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First-line durvalumab in patients with PD-L1 positive, advanced non-small cell lung cancer (NSCLC) with a performance status of 2 (PS2). Primary analysis of the multicenter, single-arm phase II trial SAKK 19/17.
No full textINTRODUCTION
The safety and efficacy of first-line durvalumab in PS2 patients with advanced NSCLC is unknown. Here, we present the primary analysis of first-line durvalumab in PS2 patients, unsuitable for combination chemotherapy.
METHODS
In this single-arm, multicenter, phase II trial patients with PD-L1 positive (tumor proportional score ≥25%), advanced NSCLC with PS2, received four-weekly durvalumab 1500 mg. The primary endpoint was overall survival (OS) at 6 months.
RESULTS
Forty-eight patients were included. Median follow-up was 23.3 months (95% CI: 14.3-28.6). OS at 6 months was 60% (95% CI: 45-74%). Median OS was 8.5 months (95%CI: 4.4-16.7). Objective response rate and median progression free survival were 17% (95% CI: 8-30%) and 2.5 months (95% CI: 1.8-7.1), respectively. Thirty-three deaths were observed at the time point of the analysis. Seven early fatal events considered not treatment-related occurred during the first 5 weeks of treatment. Four out of the first 7 early fatal events (4/7; 57%) were respiratory failure in patients with advanced symptomatic primary lung tumors. Three more early fatal events occurred after exclusion of patients with grade ≥ 3 dyspnea. Treatment-related AEs ≥G3 were reported in 9 patients (19%) and included colonic perforation in one patient (grade 5), colitis in 4 patients (8%), increased lipase in 3 patients (6%), and hepatitis in 2 patients (4%).
CONCLUSIONS
First-line durvalumab in PS2 patients with advanced PD-L1 positive NSCLC results in a high number of early fatal events. When patients with grade ≥ 3 dyspnea are excluded a promising 6-month OS with an acceptable toxicity profile can be observed. Durvalumab could be an option instead of single agent chemotherapy for PS2 patients who are not candidates for platinum doublet chemotherapy provided they are well selected
Body weight and blood pressure changes on dolutegravir-, efavirenz- or atazanavir-based antiretroviral therapy in Zimbabwe: a longitudinal study.
Get PDFINTRODUCTION
Dolutegravir (DTG) is widely used for antiretroviral therapy (ART). We compared weight and blood pressure trends and examined the association between high blood pressure and weight gain among people living with HIV (PLHIV) switching to or starting DTG-based, efavirenz (EFV)-based and ritonavir-boosted atazanavir (ATV/r)-based ART in Zimbabwe.
METHODS
PLHIV aged 18 years or older who started or switched to DTG, EFV or ATV/r-based ART between January 2004 and June 2022 at Newlands Clinic in Harare, Zimbabwe, were eligible. Weight was measured at all visits (Seca floor scales); blood pressure only at clinician-led visits (Omron M2 sphygmomanometer). We used Bayesian additive models to estimate trends in weight gain and the proportion with high blood pressure (systolic >140 mmHg or diastolic >90 mmHg) in the first 2 years after starting or switching the regimen. Finally, we examined whether trends in the proportion with high blood pressure were related to weight change.
RESULTS
We analysed 99,969 weight and 35,449 blood pressure records from 9487 adults (DTG: 4593; EFV: 3599; ATV/r: 1295). At 24 months after starting or switching to DTG, estimated median weight gains were 4.54 kg (90% credibility interval 3.88-5.28 kg) in women and 3.71 kg (3.07-4.45 kg) in men, around twice that observed for ATV/r and over four-times the gain observed for EFV. Prevalence of high blood pressure among PLHIV receiving DTG-based ART increased from around 5% at baseline to over 20% at 24 months, with no change in PLHIV receiving EFV- or ATV/r-based ART. High blood pressure in PLHIV switching to DTG was associated with weight gain, with stronger increases in the proportion with high blood pressure for larger weight gains.
CONCLUSIONS
Among PLHIV starting ART or switching to a new regimen, DTG-based ART was associated with larger weight gains and a substantial increase in the prevalence of high blood pressure. Routine weight and blood pressure measurement and interventions to lower blood pressure could benefit PLHIV on DTG-based ART. Further studies are needed to elucidate the mechanisms and reversibility of these changes after discontinuation of DTG
A 10-step participatory program for developing, implementing, and evaluating physical activity promoting actions in nursing homes in Germany.
