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Cardiovascular Risk in Cancer Patients Treated with Immune Checkpoint Inhibitors: Challenges and Future Directions.
No full textCardiovascular disease is the leading cause of non-cancer related mortality and morbidity among people living with or cured from cancer. Immune checkpoint inhibitors (ICIs) are systemic anti-cancer therapies that have revolutionised the treatment of numerous cancers, even achieving durable long-term responses among patients with metastatic disease. However, the pro-inflammatory effects of ICIs have been postulated to increase the risk of atherosclerotic cardiovascular disease (ASCVD) in cancer survivorship. Standard modifiable cardiovascular risk factors can further contribute to ASCVD risk during cancer survivorship but are not routinely screened and are often untreated in patients with cancer. With the expanding use of ICIs leading to improved cancer survivorship, cardiovascular risk identification and prevention will be paramount in the care of patients with cancer. This review highlights the practical challenges associated with ASCVD prevention among the growing number of patients treated with ICIs for cancer, including balancing competing mortality risks from cancer and ASCVD, the lack of ICI-specific cardiovascular risk stratification tools, potential interactions between cardiovascular and oncological therapies, and barriers to implementation of cardiovascular screening and prevention within existing healthcare systems
Comparative Efficacy and Acceptability of Treatment Strategies for Antipsychotic-Induced Akathisia: A Systematic Review and Network Meta-analysis.
No full textBACKGROUND
Antipsychotics are the treatment of choice for schizophrenia, but they often induce akathisia. However, comparative efficacy of treatment strategies for akathisia remains unclear.
DESIGN
We performed a systematic review and network meta-analyses (PROSPERO CRD42023450720). We searched multiple databases on July 24, 2023. We included randomized clinical trials comparing 1 or more treatment strategies for antipsychotic-induced akathisia against each other or control conditions. We included adults with schizophrenia or other psychiatric disorders treated with antipsychotics. The primary outcome was akathisia severity at posttreatment. Secondary outcomes included akathisia response, all-cause dropout, psychotic symptoms, and long-term akathisia severity. We synthesized data in random effects frequentist network meta-analyses and assessed confidence in the evidence using CINeMA.
RESULTS
We identified 19 trials with 661 randomized participants (mean age 35.9 [standard deviation 12.0]; 36.7% [195 of 532] women). No trials examined dose reduction or switching of antipsychotics. Findings suggested 5-HT2A antagonists (k = 6, n = 108; standardized mean difference [SMD] -1.07 [95% confidence interval, -1.42; -0.71]) and beta-blockers (k = 8, n = 105; SMD -0.46 [-0.85; -0.07]) may improve akathisia severity, but confidence in the evidence was deemed low. We also found that benzodiazepines (k = 2, n = 13; SMD -1.62 [-2.64; -0.59]) and vitamin B6 (k = 3, n = 67; SMD -0.99 [-1.49; -0.50]) might also be beneficial, but confidence in the evidence was very low. Analyses of secondary outcomes did not provide additional insights.
CONCLUSIONS
Our findings suggest that 5-HT2A antagonists, beta-blockers, and with a lesser certainty, benzodiazepines, and vitamin B6 might improve akathisia. Given the low to very low confidence in the evidence of add-on agents and the absence of evidence of their long-term efficacy, careful consideration of side effects is warranted. These recommendations are extremely preliminary and further trials are needed
Acute post-renal kidney graft dysfunction due to cytomegalovirus-positive nephrogenic adenoma-case report and review of the literature.
Get PDFTissue-invasive cytomegalovirus (CMV) disease represents a well-recognized complication after kidney transplantation. However, direct involvement of the urogenital tract and CMV-ureteritis occur less frequently. Nephrogenic adenomas are benign lesions of the urinary tract preferentially reported in kidney transplant recipients. We herein report a second case of a 33-year-old male kidney transplant recipient with acute post-renal allograft dysfunction due to CMV-positive ureteral nephrogenic adenoma. A causal connection might be suspected but remains to be proven
Population pharmacokinetics of TLD-1, a novel liposomal doxorubicin, in a phase I trial.
