Explore the vast range of titles available.

Chronic obstructive pulmonary disease (COPD) is a prevalent condition characterized by persistent airflow obstruction and respiratory symptoms. Single-Inhaler Triple Therapy (SITT) has been shown to improve patient adherence, reduce exacerbations, and lower healthcare resource utilization in patients who are not controlled despite being on dual therapy or Multiple-Inhaler Triple Therapy (MITT). Despite evidence supporting SITT, payer-driven access rules across Europe sometimes limit its use in primary care, creating barriers to optimal COPD management. Through expert consensus, the study seeks to generate a shared understanding of the unintended consequences of payer-driven access criteria for SITT in managing moderate-to-severe COPD in primary care. A targeted literature review (TLR) was conducted to assess SITT initiation in primary care across Europe and examine the impact of access criteria. Semi-structured interviews were held with 14 experts from nine European countries, including clinicians, health economists, and patient advocacy representatives. A consensus generation workshop was conducted, where experts evaluated the findings and developed position statements to highlight the challenges posed by payer-driven access criteria. The TLR identified variability in access to SITT in Europe, with several countries restricting its initiation to specialists, thus limiting primary care physicians' (PCPs) ability to prescribe SITT. The expert panel generated seven consensus points stating that enabling PCPs to step up or switch eligible patients to SITT has the potential to support care continuity, enhance clinical autonomy for PCPs, reduce reliance on potentially less effective treatment options, improve patient and healthcare system outcomes, avoid unnecessary referrals to specialists, enable prompt initiation of guideline-directed medical therapy for COPD in primary care and reduce access inequalities. Restrictions for SITT initiation in primary care may need to be revisited to mitigate their unintended health and cost consequences and improve equitable access to treatment. This should take into consideration each country's unique healthcare system.

More and more automotive applications require exact position sensing. Today resistive potentiometers are the most frequently used sensors. For reasons of reliability, there are increasing demands to replace these kinds of sensors by contactless displacement sensors, with almost no increases in the system costs. Beside the \"contactless\" demand, the sensor should work without friction of moving parts and thus allows big airgaps. To avoid additional developments and risks, the technology should be standardised for all kind of displacements (rotary and linear). A high performance sensor technology for displacement sensing has been developed to fulfil these requirements.

Background Inflammation is associated with a worse outcome in cancer and neutrophil:lymphocyte ratio (NLR) is a strong prognostic value. In cancer, nonsteroidal anti-inflammatory drugs (NSAIDs) could be of interest. We investigated the prognostic significance of NLR and the impact of intraoperative NSAIDs in cancer surgeries. Methods We performed an observational study in early breast, kidney, and lung cancers (357, 227, and 255 patients) with uni- and multivariate analyses (Cox model). Results In breast cancer (Centre 1), NLR ≥ 4 is associated with a higher risk of relapse (hazards ratio (HR) = 2.41; 95 % confidence interval (CI) 1.01–5.76; P  = 0.048). In breast cancer (Centre 2), NLR ≥ 3 is associated with a higher risk of relapse (HR = 4.6; 95 % CI 1.09–19.1; P  = 0.04) and higher mortality (HR = 4.0; 95 % CI 1.12–14.3; P  = 0.03). In kidney cancer, NLR ≥ 5 is associated with a higher risk of relapse (HR = 1.63; 95 % CI 1.00–2.66; P  = 0.05) and higher mortality (HR = 1.67; 95 % CI 1.0–2.81; P  = 0.05). In lung cancer, NLR ≥ 5 is associated with higher mortality (HR = 1.45; 95 % CI 1.02–2.06; P  = 0.04). The intraoperative use of NSAIDs in breast cancer patients (Centre 1) is associated with a reduced recurrence rate (HR = 0.17; 95 % CI 0.04–0.43; P  = 0.0002) and a lower mortality (HR = 0.25; 95 % CI 1.08–0.75; P  = 0.01). NSAIDs use at the beginning of the surgery is independently associated with a lower metastases risk after lung cancer surgery (HR = 0.16; 95 % CI 0.04–0.63; P  = 0.009). Ketorolac use is independently associated with longer survival (HR = 0.55; 95 % CI 0.31–0.95; P  = 0.03). Conclusions In these cohorts, these analyses show that NLR is a strong perioperative prognosis factor for breast, lung, and kidney cancers. In this context, intraoperative NSAIDs administration could be associated with a better outcome.