Get PDFBACKGROUND
Since multidimensional barriers challenge nursing homes, a socio-ecological approach is needed for physical activity promotion in this setting. So far, little is known about how such an approach can be transferred into the successful development and implementation of PA-promoting actions together with stakeholders on-site. We aimed to investigate the actions and dimensions of PA-promoting actions and their sustainable implementation. To contribute to closing this gap, we present a 10-step program for co-developing and co-evaluating PA-promoting actions in nursing homes through an integrated counselling approach.
METHODS
We used a multiple case study approach that built upon manifold data sources, collected in 7 nursing homes over 3 years between 2021 and 2023. We collected fieldnotes and photologs from 14 future workshops (2 per home); 7 evaluation workshops (1 per home); 36 individual counsellings (2 sessions per resident), as well as 87 implementation protocols (action type and frequency), 11 evaluation questionnaires (changes among resources, cooperations, and collaborations); 7 goal attainment scales and 18 individual activity schedules. In addition, we retrieved and documented progress information at regular intervals by phone or email.
RESULTS
With staff, residents, relatives, and volunteers, we co-developed 112 ideas for PA promotion; from which 54 ideas were implemented and integrated into everyday life, differentiated into "activities of daily living," "structured activities," and "activity-friendly environments."; 18 residents in 4 homes participated in individual counselling to develop individual activity schedules. Eighteen actions were rated as "(much) more successful than expected"; 10 "(much) worse than expected," and 23 "as successful as expected." Three actions were not evaluated.
DISCUSSION
The participatory integrated counselling approach led to home-specific actions and promoted implementation into everyday life. The number and dimensions of actions implemented largely depended on the mission and vision of the respective home. The lack of staff could partially be compensated for by involving neighbourhoods, volunteers, and community organisations, such as local clubs.
CONCLUSION
To effectively promote PA in nursing homes, a tailored approach considering structural conditions, locations, volunteer engagement, and organisational visions is essential. Long-lasting partnerships and low-threshold opportunities prove promising. Future research should delve into structural-level change processes and outcomes in this context
Light Color-Controlled pH-Adjustment of Aqueous Solutions Using Engineered Proteoliposomes.
Get PDFControlling the pH at the microliter scale can be useful for applications in research, medicine, and industry, and therefore represents a valuable application for synthetic biology and microfluidics. The presented vesicular system translates light of different colors into specific pH changes in the surrounding solution. It works with the two light-driven proton pumps bacteriorhodopsin and blue light-absorbing proteorhodopsin Med12, that are oriented in opposite directions in the lipid membrane. A computer-controlled measuring device implements a feedback loop for automatic adjustment and maintenance of a selected pH value. A pH range spanning more than two units can be established, providing fine temporal and pH resolution. As an application example, a pH-sensitive enzyme reaction is presented where the light color controls the reaction progress. In summary, light color-controlled pH-adjustment using engineered proteoliposomes opens new possibilities to control processes at the microliter scale in different contexts, such as in synthetic biology applications
Techniques of Endoscopic Ossiculoplasty.
Get PDFThe utilization of endoscopes in modern otology has evolved from diagnostic purposes to the development of exclusive endoscopic ear surgery. This technique offers a panoramic view of the middle ear and provides an optimal magnification of the oval window region, the stapes' suprastructure, and the footplate, allowing great precision in prosthesis positioning during ossiculoplasty (OPL). Various techniques for ossicular chain reconstruction have been described in the literature. Either autologous or synthetic materials can be used for reconstruction. The use of a patient's own tissue minimizes the risk of implant rejection or extrusion of the prosthesis through the tympanic membrane. On the other hand, synthetic materials like titanium are light and rigid and do not require time-consuming prosthesis remodeling. The main objective of this article is to present a comprehensive step-by-step guide that serves as a surgical manual for exclusive endoscopic OPL. This guide will explain various forms of OPL using synthetic and autologous materials. The goal is to provide a comprehensive understanding of the various surgical techniques and support the integration into clinical practice
Evolutionary trade-offs between testes size and parenting in Neotropical glassfrogs.
Get PDFIn males, large testes size signifies high sperm production and is commonly linked to heightened sperm competition levels. It may also evolve as a response to an elevated risk of sperm depletion due to multiple mating or large clutch sizes. Conversely, weapons, mate or clutch guarding may allow individuals to monopolize mating events and preclude sperm competition, thereby reducing the selection of large testes. Herein, we examined how paternal care, sexual size dimorphism (SSD), weaponry and female fecundity are linked to testes size in glassfrogs. We found that paternal care was associated with a reduction in relative testes size, suggesting an evolutionary trade-off between testes size and parenting. Although females were slightly larger than males and species with paternal care tended to have larger clutches, there was no significant relationship between SSD, clutch size and relative testes size. These findings suggest that the evolution of testes size in glassfrogs is influenced by sperm competition risk, rather than sperm depletion risk. We infer that clutch guarding precludes the risk of fertilization by other males and consequently diminishes selective pressure for larger testes. Our study highlights the prominent role of paternal care in the evolution of testes size in species with external fertilization
Bad social norms rather than bad believers: examining the role of social norms in bad beliefs.
