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IntroductionThe 2002 American Thoracic Society (ATS) 6-Minute Walk Test (6MWT) guidelines advise ‘repeat testing should be performed about the same time of day to minimize intraday variability’. It is currently unknown if there is diurnal and/or seasonal variation in the 6MWT in pulmonary vascular disease (PVD).AimsTo investigate the association between 6-Minute Walk Distance (6MWD), time of day and season of testing.MethodRetrospective 6MWT data was collected from 2019–2025. The 6MWT was conducted in accordance with ATS 6MWT guidelines (2002). Independent sample t-test was performed to determine morning vs afternoon differences in 6MWD. One way ANOVA was performed to determine seasonal differences. Time of day and seasonal effects were further investigated using multivariate linear regression analyses, adjusted for age, sex, BMI and WHO functional class. Time was modelled as a continuous variable (per 1 hour increment) and as a binary predictor of morning (08:00–12:00 am) vs afternoon (12–18:00 pm).ResultsThe cohort consisted of 1618 patients, WHO PH Groups 1 (n= 322), 2 (n=72), 3 (n= 51), 4 (n = 946), and chronic thromboembolic pulmonary disease (n= 227). 6MWD was significantly higher in the morning (363 ± 134 meters; n=684) than in the afternoon (333 ± 144 meters; n=865) (p<0.001). 6MWD was not significantly impacted by season (p=0.75). Multivariable linear regression analyses demonstrated that the 6MWD decreased by 4.1 meters (95% CI 1.57–6.64) (p=0.002) for every hour increment in the time of the day, and by 16.34 meters (95% CI 5.72–29.95) (p=0.0003) in the afternoon compared to the morning.ConclusionThe time of day was found to impact 6MWD, with patients with PVD achieving higher 6MWD in the morning. 6MWTs should be conducted at the same time to eliminate this possible fatiguing effect and optimise interpretation of intertest differences in clinical practice and trials. Prospective studies are needed with repeated measurements in the same individuals at different times of the day to validate these findings.

In patients with locally advanced non–small-cell lung cancer who have undergone concurrent chemotherapy and radiation therapy, the use of durvalumab in the year after completing treatment significantly prolonged disease-free and overall survival as compared with placebo.

Objectives To compare the effectiveness of rituximab versus an alternative tumour necrosis factor (TNF) inhibitor (TNFi) in patients with rheumatoid arthritis (RA) with an inadequate response to one previous TNFi. Methods SWITCH-RA was a prospective, global, observational, real-life study. Patients non-responsive or intolerant to a single TNFi were enrolled ≤4 weeks after starting rituximab or a second TNFi. Primary end point: change in Disease Activity Score in 28 joints excluding patient's global health component (DAS28-3)–erythrocyte sedimentation rate (ESR) over 6 months. Results 604 patients received rituximab, and 507 an alternative TNFi as second biological therapy. Reasons for discontinuing the first TNFi were inefficacy (n=827), intolerance (n=263) and other (n=21). A total of 728 patients were available for primary end point analysis (rituximab n=405; TNFi n=323). Baseline mean (SD) DAS28-3–ESR was higher in the rituximab than the TNFi group: 5.2 (1.2) vs 4.8 (1.3); p<0.0001. Least squares mean (SE) change in DAS28-3–ESR at 6 months was significantly greater in rituximab than TNFi patients: −1.5 (0.2) vs −1.1 (0.2); p=0.007. The difference remained significant among patients discontinuing the initial TNFi because of inefficacy (−1.7 vs −1.3; p=0.017) but not intolerance (−0.7 vs −0.7; p=0.894). Seropositive patients showed significantly greater improvements in DAS28-3–ESR with rituximab than with TNFi (−1.6 (0.3) vs −1.2 (0.3); p=0.011), particularly those switching because of inefficacy (−1.9 (0.3) vs −1.5 (0.4); p=0.021). The overall incidence of adverse events was similar between the rituximab and TNFi groups. Conclusions These real-life data indicate that, after discontinuation of an initial TNFi, switching to rituximab is associated with significantly improved clinical effectiveness compared with switching to a second TNFi. This difference was particularly evident in seropositive patients and in those switched because of inefficacy.