Get PDFSTUDY OBJECTIVES
TLD-1 is a novel pegylated liposomal doxorubicin (PLD) formulation aiming to optimise the PLD efficacy-toxicity ratio. We aimed to characterise TLD-1's population pharmacokinetics using non-compartmental analysis and nonlinear mixed-effects modelling.
METHODS
The PK of TLD-1 was analysed by performing a non-compartmental analysis of longitudinal doxorubicin plasma concentration measurements obtained from a clinical trial in 30 patients with advanced solid tumours across a 4.5-fold dose range. Furthermore, a joint parent-metabolite PK model of doxorubicinentrapped, doxorubicinfree, and metabolite doxorubicinol was developed. Interindividual and interoccasion variability around the typical PK parameters and potential covariates to explain parts of this variability were explored.
RESULTS
Medians standard deviations of dose-normalised doxorubicinentrapped+free Cmax and AUC0-∞ were 0.342 0.134 mg/L and 40.1 18.9 mg·h/L, respectively. The median half-life (95 h) was 23.5 h longer than the half-life of currently marketed PLD. The novel joint parent-metabolite model comprised a one-compartment model with linear release (doxorubicinentrapped), a two-compartment model with linear elimination (doxorubicinfree), and a one-compartment model with linear elimination for doxorubicinol. Body surface area on the volumes of distribution for free doxorubicin was the only significant covariate.
CONCLUSION
The population PK of TLD-1, including its release and main metabolite, were successfully characterised using non-compartmental and compartmental analyses. Based on its long half-life, TLD-1 presents a promising candidate for further clinical development. The PK characteristics form the basis to investigate TLD-1 exposure-response (i.e., clinical efficacy) and exposure-toxicity relationships in the future. Once such relationships have been established, the developed population PK model can be further used in model-informed precision dosing strategies.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov-NCT03387917-January 2, 2018
Fracture resistance of CAD/CAM milled versus direct hand-made interim laminate veneers.
Get PDFBACKGROUND
Comparative studies of interim veneer restorations crafted using subtractive computer-aided manufacturing (s-CAM) milling technology and traditional direct hand-made approaches are needed.
PURPOSE
This comparative in vitro study evaluated the fracture resistance of two types of provisional veneer restorations for maxillary central incisors: milled (s-CAM) and traditional direct hand-made bis-acryl veneers.
MATERIALS AND METHODS
Fifty maxillary right central incisor veneers (25 specimens per group) were fabricated and divided according to the fabrication method: (1) s-CAM milled (Structure CAD, VOCO Dental); and (2) hand-made (Protemp Plus, 3M). The restorations were cemented onto 3D-printed resin dies using temporary cement and subjected to 1000 cycles of thermal cycling between 5° and 55 °C. These restorations subsequently were subjected to compressive loading until fracture occurred. Images of the fractured samples were captured using a scanning electron microscope (SEM). Statistical analysis was performed using the one-way ANOVA test and the Mann-Whitney U test.
RESULTS
Significant differences (p < 0.001) in the fracture resistance were observed between the two groups. s-CAM milled interim veneers displayed higher fracture resistance values (439.60 ± 26 N) compared to the traditional method (149.15 ± 10 N).
