T cell engagers represent a novel promising class of cancer-immunotherapies redirecting T cells to tumor cells and have some promising outcomes in the clinic. These molecules can be associated with a mode-of-action related risk of cytokine release syndrome (CRS) in patients. CRS is characterized by the rapid release of pro-inflammatory cytokines such as TNF-α, IFN-γ, IL-6 and IL-1β and immune cell activation eliciting clinical symptoms of fever, hypoxia and hypotension. In this work, we investigated the biological mechanisms triggering and amplifying cytokine release after treatment with T cell bispecific antibodies (TCBs) employing an in vitro co-culture assay of human PBMCs or total leukocytes (PBMCs + neutrophils) and corresponding target antigen-expressing cells with four different TCBs. We identified T cells as the triggers of the TCB-mediated cytokine cascade and monocytes and neutrophils as downstream amplifier cells. Furthermore, we assessed the chronology of events by neutralization of T-cell derived cytokines. For the first time, we demonstrate the contribution of neutrophils to TCB-mediated cytokine release and confirm these findings by single-cell RNA sequencing of human whole blood incubated with a B-cell depleting TCB. This work could contribute to the construction of mechanistic models of cytokine release and definition of more specific molecular and cellular biomarkers of CRS in the context of treatment with T-cell engagers. In addition, it provides insight for the elaboration of prophylactic mitigation strategies that can reduce the occurrence of CRS and increase the therapeutic index of TCBs.
This paper characterizes the relationship between monetary aggregates, inflation and economic activity in Switzerland since the mid-1970s. Traditional forms of money demand and quantity theory relationships have remained stable over the whole period. Broad money excesses over trend values, accounting for a secular decline in interest rates and thus in trend velocity, have been followed by persistently higher inflation and output with the usual monetary policy transmission lags. Money and exchange rate fluctuations can explain the major inflation developments in Switzerland over the past four decades.
Background: Schistosomiasis remains an important public health problem, also among adults, and infected individuals not treated serve as a reservoir for continued transmission. Despite this fact, evidence on the epidemiology of schistosomiasis in adults in Côte d'Ivoire is scanty. This study aimed to determine the prevalence and risk factors of Schistosoma infection and co-infection with other helminth species and Plasmodium among adults in the Taabo region in the south-central part of Côte d'Ivoire. Methods: A cross-sectional survey was carried out in April and May 2017 in the frame of the "Côte d'Ivoire Dual Burden of Disease Study" (CoDuBu). A total of 901 randomly selected individuals, aged 18-90 years, provided blood, stool and urine samples for the diagnosis of malaria and helminth infections. Stool samples were subjected to the Kato-Katz technique for detection of Schistosoma mansoni and soil-transmitted helminth eggs, while urine samples were examined for eggs of Schistosoma haematobium and circulating cathodic antigen of S. mansoni. Risk factors and morbidity profiles were assessed using health examination and questionnaires. Multinomial logistic regressions were employed to identify risk factors and morbidity patterns associated with S. mansoni mono- and co-infections. Results: The prevalence of S. mansoni and S. haematobium was 23.2% and 1.0%, respectively. Most S. mansoni were mono-infections (81.3%). Independent determinants of S. mansoni infection were young age, low socioeconomic status (mono- and co-infection) and poor hygiene practices (co-infection) (P < 0.05). S. mansoni infection was independently associated with higher pain and symptom scores (mono-infection), poor self-rated health and low healthcare use (co-infection) (P < 0.05). Conclusions: This study showed that adults represent a substantial reservoir of S. mansoni. To sustain schistosomiasis control and improve people's wellbeing, it is important to expand preventive chemotherapy from school-aged children to adults, coupled with hygiene and health education.
Background The aim of this study was to explore the relationship between follow-up imaging characteristics and overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients under sorafenib treatment. Methods Associations between OS and objective response (OR) by mRECIST or early tumor shrinkage (ETS; ≥20% reduction in enhancing tumor diameter at the first follow-up imaging) were analyzed in HCC patients treated with sorafenib within a multicenter phase II trial (SORAMIC). 115 patients were included in this substudy. The relationship between survival and OR or ETS were explored. Landmark analyses were performed according to OR at fixed time points. Cox proportional hazards models with OR and ETS as a time-dependent covariate were used to compare survival with factors known to influence OS. Results The OR rate was 29.5%. Responders had significantly better OS than non-responders (median 30.3 vs. 11.4 months; HR, 0.38 [95% CI, 0.22–0.63], p < 0.001), and longer progression-free survival (PFS; median 10.1 vs. 4.3 months, p = 0.015). Patients with ETS ≥ 20% had longer OS (median 22.1 vs. 11.4 months, p = 0.002) and PFS (median 8.0 vs. 4.3 months, p = 0.034) than patients with ETS < 20%. Besides OR and ETS, male gender, lower bilirubin and ALBI grade were associated with improved OS in univariate analysis. Separate models of multivariable analysis confirmed OR and ETS as independent predictors of OS. Conclusion OR according to mRECIST and ETS in patients receiving sorafenib treatment are independent prognostic factors for OS. These parameters can be used for assessment of treatment benefit and optimal treatment sequencing in patients with advanced HCC.