GABA A receptors are pentameric ligand-gated ion channels involved in fast inhibitory neurotransmission and are allosterically modulated by the anxiolytic, anticonvulsant, and sedative-hypnotic benzodiazepines. Here we show that the prokaryotic homolog ELIC also is activated by GABA and is modulated by benzodiazepines with effects comparable to those at GABA A receptors. Crystal structures reveal important features of GABA recognition and indicate that benzodiazepines, depending on their concentration, occupy two possible sites in ELIC. An intrasubunit site is adjacent to the GABA-recognition site but faces the channel vestibule. A second intersubunit site partially overlaps with the GABA site and likely corresponds to a low-affinity benzodiazepine-binding site in GABA A receptors that mediates inhibitory effects of the benzodiazepine flurazepam. Our study offers a structural view how GABA and benzodiazepines are recognized at a GABA-activated ion channel.

Replication Protein A (RPA) is a heterotrimeric single stranded DNA-binding protein with essential roles in DNA replication, recombination and repair. Little is known about the structure of RPA in Archaea, the third domain of life. By using an integrative structural, biochemical and biophysical approach, we extensively characterize RPA from Pyrococcus abyssi in the presence and absence of DNA. The obtained X-ray and cryo-EM structures reveal that the trimerization core and interactions promoting RPA clustering on ssDNA are shared between archaea and eukaryotes. However, we also identified a helical domain named AROD ( A cidic R pa1 O B-binding D omain), and showed that, in Archaea, RPA forms an unanticipated tetrameric supercomplex in the absence of DNA. The four RPA molecules clustered within the tetramer could efficiently coat and protect stretches of ssDNA created by the advancing replisome. Finally, our results provide insights into the evolution of this primordial replication factor in eukaryotes. Here the authors present the structure of Replication Protein A (RPA) in Archaea. The RPA structure from P. abyssi has been determined in presence and absence of DNA, providing insights into the evolution of this replication factor in eukaryotes

Meiotic recombination is a major factor of genome evolution, deeply characterized in only a few model species, notably the yeast Saccharomyces cerevisiae. Consequently, little is known about variations of its properties across species. In this respect, we explored the recombination landscape of Lachancea kluyveri, a protoploid yeast species that diverged from the Saccharomyces genus more than 100 million years ago and we found striking differences with S. cerevisiae. These variations include a lower recombination rate, a higher frequency of chromosomes segregating without any crossover and the absence of recombination on the chromosome arm containing the sex locus. In addition, although well conserved within the Saccharomyces clade, the S. cerevisiae recombination hotspots are not conserved over a broader evolutionary distance. Finally and strikingly, we found evidence of frequent reversal of commitment to meiosis, resulting in return to mitotic growth after allele shuffling. Identification of this major but underestimated evolutionary phenomenon illustrates the relevance of exploring non-model species.

Background Intensive care unit (ICU) survivors have reduced long-term survival compared to the general population. Identifying parameters at ICU discharge that are associated with poor long-term outcomes may prove useful in targeting an at-risk population. The main objective of the study was to identify clinical and biological determinants of death in the year following ICU discharge. Methods FROG-ICU was a prospective, observational, multicenter cohort study of ICU survivors followed 1 year after discharge, including 21 medical, surgical or mixed ICUs in France and Belgium. All consecutive patients admitted to intensive care with a requirement for invasive mechanical ventilation and/or vasoactive drug support for more than 24 h following ICU admission and discharged from ICU were included. The main outcome measure was all-cause mortality at 1 year after ICU discharge. Clinical and biological parameters on ICU discharge were measured, including the circulating cardiovascular biomarkers N-terminal pro-B type natriuretic peptide, high-sensitive troponin I, bioactive-adrenomedullin and soluble-ST2. Socioeconomic status was assessed using a validated deprivation index (FDep). Results Of 1570 patients discharged alive from the ICU, 333 (21%) died over the following year. Multivariable analysis identified age, comorbidity, red blood cell transfusion, ICU length of stay and abnormalities in common clinical factors at the time of ICU discharge (low systolic blood pressure, temperature, total protein, platelet and white cell count) as independent factors associated with 1-year mortality. Elevated biomarkers of cardiac and vascular failure independently associated with 1-year death when they are added to multivariable model, with an almost 3-fold increase in the risk of death when combined (adjusted odds ratio 2.84 (95% confidence interval 1.73–4.65), p  < 0.001). Conclusions The FROG-ICU study identified, at the time of ICU discharge, potentially actionable clinical and biological factors associated with poor long-term outcome after ICU discharge. Those factors may guide discharge planning and directed interventions. Trial registration ClinicalTrials.gov NCT01367093 . Registered on 6 June 2011.