CONCLUSION
The manufacturing method significantly influences the fracture resistance of interim veneer restorations. s-CAM interim laminate veneer restorations for maxillary central incisors exhibit a fracture resistance superior to that of the traditional method using bis-acryl.Clinical relevanceClinicians should consider CAD/CAM milled veneers for scenarios demanding long-term interim restoration and the withstanding of high occlusal forces
Embodied Geopolitics: The Discursive Construction of Refugee Men and Masculinities in Turkey
No full textA new wave of displaced people from Afghanistan arriving in
Turkey in August-September 2021 generated public debates
about how the country would protect its borders while continuing
to face the ‘problem’ posed by more than 3 million displaced
Syrians. Much of these debates centred on refugee men and
scrutinised their bodies and bodily acts to produce them as
Other. This article analyses how the racialised and gendered
depictions of refugee men in Turkey discursively produce geopolitical
spatial hierarchies. Our analysis includes political leaders’
speeches, news articles, and opinion pieces published in
mainstream media outlets and social media about displaced
people from Syria and Afghanistan since 2016. We build on
and contribute to feminist geopolitics and refugee studies by
focusing on refugee men and masculinities, teasing out the
contradictions in the geopolitical narratives centred on refugee
men’s bodies, and analysing their implications for representing
civilisational hierarchies. Using the concept of embodied geopolitics,
we show how the dominant anti-refugee discourse in
Turkey operates through a series of contradictory -but eventually
complementary- geopolitical depictions of refugee men’s
bodies, appearance, and behaviour that simultaneously masculinise
and feminise them. These portrayals present refugee men
either as fighters or cowards, as modern or backward. We argue
that gendered and racialised refugee bodies animate geopolitical
narratives and demonstrate that bodies are not simply
territories with fixed meanings. Instead, they are constantly
and simultaneously inscribed with multiple meanings that operate
together and, ultimately, produce international hierarchies,
ethnic boundaries, and the modern/backward dualism
The applicative constructions of Mapudungun
No full textThis chapter surveys the morphology, syntax, and semantics of the applicative constructions of Mapudungun (isolate; Chile/Argentina). The four markers addressed are the verbal suffixes -l, -ñma, -tu, and -ye. With respect to syntax, the Mapudungun constructions introduce to the clausal core an argument in P role (which, given the symmetrical-voice make-up of clausal syntax in the language, appears as either a subject or an object, depending on factors unrelated to applicativization). With respect to the semantic role of the applied phrase, the markers are relatively underspecified, albeit with some tendencies: l- and ñma-applicatives center around the notions of approach/benefaction and separation/malefaction, respectively, but they can also express a broader Concernee-Concern relation; tu-applicatives typically introduce Stimuli, Goals, or Patients; and ye-applicatives introduce Comitatives or Speech/Thought Topics. The marker -l also causativizes (with some complicating aspects in the allomorphy found with both processes), -ñma appears on verbal/adverbial roots expressing spatial, temporal, and manner notions, and -tu and -ye also function as denominal verbalizers. The suffix -tu also has a number of other functions, including telicization and the derivation of reversionary/repetitive forms (both of which are frequent), as well as antipassivization (which is severely restricted and infrequent)
Hematopoietic cell transplantation and cellular therapies in Switzerland. Evolution over 25 years. A report from the stem cell transplantation and cellular therapies working groups of the SBST 1997-2021.
