and 1 was lost to follow-up. Although the precise cause of encephalopathy cannot be determined, it is important to consider the role that SBP hypotension (as well as hypoglycemia, hyperthermia, hyperoxia, and hypocapnia) plays during general anesthesia in young infants in the development of infantile postoperative encephalopathy. Our observations highlight the lack of evidence-based recommendations for the lower limits of adequate SBP and end-tidal carbon dioxide in anesthetized infants.
We hypothesised that patients with acute respiratory distress syndrome (ARDS) can be clustered based on concentrations of plasma biomarkers and that the thereby identified biological phenotypes are ...associated with mortality.
Consecutive patients with ARDS were included in this prospective observational cohort study. Cluster analysis of 20 biomarkers of inflammation, coagulation and endothelial activation provided the phenotypes in a training cohort, not taking any outcome data into account. Logistic regression with backward selection was used to select the most predictive biomarkers, and these predicted phenotypes were validated in a separate cohort. Multivariable logistic regression was used to quantify the independent association with mortality.
Two phenotypes were identified in 454 patients, which we named 'uninflamed' (N=218) and 'reactive' (N=236). A selection of four biomarkers (interleukin-6, interferon gamma, angiopoietin 1/2 and plasminogen activator inhibitor-1) could be used to accurately predict the phenotype in the training cohort (area under the receiver operating characteristics curve: 0.98, 95% CI 0.97 to 0.99). Mortality rates were 15.6% and 36.4% (p<0.001) in the training cohort and 13.6% and 37.5% (p<0.001) in the validation cohort (N=207). The 'reactive phenotype' was independent from confounders associated with intensive care unit mortality (training cohort: OR 1.13, 95% CI 1.04 to 1.23; validation cohort: OR 1.18, 95% CI 1.06 to 1.31).
Patients with ARDS can be clustered into two biological phenotypes, with different mortality rates. Four biomarkers can be used to predict the phenotype with high accuracy. The phenotypes were very similar to those found in cohorts derived from randomised controlled trials, and these results may improve patient selection for future clinical trials targeting host response in patients with ARDS.
The Paleocene–Eocene Thermal Maximum (PETM, ~ 56 Ma) was a ~ 200 kyr episode of global warming, associated with massive injections of 13C-depleted carbon into the ocean–atmosphere system. Although ...climate change during the PETM is relatively well constrained, effects on marine oxygen concentrations and nutrient cycling remain largely unclear. We identify the PETM in a sediment core from the US margin of the Gulf of Mexico. Biomarker-based paleotemperature proxies (methylation of branched tetraether–cyclization of branched tetraether (MBT–CBT) and TEX86) indicate that continental air and sea surface temperatures warmed from 27–29 to ~ 35 °C, although variations in the relative abundances of terrestrial and marine biomarkers may have influenced these estimates. Vegetation changes, as recorded from pollen assemblages, support this warming. The PETM is bracketed by two unconformities. It overlies Paleocene silt- and mudstones and is rich in angular (thus in situ produced; autochthonous) glauconite grains, which indicate sedimentary condensation. A drop in the relative abundance of terrestrial organic matter and changes in the dinoflagellate cyst assemblages suggest that rising sea level shifted the deposition of terrigenous material landward. This is consistent with previous findings of eustatic sea level rise during the PETM. Regionally, the attribution of the glauconite-rich unit to the PETM implicates the dating of a primate fossil, argued to represent the oldest North American specimen on record. The biomarker isorenieratene within the PETM indicates that euxinic photic zone conditions developed, likely seasonally, along the Gulf Coastal Plain. A global data compilation indicates that O2 concentrations dropped in all ocean basins in response to warming, hydrological change, and carbon cycle feedbacks. This culminated in (seasonal) anoxia along many continental margins, analogous to modern trends. Seafloor deoxygenation and widespread (seasonal) anoxia likely caused phosphorus regeneration from suboxic and anoxic sediments. We argue that this fueled shelf eutrophication, as widely recorded from microfossil studies, increasing organic carbon burial along many continental margins as a negative feedback to carbon input and global warming. If properly quantified with future work, the PETM offers the opportunity to assess the biogeochemical effects of enhanced phosphorus regeneration, as well as the timescales on which this feedback operates in view of modern and future ocean deoxygenation.