Background. Chronic disseminated candidiasis (CDC) is typically observed during neutrophil recovery in patients with acute leukemia and requires protracted antifungal therapy. Objective. Our objective was to document the efficacy and tolerance of corticosteroid therapy (CST) in patients with symptomatic CDC, including those who experienced fever and abdominal pain despite ongoing antifungal therapy. Methods. We performed a retrospective, multicenter study involving 10 pediatric and adult patients who experienced ongoing symptomatic CDC despite receipt of appropriate antifungal therapy for whom adjuvant oral CST was initiated. Results. All cases of CDC were proven or probable, as determined on the basis of the European Organization for Research and Treatment of Cancer-Mycosis Study Group definition criteria, and occurred in patients with leukemia. CDC-attributable clinical symptoms resolved with CST, which was started a mean of 33.8 days after antifungal therapy had been initiated. Fever and abdominal pain disappeared a median of 4–5 days, and serum fibrinogen and C-reactive protein levels returned to normal values within 14–30 days. The median duration of hospitalization after CST initiation was 8.8 days. Hepatosplenic microabscesses decreased or disappeared within a mean period of 107 days (range, 30–210 days). No relapses of CDC were observed during a median duration of follow-up of 6.5 years (range, 4–9 years). Conclusions. In children and adults who experience persistently symptomatic CDC despite ongoing receipt of antifungal therapy, CST involving a prednisone equivalent at a dosage of ⩾0.5 mg/kg per day for at least 3 weeks is associated with a prompt resolution of symptoms and of inflammatory response. These findings support the pathophysiological hypothesis that CDC belongs to the spectrum of fungus-related immune reconstitution inflammatory syndrome.

Measurement error in the continuous covariates of a model generally yields bias in the estimators. It is a frequent problem in practice, and many correction procedures have been developed for different classes of models. However, in most cases, some information about the measurement error distribution is required. When neither validation nor auxiliary data (e.g., replicated measurements) are available, this specification turns out to be tricky. In this article, we develop a flexible likelihood-based procedure to estimate the variance of classical additive error of Gaussian distribution, without additional information, when the covariate has compact support. The performance of this estimator is investigated both in an asymptotic way and through finite sample simulations. The usefulness of the obtained estimator when using the simulation extrapolation (SIMEX) algorithm, a widely used correction method, is then analyzed in the Cox proportional hazards model through other simulations. Finally, the whole procedure is illustrated on real data.

Background Diagnostic work-up of patients with hypertrophic cardiomyopathy is crucial for appropriate management. However, the optimal genetic strategy remains debatable. We compared two strategies: targeted testing based on careful examination of clinical red flags versus large multigene panel analysis without gene prioritization. We applied the strategy to the diagnosis of Fabry disease or Hereditary Transthyretin Amyloidosis ( GLA or TTR genes respectively). Results We studied 341 hypertrophic cardiomyopathy index patients. Patients of subgroup 1 (n = 42) had careful clinical analysis and high suspicion of Hereditary Transthyretin Amyloidosis or Fabry disease. They underwent targeted Sanger sequencing. Patients in subgroup 2 (n = 299) did not have clinical selection, and underwent next-generation sequencing analysis of 107 cardiac genes. The yield of genetic testing for pathogenic/likely pathogenic variants in GLA and/or TTR was 28.6% in subgroup 1 (12/42: 5 TTR and 7 GLA ) versus 1.0% in subgroup 2 (3/299: 1 TTR and 2 GLA ), p  < 0.01. Genetic results were obtained after a median of 26.0 days [IQR = 18–59.8] in subgroup 1 versus 193.5 days [IQR = 174–218] in subgroup 2, p  < 0.01. Finally, genetic testing cost was 615.60€ or 769.50€ for TTR or GLA targeted analysis respectively, versus 1503.90€ for multigene panel analysis. Conclusions Both molecular strategies in hypertrophic cardiomyopathy patients are useful for the identification of pathogenic/likely pathogenic variants in TTR/GLA genes. However, targeted genetic testing based on clinical red flags identified causal mutations more efficiently, faster and at a lower cost. Careful clinical analysis is therefore important in guiding molecular strategy and may reduce diagnostic wandering and accelerate delivery of appropriate therapy.