No full textThe Swiss Blood Stem Cell Transplantation and Cellular Therapy Group (SBST) leads a mandatory national registry for all hematopoietic stem cell transplants (HCT) and cellular therapies. After 25 years, information was available for 11,226 patients receiving an HCT (4031 allogeneic and 7195 autologous), including 925 pediatric patients. We compared patient characteristics and outcome by quinquennia 1997-2001, 2002-2006, 2007-2011, 2012-2016, and 2017-2021. There were numerous changes over time. Allogeneic transplant recipients became older (median age 33.7 vs. 54.3) and had more frequently unrelated donors and reduced intensity conditioning in later quinquennia. Similarly, age increased for recipients of autologous HCT (median 48.3 vs. 59.9). We did not see a significant drop in transplant activity during the SARS-CoV-2 pandemic. Analysis of outcome showed overall survival (relative risk (RR) of death 0.664 (0.529-0.832) and progression free survival (RR 0.708 (0.577-0.870) being improved over time comparing the latest to the first quinquennium adjusting for risk factors. Non-relapse mortality decreased in recipients of allogeneic HCT (RR: 0.371 (0.270-0.509)) over time but relapse risks did not. Outcome of autologous HCT improved as well across quinquennia, this improvement was mainly due to decreased relapse risks (RR 0.681 (0.597-0.777)), possibly related to maintenance treatment or rescue treatment for relapse mainly in myeloma patients. Cellular therapies other than allogeneic or autologous HCT, particularly chimeric antigen receptor T-cells (CAR-T) treatment have started to increase after 2019, year of approval of the first commercial CAR-T product in Switzerland. Data on chimeric antigen receptor T-cell treatment are too early for comparative analyses. Detailed analyses of changes over time are presented. This study includes all HCTs, and cellular therapies, data useful for quality assurance programs, health care cost estimation and benchmarking. Between 50% and 60% of patients are long-term survivors after both types of HCT, indicating growing populations of surviving patients requiring long-term care
Cation-exchange properties of the Mesozoic sedimentary sequence of northern Switzerland and modelling of the Opalinus Clay porewater
Get PDFIn Switzerland, radioactive waste management requires the safe disposal of nuclear waste within a deep geological argillaceous sequence that includes the Jurassic-age Opalinus Clay. The process of selecting a suitable site for the disposal is ongoing and involves a rigorous site selection process. As part of this process, site-specific physico-chemical data were collected, which include parameters such as cation exchange capacities (CEC) and exchangeable cation occupancies, in addition to other geochemical and mineralogical data. The mineralogy, CEC and exchangeable cation occupancies of rock samples collected from the various lithologies of cores from seven boreholes across the study areas, namely Zürich Nordost (ZNO), Nördlich Lägern (NL) and Jura Ost (JO) were investigated. Four different CEC methods were applied, and the results obtained are in good agreement. The general trend in the CEC data follows: Cs-CEC ≥ (ΣCations) > Ni-CEC. The higher Cs-CEC values are due to the higher interlayer extraction yields of low hydration cations K+ and NH4+ in illite rich rock samples by the highly selective Cs+. A clear correlation between the 2:1 phyllosilicate content and the CEC values is observed over the entire sequence, so clay minerals primarily govern cation exchange processes and thus the retention of cations. Finally, for the Opalinus Clay of each of the three study areas, porewater chemistries were modelled based on a combination of mineralogical and physico-chemical data. The calculated porewater compositions are in good agreement with the compositions obtained from squeezing and advective displacement experiments in the laboratory
Staatszeremoniell und Sicherheitsmanagement des Schweizer Bundesstaates im frühen 20. Jahrhundert am Beispiel des Staatsbesuches von Kaiser Wilhelm II. 1912
Get PDFZiel der vorliegenden Monografie ist es, das Sicherheitsmanagement und das Staatszeremoniell des Kaiserbesuchs zu untersuchen. Es interessieren dabei nicht nur die vielschichtigen festgelegten Sicherheitsmassnahmen zum Schutz des Kaisers, sondern auch die übergeordneten Feindbilder der beteiligten Schweizer Sicherheitsbehörden und den ihnen zu Hilfe gesandten deutschen Kriminalbeamten. Di Untersuchung zeigt auf, wie anarchistische oder anarchistisch deklarierte Terroranschläge die anarchistische Bewegung zum archetypischen Feindbild machten. Das Attentat auf Kaiserin Elisabeth in Genf 1898 führte zu national und international koordinierten Bemühungen zur Bekämpfung des Anarchismus. Gegen Ende des langen 19. Jahrhunderts kam es zudem in der europäischen Politik mit Blick auf Staatsbesuche zu einem Prozess der Theatralisierung. Dazu kam ein neuartiger Glanz, mit dem sich die Königshäuser Europas präsentierten und inszenierten. Diese Theatralisierung kann die Monografie auch für den Kaiserbesuch 1912 in der Schweiz nachgewiesen
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