Meiosis in the haploid plant-pathogenic fungus Mycosphaerella graminicola results in eight ascospores due to a mitotic division following the two meiotic divisions. The transient diploid phase allows ...for recombination among homologous chromosomes. However, some chromosomes of M. graminicola lack homologs and do not pair during meiosis. Because these chromosomes are not present universally in the genome of the organism they can be considered to be dispensable. To analyze the meiotic transmission of unequal chromosome numbers, two segregating populations were generated by crossing genetically unrelated parent isolates originating from Algeria and The Netherlands that had pathogenicity towards durum or bread wheat, respectively. Detailed genetic analyses of these progenies using high-density mapping (1793 DArT, 258 AFLP and 25 SSR markers) and graphical genotyping revealed that M. graminicola has up to eight dispensable chromosomes, the highest number reported in filamentous fungi. These chromosomes vary from 0.39 to 0.77 Mb in size, and represent up to 38% of the chromosomal complement. Chromosome numbers among progeny isolates varied widely, with some progeny missing up to three chromosomes, while other strains were disomic for one or more chromosomes. Between 15-20% of the progeny isolates lacked one or more chromosomes that were present in both parents. The two high-density maps showed no recombination of dispensable chromosomes and hence, their meiotic processing may require distributive disjunction, a phenomenon that is rarely observed in fungi. The maps also enabled the identification of individual twin isolates from a single ascus that shared the same missing or doubled chromosomes indicating that the chromosomal polymorphisms were mitotically stable and originated from nondisjunction during the second division and, less frequently, during the first division of fungal meiosis. High genome plasticity could be among the strategies enabling this versatile pathogen to quickly overcome adverse biotic and abiotic conditions in wheat fields.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Studies of see‐and‐treat management of cervical intraepithelial neoplasia (CIN) vary in their inclusion criteria, resulting in a broad range of overtreatment rates.
Objectives
To determine ...overtreatment rates in see‐and‐treat management of women referred for colposcopy because of suspected CIN, in order to define circumstances supporting see‐and‐treat management.
Search strategy
MEDLINE, EMBASE, and the Cochrane Library were searched from inception up to 12 May 2014.
Selection criteria
Studies of see‐and‐treat management in women with a reported cervical smear result, colposcopic impression, and histology result were included.
Data collection and analysis
Methodological quality was assessed with the Newcastle–Ottawa scale. We used the inverse variance method for pooling incidences, and a random‐effects model was used to account for heterogeneity between studies. Overtreatment was defined as treatment in patients with no CIN or CIN1.
Main results
Thirteen studies (n = 4611) were included. The overall overtreatment rate in women with a high‐grade cervical smear and a high‐grade colposcopic impression was 11.6% (95% CI 7.8–15.3%). The overtreatment rate in women with a high‐grade cervical smear and low‐grade colposcopic impression was 29.3% (95% CI 16.7–41.9%), and in the case of a low‐grade smear and high‐grade colposcopic impression it was 46.4% (95% CI 15.7–77.1%). In women with a low‐grade smear and low‐grade colposcopic impression, the overtreatment rate was 72.9% (95% CI 68.1–77.7%).
Author's conclusions
The pooled overtreatment rate in women with a high‐grade smear and high‐grade colposcopic impression is at least comparable with the two‐step procedure, which supports the use of see‐and‐treat management in this subgroup of women.
Tweetable
See‐and‐treat management is justified in the case of a high‐grade smear and a high‐grade colposcopic impression.
Tweetable
See‐and‐treat management is justified in the case of a high‐grade smear and a high‐grade colposcopic impression.
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