People living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n = 600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n = 8111) from blood DNA-derived exome sequences. We observed that HIV is associated with a twofold increase in CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p = 0.005). We also observed that ASXL1 is the most commonly mutated CHIP-associated gene in PLWH. Our results suggest that CHIP may contribute to the excess cardiovascular risk observed in PLWH.
Mapping the thermal transport properties of materials at the nanoscale is of critical importance for optimizing heat conduction in nanoscale devices. Several methods to determine the thermal conductivity of materials have been developed, most of them yielding an average value across the sample, thereby disregarding the role of local variations. Here, we present a method for the spatially resolved assessment of the thermal conductivity of suspended graphene by using a combination of confocal Raman thermometry and a finite-element calculations-based fitting procedure. We demonstrate the working principle of our method by extracting the two-dimensional thermal conductivity map of one pristine suspended single-layer graphene sheet and one irradiated using helium ions. Our method paves the way for spatially resolving the thermal conductivity of other types of layered materials. This is particularly relevant for the design and engineering of nanoscale thermal circuits (e.g. thermal diodes).
Background In recent years, a programme of vector control, screening and treatment of gambiense human African trypanosomiasis (gHAT) infections led to a rapid decline in cases in the Mandoul focus of Chad. To represent the biology of transmission between humans and tsetse, we previously developed a mechanistic transmission model, fitted to data between 2000 and 2013 which suggested that transmission was interrupted by 2015. The present study outlines refinements to the model to: (1) Assess whether elimination of transmission has already been achieved despite low-level case reporting; (2) quantify the role of intensified interventions in transmission reduction; and (3) predict the trajectory of gHAT in Mandoul for the next decade under different strategies. Method Our previous gHAT transmission model for Mandoul was updated using human case data (2000–2019) and a series of model refinements. These include how diagnostic specificity is incorporated into the model and improvements to the fitting method (increased variance in observed case reporting and how underreporting and improvements to passive screening are captured). A side-by-side comparison of fitting to case data was performed between the models. Results We estimated that passive detection rates have increased due to improvements in diagnostic availability in fixed health facilities since 2015, by 2.1-fold for stage 1 detection, and 1.5-fold for stage 2. We find that whilst the diagnostic algorithm for active screening is estimated to be highly specific (95% credible interval ( CI ) 99.9–100%, Specificity = 99.9%), the high screening and low infection levels mean that some recently reported cases with no parasitological confirmation might be false positives. We also find that the focus-wide tsetse reduction estimated through model fitting (95% CI 96.1–99.6%, Reduction = 99.1%) is comparable to the reduction previously measured by the decline in tsetse catches from monitoring traps. In line with previous results, the model suggests that transmission was interrupted in 2015 due to intensified interventions. Conclusions We recommend that additional confirmatory testing is performed in Mandoul to ensure the endgame can be carefully monitored. More specific measurement of cases, would better inform when it is safe to stop active screening and vector control, provided there is a strong passive surveillance system in place. Graphical Abstract
Background Noise exposure leads to a reduction in cognitive abilities in diverse settings, however, only limited data exist examining the effects of environmental ICU noise on the cognitive performance of ICU professionals. A frequently occurring and demanding retention task in ICUs are ward rounds, which are considered key for the provision of medical care. Here, we investigate the influence of noise on information retention in a simulated ward round. Methods ICU professionals were exposed to a recorded, ICU ward round, simulated partly with and partly without environmental ICU noise. Ward rounds were followed by specific questions about previously provided information. Results 56 ICU professionals (aged 26–59 years) were included. A logistic mixed model showed a reduction of 27% ( P < 0.001) in the ward round test performance when participants were exposed to environmental ICU noise. Furthermore, advanced age was associated with reduced retention (− 28%, P < 0.001), questions containing important information performed better (+ 36%, P < 0.001), and higher stress led to better performance in retention (+ 24%, P = 0.01). Conclusions Our data showed a considerable negative influence of environmental ICU noise during a simulated ward round. Therefore, reduction of environmental ICU noise is recommended. The influence of additional factors, including stress, priorities, and demographic factors should be pursued in subsequent investigations.
