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Abstract Current antibody-based immunotherapy depends on tumor antigen shedding for proper T cell priming. Here we select a novel human CD40 agonistic drug candidate and generate a bispecific antibody, herein named BiA9*2_HF, that allows for rapid antibody-peptide conjugate formation. The format is designed to facilitate peptide antigen delivery to CD40 expressing cells combined with simultaneous CD40 agonistic activity. In vivo, the selected bispecific antibody BiA9*2_HF loaded with peptide cargos induces improved antigen-specific proliferation of CD8+ (10-15 fold) and CD4+ T cells (2-7 fold) over control in draining lymph nodes. In both virus-induced and neoantigen-based mouse tumor models, BiA9*2_HF demonstrates therapeutic efficacy and elevated safety profile, with complete tumor clearance, as well as measured abscopal impact on tumor growth. The BiA9*2_HF drug candidate can thus be utilized to tailor immunotherapeutics for cancer patients.

In the current study, we designed, synthesized, and characterized a series of substituted pyrazolo[4,3-c]pyrazoles. These novel compounds were evaluated in vitro for their inhibitory activity over a panel of protein kinases to determine their potential therapeutic applications against Alzheimer's disease. To gain deeper insight into the binding interactions between the most potent analogues and their respective kinase targets, advanced molecular simulations were performed. In parallel, the ability of pyrazolo[4,3-c]pyrazoles to inhibit Aβ40 aggregation was assessed using biophysical techniques such as circular dichroism and Thioflavin T assays. Our results highlight the specific heterocycle as a highly promising and synthetically versatile scaffold for developing inhibitors of both AD-relevant kinases and amyloid-β aggregation. Although more effort is needed to assess the possibility of developing multi-target inhibitors, pyrazolo[4,3-c]pyrazole analogues demonstrated significant activities against their individual targets, indicating substantial capacity of the heterocyclic scaffold for further optimization toward both directions. Overall, our findings emphasize the potential of properly substituted pyrazolo[4,3-c]pyrazoles as multifunctional agents targeting key processes in Alzheimer's disease pathology.

Environmental deterioration is a significant and multi-dimensional issue that concerns the modern world. During the last decades, research has been conducted to address this argument, intending to provide holistic policies that drive sustainable development. However, the European Union (EU) should further provoke the complementarity between growth and environmental quality. Recognizing that gender equality must be introduced in Agenda (2030), this paper intends to examine the impact of well-established macroeconomic and socioeconomic variables in existing literature alongside the role of women in governance. More specifically, this study uses panel data analysis to investigate the understanding of the effects of economic growth, renewable energy, human capital, female representation in parliaments, and environmental regulation on carbon dioxide (CO2) emissions in 20 European countries from 2004 to 2018. Empirically, the study employs several econometric tests and approaches. Findings partially confirm the Environmental Kuznets Curve (EKC) hypothesis, while renewable energy and tertiary education enhance sustainability. Environmental regulation is significant for policymakers as it decreases pollution. The role of women in parliaments, which has been scarcely examined in existing literature, appears to be beneficial for the prosperity of EU societies. All empirical findings leave ample room for further discussion among European stakeholders and policymakers, emphasizing the importance of female participation in governance.

Offshore wind farms are becoming an increasingly common feature in the marine environment as a renewable energy source. There is a growing body of evidence on the effects of wind farms on the seabed and its organisms. However, an important and understudied aspect of site development is the interaction of turbine foundations on the surrounding marine environment. Structures exert significant disturbance on tides, waves and currents; these are visible as optically-distinct, elongate wakes at the sea surface with elevated suspended particulate matter. Despite this, there is uncertainty on the mechanisms that lead to the visible manifestation of wakes at turbine foundations, primarily due to a lack of direct measurements. Here, in situ measurements along with a 15-year time series of satellite images of the Thanet offshore wind farm, located within the Thames Estuary, were used to investigate the formation of visible monopile wakes, and the effects these have on the surrounding water column. We show the optically distinct wakes are near-constant at Thanet; visible in >90% of all satellite images, yet no regional change in sea surface turbidity could be attributed to wind farm construction or operation. Monopile wake in situ water samples and acoustic Doppler current profiler (ADCP) backscatter measurements demonstrated colour change related to elevated sea surface sediment concentration. However, averaged water column measurements of suspended sediment within wakes, and upstream of monopiles, remained consistent. These measurements demonstrate that sediment was redistributed towards surface waters, rather than additional sediment becoming suspended in the wake. ADCP velocity measurements supported a mechanism of sediment lofting towards the surface, with enhanced vertically upwards flow recorded in wakes.

This article challenges the belief in high-tech solutions to solve socio-environmental crises, proposing a political vision beyond ''green growth'' and ''ecomodernism.''. It advocates for a commons-based technology framework, promoting collective resource management for sustainability. We thus introduce ''cosmolocal'' production, a configuration that strives to connect communities around shared resources and serve their needs while minimizing ecological impact. Despite acknowledged tensions, we contend that the cosmolocal framework could foster institutional and social change, aiming to address environmental degradation and wealth inequality. To support this contention on cosmolocal production's potential, we point to several successful examples from the open-source technology paradigm.