New therapeutic strategies for malignant mesothelioma are urgently needed. In the DETERMINE study, we investigated the effects of the cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibody tremelimumab in patients with previously treated advanced malignant mesothelioma. DETERMINE was a double-blind, placebo-controlled, phase 2b trial done at 105 study centres across 19 countries in patients with unresectable pleural or peritoneal malignant mesothelioma who had progressed after one or two previous systemic treatments for advanced disease. Eligible patients were aged 18 years or older with Eastern Cooperative Oncology Group performance status of 0 or 1 and measurable disease as defined in the modified Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 for pleural mesothelioma or RECIST version 1.1 for peritoneal mesothelioma. Patients were randomly assigned (2:1) in blocks of three, stratified by European Organisation for Research and Treatment of Cancer status (low risk vs high risk), line of therapy (second line vs third line), and anatomic site (pleural vs peritoneal), by use of an interactive voice or web system, to receive intravenous tremelimumab (10 mg/kg) or placebo every 4 weeks for 7 doses and every 12 weeks thereafter until a treatment discontinuation criterion was met. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. The trial is ongoing but no longer recruiting participants, and is registered with ClinicalTrials.gov, number NCT01843374. Between May 17, 2013, and Dec 4, 2014, 571 patients were randomly assigned to receive tremelimumab (n=382) or placebo (n=189), of whom 569 patients received treatment (two patients in the tremelimumab group were excluded from the safety population because they did not receive treatment). At the data cutoff date (Jan 24, 2016), 307 (80%) of 382 patients had died in the tremelimumab group and 154 (81%) of 189 patients had died in the placebo group. Median overall survival in the intention-to-treat population did not differ between the treatment groups: 7·7 months (95% CI 6·8–8·9) in the tremelimumab group and 7·3 months (5·9–8·7) in the placebo group (hazard ratio 0·92 [95% CI 0·76–1·12], p=0·41). Treatment-emergent adverse events of grade 3 or worse occurred in 246 (65%) of 380 patients in the tremelimumab group and 91 (48%) of 189 patients in the placebo group; the most common were dyspnoea (34 [9%] patients in the tremelimumab group vs 27 [14%] patients in the placebo group), diarrhoea (58 [15%] vs one [<1%]), and colitis (26 [7%] vs none). The most common serious adverse events were diarrhoea (69 [18%] patients in the tremelimumab group vs one [<1%] patient in the placebo group), dyspnoea (29 [8%] vs 24 [13%]), and colitis (24 [6%] vs none). Treatment-emergent events leading to death occurred in 36 (9%) of 380 patients in the tremelimumab group and 12 (6%) of 189 in the placebo group; those leading to the death of more than one patient were mesothelioma (three [1%] patients in the tremelimumab group vs two [1%] in the placebo group), dyspnoea (three [1%] vs two [1%]); respiratory failure (one [<1%] vs three [2%]), myocardial infarction (three [1%] vs none), lung infection (three [1%] patients vs none), cardiac failure (one [<1%] vs one [<1%]), and colitis (two [<1%] vs none). Treatment-related adverse events leading to death occurred in five (1%) patients in the tremelimumab group and none in the placebo group. The causes of death were lung infection in one patient, intestinal perforation and small intestinal obstruction in one patient; colitis in two patients, and neuritis and skin ulcer in one patient. Tremelimumab did not significantly prolong overall survival compared with placebo in patients with previously treated malignant mesothelioma. The safety profile of tremelimumab was consistent with the known safety profile of CTLA-4 inhibitors. Investigations into whether immunotherapy combination regimens can provide greater efficacy than monotherapies in malignant mesothelioma are ongoing. AstraZeneca.

The development of multiphase steels to obtain an optimum balance between strength and ductility is a very active topic of research. In particular, carbide-free bainitic steels have shown promising mechanical properties, making them good candidates for replacing well-established first-generation steels in the automotive industry. In this work, a detailed analysis of the microstructures attainable through overaging treatments is tackled in two bainitic steels with different Si contents. The focus has been put onto the mechanical characterization, via nanoindentation, of the phases that are generated as a consequence of the change in the bainitic treatment conditions and the final cooling to room temperature. The results show the suitability of the nanoindentation technique for gaining knowledge about the underlying transformation-related phenomena and for measuring the relative difference in hardness of the various micro-constituents. The latter is a key factor in understanding the origin of the damage in this kind of steels.

This work studies the physical and mechanical properties of recycled concrete aggregate (recycled aggregate from concrete waste) and their influence in structural recycled concrete compressive strength. For said purpose, a database has been developed with the experimental results of 152 works selected from over 250 international references. The processed database results indicate that the most sensitive properties of recycled aggregate quality are density and absorption. Moreover, the study analyses how the recycled aggregate (both percentage and quality) and the mixing procedure (pre-soaking or adding extra water) influence the recycled concrete strength of different categories (high or low water to cement ratios). When recycled aggregate absorption is low (under 5%), pre-soaking or adding extra water to avoid loss in workability will negatively affect concrete strength (due to the bleeding effect), whereas with high water absorption this does not occur and both of the aforementioned correcting methods can be accurately employed.

A lensless compact arrangement based on digital in-line holography under Gabor’s regime is proposed as a novel contactless method to assess the profile of multifocal intraocular lenses (MIOLs) which are conformed by several diffractive rings. Diffractive MIOLs are a widely adopted ophthalmologic option for the correction of presbyopia in patients undergoing cataract surgery. The MIOL optical design might introduce non-negligible optical performance differences between lenses as well as the introduction of undesirable photic phenomena (such as halos and glare) affecting the vision of users. Therefore, the customized topographic control of each manufactured MIOL model, along with the advancement of optical simulation routines, is increasingly necessary to provide users with optimized performance of these implanted optics, as well as predictable and realistic expectations of their future vision with these solutions. In this manuscript, experimental results of the reconstruction of different smooth and highly edged diffractive profiles from a pair of commercially available MIOLs are presented. Besides, a study evaluating the convergence and robustness of the proposed iterative phase-retrieval routine based on a modified classical Gerchberg-Saxton algorithm is performed. These results provide experimental validation of the proposed technique for accurately measuring the optical profiles of MIOLs.