Background The Livelihood Empowerment against Poverty (LEAP) programme in Ghana as part of its beneficiary programme, identifies the poor/indigents for exemptions from premium payments in the National Health Insurance Scheme (NHIS). This paper sought to understand community perceptions of enrolling the poor in the NHIS through LEAP in order to inform policy. Methods The study adopted a descriptive cross-sectional study design by using a qualitative approach. The study was conducted in three geographical regions of Ghana: Greater Accra, Brong-Ahafo and Northern region representing the three ecological zones of Ghana between October 2017 and February 2018. The study population included community members, health workers, NHIS staff and social welfare officers/social development officers. Eighty-one in-depth interviews and 23 Focus Group Discussions were conducted across the three regions. Data were analysed thematically and verbatim quotes from participants were used to support the views of participants. Results The study shows that participants were aware of the existence of LEAP and its benefits. There was, however, a general belief that the process of LEAP had been politicized and therefore favours only people who were sympathizers of the ruling government as they got enrolled into the NHIS. Participants held the view that the process of selecting beneficiaries lacked transparency, thus, they were not satisfied with the selection process. However, the study shows the ability of the community to identify the poor. The study reports varying concepts of poverty and its identification across the three ecological zones of Ghana. Conclusion There is a general perception of politicization and lack of transparency of the selection of the poor into the NHIS through the LEAP programme in Ghana. Community-based approaches in the selection of the indigent are recommended to safeguard the NHIS-LEAP beneficiary process.
The identification of nanomaterials with the properties required for energy-efficient electronic systems is usually a tedious human task. A workflow to rapidly localize and characterize nanomaterials at the various stages of their integration into large-scale fabrication processes is essential for quality control and, ultimately, their industrial adoption. In this work, we develop a high-throughput approach to rapidly identify suspended carbon nanotubes (CNTs) by using high-speed Raman imaging and deep learning analysis. Even for Raman spectra with extremely low signal-to-noise ratios (SNRs) of 0.9, we achieve a classification accuracy that exceeds 90%, while it reaches 98% for an SNR of 2.2. By applying a threshold on the output of the softmax layer of an optimized convolutional neural network (CNN), we further increase the accuracy of the classification. Moreover, we propose an optimized Raman scanning strategy to minimize the acquisition time while simultaneously identifying the position, amount, and metallicity of CNTs on each sample. Our approach can readily be extended to other types of nanomaterials and has the potential to be integrated into a production line to monitor the quality and properties of nanomaterials during fabrication.
Patients developing perioperative myocardial infarction/injury (PMI) have a high mortality. PMI work-up and therapy remain poorly defined. This prospective multicenter study included high-risk patients undergoing major non-cardiac surgery within a systematic PMI screening and clinical response program. The frequency of cardiovascular imaging during PMI work-up and its yield for possible type 1 myocardial infarction (T1MI) was assessed. Automated PMI detection triggered evaluation by the treating physician/cardiologist, who determined selection/timing of cardiovascular imaging. T1M1 was considered with the presence of a new wall motion abnormality within 30 days in transthoracic echocardiography (TTE), a new scar or ischemia within 90 days in myocardial perfusion imaging (MPI), and Ambrose-Type II or complex lesions within 7 days of PMI in coronary angiography (CA). In patients with PMI, 21% (268/1269) underwent at least one cardiac imaging modality. TTE was used in 13% (163/1269), MPI in 3% (37/1269), and CA in 5% (68/1269). Cardiology consultation was associated with higher use of cardiovascular imaging (27% versus 13%). Signs indicative of T1MI were found in 8% of TTE, 46% of MPI, and 63% of CA. Most patients with PMI did not undergo any cardiovascular imaging within their PMI work-up. If performed, MPI and CA showed high yield for signs indicative of T1MI. Trial registration: https://clinicaltrials.gov/ct2/show/NCT02573532 .
Objective In sub-Saharan Africa, 45% of the rural population uses boreholes (BHs). Despite recent gains in improved water access and coverage, parallel use of unimproved sources persists. Periodic infrastructure disrepair contributes to non-exclusive use of BHs. Our study describes functionality of BHs in 2014, 2015, and 2016 in 15 rural towns in the Eastern Region of Ghana sourced from three groundwater quality clusters (high iron, high salinity, and control). We also assess factors affecting cross-sectional and longitudinal functionality using logistic regression. Results BH functionality rates ranged between 81 and 87% and were similar across groundwater quality clusters. Of 51 BHs assessed in all three years, 34 (67%) were consistently functional and only 3 (6%) were consistently broken. There was a shift toward proactive payment for water over the course of the study in the control and high-salinity clusters. Payment mechanism, population served, presence of nearby alternative water sources, and groundwater quality cluster were not significant predictors of cross-sectional or longitudinal BH functionality. However, even in the high iron cluster, where water quality is poor and no structured payment mechanism for water exists, BHs are maintained, showing that they are important community resources.