Get PDFPeople with bad beliefs - roughly beliefs that conflict with those of the relevant experts and are maintained regardless of counter-evidence - are often cast as bad believers. Such beliefs are seen to be the result of, e.g., motivated or biased cognition and believers are judged to be epistemically irrational and blameworthy in holding them. Here I develop a novel framework to explain why people form bad beliefs. People with bad beliefs follow the social epistemic norms guiding how agents are supposed to form and share beliefs within their respective communities. Beliefs go bad because these norms aren't reliably knowledge-conducive. In other words, bad beliefs aren't due to bad believers but due bad social epistemic norms. The framework also unifies different explanations of bad beliefs, is testable and provides distinct interventions to combat such beliefs. The framework also helps to capture the complex and often contextual normative landscape surrounding bad beliefs more adequately. On this picture, it's primarily groups that are to be blamed for bad beliefs. I also suggest that some individuals will be blameless for forming their beliefs in line with their group's norms, whereas others won't be. And I draw attention to the factors that influence blameworthiness-judgements in these contexts
An der Schnittstelle zwischen Lexik und Pragmatik: Asymmetrien im Gebrauch der Intensivierung bei L1- und L2-Sprechenden des Deutschen mit Rätoromanisch als Erstsprache.
No full textZiel dieses Beitrags ist es, die lexikalisch-syntaktische Intensivierung von Adjektiven im Schweizerdeutschen zweier Gruppen von Rätoromanischsprechenden zu untersuchen: eine Gruppe mit L1 Rätoromanisch und Deutsch (d. h. bilingualer Spracherwerb) sowie eine Gruppe mit L1 Rätoromanisch und L2 (Schweizer)Deutsch. Die Intensivierung betrifft „das semantisch-funktionale Phänomen der Gradspezifikation“ (Kirchbaum 2002: 201), wobei Intensivierer Ausdrücke darstellen „that scale upwards on an imaginary scale of intensity such as very and terribly, and words that scale downwards, such as slightly and a bit“ (Paradis 1994: 157–158).
Die Erforschung von Intensivierer-Ausdrücken in L2-Varietäten (ausser Englisch) gilt insofern als vielversprechend, als L2-Sprechende über weniger Wissen von Kollokationen hinsichtlich Intensifier-Ausdrücke verfügen als L1-Sprechende, d. h., dass sich L2-Sprechende in ihrem Gebrauch von der L1-„Norm“ unterscheiden (vgl. Czerwionka & Olson 2020). Bislang nicht untersucht sind L2-Sprechende im ungesteuerten Erwerbsprozess in einer soziolinguistischen Konstellation, in der sie im Alltag intensiven Kontakt mit der L2 haben und diese Sprache nahezu auf L1-Niveau beherrschen. Ausserdem gilt die Erforschung der syntaktischen Intensivierung von Adjektiven insbesondere in den Dialekten des Deutschen im Gegensatz zur anglistisch orientierten Variationslinguistik (z. B. Ito & Tagliamonte 2003) als „underexplored“ (Stratton 2020: 183). Wir liefern mit dieser Studie einen Beitrag zur Frage, in welcher Hinsicht L2-Sprechende soziolinguistische Kompetenz im ungesteuerten Erwerbsprozess herausbilden können (vgl. Ender 2022).
Ausgewertet wird ein aus 40 unstrukturierten Interviews, 149.000 Token zählendes Korpus „Korpus Büchler“, das 2020–2021 zur Analyse des Sprachverhaltens von in Bern wohnenden Rätoroman:innen aus Graubünden erhoben wurde. Auf Grundlage eines von Pheiff (2023) ermittelten Samples wurden 53 Intensifier-Ausdrücke frequenziell ermittelt und im Hinblick auf die zwei genannten Gruppen verglichen. Insgesamt wurden 7950 Belege gefunden, wovon 2126 auf die L1-Gruppe entfallen. Folgender Fragestellung wird im Beitrag nachgegangen:
– Welche Unterschiede zeigen die zwei untersuchten Gruppen hinsichtlich der Frequenz und Distribution in Bezug auf die lexikalische Diversität der Adjektive, Kollokationen und syntaktische Distribution von Intensifier-Ausdrücken?