B cells play an important role in the development and maintenance of rheumatoid arthritis (RA). Although IL-10-producing B cells represent a major subset of regulatory B cells (Bregs) able to suppress autoimmune and inflammatory responses, recent reports showed that B cell-mediated immune suppression may also occur independent of IL-10. For instance, B cells can modulate T cell immune responses through the expression of regulatory molecules such as PD-L1. So far, PD-L1-expressing B cells have not been analyzed in RA patients. To analyze the frequency of PD-L1-expressing B cells in the peripheral blood of RA patients compared to healthy controls (HC) matched for sex and age, their function on T cell response and their changes in response to therapy. Fresh peripheral blood B cells from RA patients and HC were characterized by flow cytometry and their functionality assessed in a co-culture system with autologous T cells. The frequencies of CD19 PD-L1 B cells, CD24 CD38 PD-L1 and CD24 CD38 PD-L1 B cells were significantly lower in untreated RA patients than in HC. In a follow-up study, the frequencies of PD-L1 B cells (CD19 PD-L1 B cells, CD24 CD38 PD-L1 and CD24 CD38 PD-L1 B cells) increased significantly after treatment in good responder patients, although the frequency of total CD24 CD38 B cells decreased. CD19 B cells from untreated RA patients and HC upregulated PD-L1 expression similarly upon stimulation with CpG plus IL-2 and were able to suppress, , CD8 T cell proliferation and cytokine production in a PD-L1-dependent manner. Our results show that PD-L1 B cells exhibiting T cell suppressive capacity are significantly decreased in untreated RA patients but increase in response to successful treatment. PD-L1 expression on B cells from RA patients can be modulated and PD-L1 B cells could thus provide new perspectives for future treatment strategies.

Polariton canalization is characterized by intrinsic collimation of energy flow along a single crystalline axis. This optical phenomenon has been experimentally demonstrated at the nanoscale by stacking and twisting van der Waals (vdW) layers of α-MoO 3 , by combining α-MoO 3 and graphene, or by fabricating an h-BN metasurface. However, these material platforms have significant drawbacks, such as complex fabrication and high optical losses in the case of metasurfaces. Ideally, it would be possible to canalize polaritons “naturally” in a single pristine layer. Here, we theoretically predict and experimentally demonstrate naturally canalized phonon polaritons (PhPs) in a single thin layer of the vdW crystal LiV 2 O 5 . In addition to canalization, PhPs in LiV 2 O 5 exhibit strong field confinement ( λ p ~ λ 0 27 ), slow group velocity (0.0015c), and ultra-low losses (lifetimes of 2 ps). Our findings are promising for the implementation of low-loss optical nanodevices where strongly directional light propagation is needed, such as waveguides or optical routers. Canalized polaritons are light-matter excitations characterized by intrinsic collimation of electromagnetic energy along a specific crystal axis. Here, the authors report the observation of intrinsically canalized phonon polaritons in a single thin layer of a van der Waals crystal, LiV 2 O 5 .

Study Design Questionnaire-based survey. Objectives Surgical site infection (SSI) is a common complication in spine surgery but universal guidelines for SSI prevention are lacking. The objectives of this study are to depict a global status quo on implemented prevention strategies in spine surgery, common themes of practice and determine key areas for future research. Methods An 80-item survey was distributed among spine surgeons worldwide via email. The questionnaire was designed and approved by an International Consensus Group on spine SSI. Consensus was defined as more than 60% of participants agreeing to a specific prevention strategy. Results Four hundred seventy-two surgeons participated in the survey. Screening for Staphylococcus aureus (SA) is not common, whereas preoperative decolonization is performed in almost half of all hospitals. Body mass index (BMI) was not important for surgery planning. In contrast, elevated HbA1c level and hypoalbuminemia were often considered as reasons to postpone surgery. Cefazoline is the common drug for antimicrobial prophylaxis. Alcohol-based chlorhexidine is mainly used for skin disinfection. Double-gloving, wound irrigation, and tissue-conserving surgical techniques are routine in the operating room (OR). Local antibiotic administration is not common. Wound closure techniques and postoperative wound dressing routines vary greatly between the participating institutions. Conclusions With this study we provide an international overview on the heterogeneity of SSI prevention strategies in spine surgery. We demonstrated a large heterogeneity for pre-, peri- and postoperative measures to prevent SSI. Our data illustrated the need for developing universal guidelines and for testing areas of controversy in prospective clinical trials. Graphical Abstract