Background Endovascular embolization techniques are nowadays well established in the management of acute arterial bleedings. However, the education and training of the next generation of interventionalists are still based on the traditional apprenticeship model, where the trainee learns and practices directly at the patient, which potentially affects the patient’s safety. The objective of this study was to design and develop a standardized endovascular simulation concept for the training of acute bleeding embolizations, based on real-life cases. Results An adaptable and cost-effective endovascular simulator was developed using an in-house 3D print laboratory. All thoracic and abdominal acute bleeding embolizations over more than a year with appropriate pre-interventional computed tomography scans were included to manufacture 3D printed vascular models. A peristaltic pump was used to generate pulsatile flow curves. Forty embolization cases were engaged in this study, and 27 cases were fully reproduced in the simulation setting (69.23%). The simulation success was significantly lower in pulmonary embolizations ( p = 0.031) and significantly higher in soft tissue ( p = 0.032) and coil embolizations ( p = 0.045). The overall simulation success was 7.8 out of 10 available points. Conclusions Using stereolithography 3D printing in a standardized simulation concept, endovascular embolization techniques for treating acute internal hemorrhages in the chest and abdomen can be simulated and trained based on the patient-specific anatomy in a majority of the cases and at a broad spectrum of different causes.
Objective The combined use of action observation and motor imagery (AOMI) is a promising technique in neurorehabilitation that can be usefully applied in addition to conventional forms of therapy. Previous studies with healthy participants showed that the mere passive observation of walking results in a phase-dependent reflex modulation in the tibialis anterior muscle that resembles the pattern occurring when walking. In patients after stroke, a similar reflex modulation was found in several lower limb muscles during the real execution of walking, but responses were blunted. To clarify whether and how lower limb reflex responses are also modulated in such patients during the combined synchronous observation and imagery of walking, medium-latency cutaneous reflexes from the tibialis anterior muscle were measured. We compared the reflex responses of seven patients after stroke during the AOMI of walking from two different conditions: (a) elicited during the end stance phase and (b) during the end swing phase, both normalized to a baseline condition. Results So far, using the identical methodological set-up as in our study with healthy individuals, we could not find any noteworthy reflex response modulation. The study was registered with the German Clinical Trials Register (DRKS00028255). Trial registration : The study was registered with the German Clinical Trials Register: DRKS00028255.
Background Substantial research is underway to develop next-generation interventions that address current malaria control challenges. As there is limited testing in their early development, it is difficult to predefine intervention properties such as efficacy that achieve target health goals, and therefore challenging to prioritize selection of novel candidate interventions. Here, we present a quantitative approach to guide intervention development using mathematical models of malaria dynamics coupled with machine learning. Our analysis identifies requirements of efficacy, coverage, and duration of effect for five novel malaria interventions to achieve targeted reductions in malaria prevalence. Methods A mathematical model of malaria transmission dynamics is used to simulate deployment and predict potential impact of new malaria interventions by considering operational, health-system, population, and disease characteristics. Our method relies on consultation with product development stakeholders to define the putative space of novel intervention specifications. We couple the disease model with machine learning to search this multi-dimensional space and efficiently identify optimal intervention properties that achieve specified health goals. Results We apply our approach to five malaria interventions under development. Aiming for malaria prevalence reduction, we identify and quantify key determinants of intervention impact along with their minimal properties required to achieve the desired health goals. While coverage is generally identified as the largest driver of impact, higher efficacy, longer protection duration or multiple deployments per year are needed to increase prevalence reduction. We show that interventions on multiple parasite or vector targets, as well as combinations the new interventions with drug treatment, lead to significant burden reductions and lower efficacy or duration requirements. Conclusions Our approach uses disease dynamic models and machine learning to support decision-making and resource investment, facilitating development of new malaria interventions. By evaluating the intervention capabilities in relation to the targeted health goal, our analysis allows prioritization of interventions and of their specifications from an early stage in development, and subsequent investments to be channeled cost-effectively towards impact maximization. This study highlights the role of mathematical models to support intervention development. Although we focus on five malaria interventions, the analysis is generalizable to other new malaria interventions. Graphical abstract
The funding ratio is a financial indicator to measure the viability of pension funds. The paper analyzes how Swiss occupational pension funds’ technical discount rate and asset allocation are related to the funding ratio. The paper shows that funds with weaker funding ratios apply higher rates to discount future pension liabilities what points toward euphemistic discounting. Further, weaker funded pension funds invest less in equities—with the exception of pension funds below the regulatory minimum threshold. The latter invest more in equities than funds above the threshold, which points to gambling for resurrection. The findings question the funding ratio as a transparent measure for pensions’ sustainability and unfold the regulatory environment’s disincentives.
Institution pages aggregate content on ResearchGate related to an institution. The members listed on this page have self-identified as being affiliated with this institution. Publications listed on this page were identified by our algorithms as relating to this institution. This page was not created or approved by the institution. If you represent an institution and have questions about these pages or wish to report inaccurate content, you can contact us here.