Erste Ergebnisse zeigen, dass die L2-Gruppe zwar eine grössere Diversität an verschiedenen Intensifier-Audrücken aufweist (L2: 41 vs. L1: 33), die Frequenz dieser Ausdrücke im Gespräch aber insgesamt etwas tiefer als bei der L1-Gruppe ist. Die Gebrauchsfrequenzen der einzelnen Intensifier-Ausdrücke unterschieden sich zum Teil deutlich zwischen den Gruppen. So zeigt sich beispielsweise, dass voll nur bei der L1-Gruppe zu den zehn tokenfrequentesten Ausdrücken gehört oder dass mega bei der L1-Gruppe deutlich frequenter verwendet wird als bei der L2-Gruppe. Interessanterweise lässt sich darüber hinaus hinsichtlich der zwei synonymen Ausdrücke chlii und bitz für die L1-Gruppe keine Präferenz feststellen, während die L2-Gruppe chlii häufiger verwendet als bitz
Plasma Protein Biomarkers Distinguish Multisystem Inflammatory Syndrome in Children From Other Pediatric Infectious and Inflammatory Diseases.
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Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious hyperinflammatory complication following infection with severe acute respiratory syndrome coronavirus 2. The mechanisms underpinning the pathophysiology of MIS-C are poorly understood. Moreover, clinically distinguishing MIS-C from other childhood infectious and inflammatory conditions, such as Kawasaki disease or severe bacterial and viral infections, is challenging due to overlapping clinical and laboratory features. We aimed to determine a set of plasma protein biomarkers that could discriminate MIS-C from those other diseases.
METHODS
Seven candidate protein biomarkers for MIS-C were selected based on literature and from whole blood RNA sequencing data from patients with MIS-C and other diseases. Plasma concentrations of ARG1, CCL20, CD163, CORIN, CXCL9, PCSK9 and ADAMTS2 were quantified in MIS-C (n = 22), Kawasaki disease (n = 23), definite bacterial (n = 28) and viral (n = 27) disease and healthy controls (n = 8). Logistic regression models were used to determine the discriminatory ability of individual proteins and protein combinations to identify MIS-C and association with severity of illness.
RESULTS
Plasma levels of CD163, CXCL9 and PCSK9 were significantly elevated in MIS-C with a combined area under the receiver operating characteristic curve of 85.7% (95% confidence interval: 76.6%-94.8%) for discriminating MIS-C from other childhood diseases. Lower ARG1 and CORIN plasma levels were significantly associated with severe MIS-C cases requiring inotropes, pediatric intensive care unit admission or with shock.
CONCLUSION
Our findings demonstrate the feasibility of a host protein biomarker signature for MIS-C and may provide new insight into its pathophysiology
Heterotopic ossification, osteolysis and implant failure following cervical total disc replacement with the M6-C™ artificial disc.
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A recent study reported a 34% mid-term revision rate after M6-C™ cervical total disc replacement (CTDR) for wear-related osteolysis. Here, we aim to investigate the prevalence, risk factors, and radiographic characteristics of periprosthetic bony changes and implant failure of the M6-C™ artificial disc.
METHODS
We retrospectively analysed radiographic (conventional X-ray, CT scan) and clinical outcomes (EQ-5D-5L, Neck Disability Index (NDI), and Visual Analog Scale (VAS) for neck and arm pain) data collected during routine follow-up of patients who underwent CTDR with the M6-C™ between 2011 and 2015.
RESULTS
In total, 85 patients underwent CTDR with the M6-C™. Follow-up data were available for 43 patients (54% female, mean age 44 years) with 50 implants and a mean follow-up of 8.1 years (6.5-11 years). Implant failure with the presence of severe osteolysis was identified in 5 (12%) patients who were all male (p = 0.016) and implanted at the C5/6 level (p = 0.11). All failed implants required revision surgery. The overall prevalence of osteolysis was 44% (22/50 implants) and 34% (17/50 implants) for significant heterotopic ossification. Patients with high-grade osteolysis showed higher VAS arm pain (p = 0.05) and lower EQ-5D-VAS health VAS (p = 0.03).
CONCLUSION
We report a lower reoperation rate for failed M6-C™ implants than previously published, but confirmed that osteolysis and heterotopic ossification are common following CTDR with the M6-C™ and may be asymptomatic. Therefore, we strongly recommend ongoing clinical and radiographic monitoring after CTDR with the M6-C™, particularly for male patients implanted at the C5/6 level
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