Τhyreostats (TSs) are veterinary drugs used in livestock farming for fattening. Their administration is banned in the European Union since 1981, and their monitoring for food quality and safety control requires sensitive and confirmatory methods. The present study describes the development and validation of a hydrophilic interaction liquid chromatography tandem mass spectrometry (HILIC-MS/MS) method for the simultaneous determination of 2-thiouracil (TU), 6-methyl-2-thiouracil (MTU), 6-propyl-2-thiouracil (PTU), 6-phenyl-2-thiouracil (PhTU), tapazole (TAP), and 2-mercaptobenzimidazole (MBI) in bovine muscle tissues. Investigation of the retention mechanism of the six analytes on the selected amide-based stationary phase showed that hydrophilic partition was the dominant interaction. The sample preparation included extraction with ACN/H2O (80/20), followed by dispersive solid-phase extraction (d-SPE) with C18 sorbent and hexane partitioning. The method was validated according to European guidelines using internal standards, including isotopically labelled ones. The method’s LODs ranged between 2.8 ng g−1 (6-phenyl-2-thiouracil) and 4.1 ng g−1 (2-thiouracil). Application of the proposed method to 48 bovine tissue samples showed non-detectable results.

Epilepsy is a common neurological disorder that affects millions of people worldwide, disrupting brain networks and causing recurrent seizures. In this regard, investigating the distinctive characteristics of brain connectivity is crucial to understanding the underlying neural processes of epilepsy. However, the various graph-theory frameworks and different estimation measures may yield significant variability among the results of different studies. On this premise, this study investigates the brain network topological variations between patients with temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy (ETLE) using both directed and undirected network connectivity methods as well as different graph-theory metrics. Our results reveal distinct topological differences in connectivity graphs between the two epilepsy groups, with TLE patients displaying more disassortative graphs at lower density levels compared to ETLE patients. Moreover, we highlight the variations in the hub regions across different network metrics, underscoring the importance of considering various centrality measures for a comprehensive understanding of brain network dynamics in epilepsy. Our findings suggest that the differences in brain network organization between TLE and ETLE patients could be attributed to the unique characteristics of each epilepsy type, offering insights into potential biomarkers for type-specific epilepsy diagnosis and treatment.

The present study investigates the relationship between food waste and sustainable development, aiming to reveal contextual insights and present novel findings regarding the pivotal importance of waste and environmental strategies toward a circular economy. This research represents an effort to delineate methodological and thematic contributions, thoroughly analyze key themes, examine co-citation patterns, assess collaboration among countries, and identify current knowledge gaps in the literature. As waste management takes precedence within the framework of sustainable development goals, policymakers, and academia will better understand how effective food waste management can contribute to environmental sustainability. Methodologically, we employ systematic review, employing the PRISMA approach, analyzing 761 final papers, and investigating the relationship between food waste and sustainable development. We delve deeper to reveal contextual insights and present empirical findings that underscore the critical role of food waste in the economy and environment. Furthermore, guided by the identified knowledge gaps, we illuminate potential future research avenues that hold immense promise for advancing our understanding of food waste and its impact on sustainable development.

Background The frequency at which patients should have their vital signs (e.g. blood pressure, pulse, oxygen saturation) measured on hospital wards is currently unknown. Current National Health Service monitoring protocols are based on expert opinion but supported by little empirical evidence. The challenge is finding the balance between insufficient monitoring (risking missing early signs of deterioration and delays in treatment) and over-observation of stable patients (wasting resources needed in other aspects of care). Objective Provide an evidence-based approach to creating monitoring protocols based on a patient’s risk of deterioration and link these to nursing workload and economic impact. Design Our study consisted of two parts: (1) an observational study of nursing staff to ascertain the time to perform vital sign observations; and (2) a retrospective study of historic data on patient admissions exploring the relationships between National Early Warning Score and risk of outcome over time. These were underpinned by opinions and experiences from stakeholders. Setting and participants Observational study: observed nursing staff on 16 randomly selected adult general wards at four acute National Health Service hospitals. Retrospective study: extracted, linked and analysed routinely collected data from two large National Health Service acute trusts; data from over 400,000 patient admissions and 9,000,000 vital sign observations. Results Observational study found a variety of practices, with two hospitals having registered nurses take the majority of vital sign observations and two favouring healthcare assistants or student nurses. However, whoever took the observations spent roughly the same length of time. The average was 5:01 minutes per observation over a ‘round’, including time to locate and prepare the equipment and travel to the patient area. Retrospective study created survival models predicting the risk of outcomes over time since the patient was last observed. For low-risk patients, there was little difference in risk between 4 hours and 24 hours post observation. Conclusions We explored several different scenarios with our stakeholders (clinicians and patients), based on how ‘risk’ could be managed in different ways. Vital sign observations are often done more frequently than necessary from a bald assessment of the patient’s risk, and we show that a maximum threshold of risk could theoretically be achieved with less resource. Existing resources could therefore be redeployed within a changed protocol to achieve better outcomes for some patients without compromising the safety of the rest. Our work supports the approach of the current monitoring protocol, whereby patients’ National Early Warning Score 2 guides observation frequency. Existing practice is to observe higher-risk patients more frequently and our findings have shown that this is objectively justified. It is worth noting that important nurse–patient interactions take place during vital sign monitoring and should not be eliminated under new monitoring processes. Our study contributes to the existing evidence on how vital sign observations should be scheduled. However, ultimately, it is for the relevant professionals to decide how our work should be used. Study registration This study is registered as ISRCTN10863045. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 17/05/03) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 6. See the NIHR Funding and Awards website for further award information. Plain language summary Patient recovery in hospital is tracked by measuring heart rate, blood pressure and other ‘vital signs’ and converting them into a score. These are ‘observed’ regularly by nursing staff so that deterioration can be spotted early. However, taking observations can disturb patients, and taking them too often causes extra work for staff. More frequent monitoring is recommended for higher scores, but evidence is lacking. To work out how often patients should be monitored, we needed to know how likely it is for patients to become more unwell between observations. We analysed over 400,000 patient records from two hospitals to understand how scores change with time. We looked at three of the most serious risks for patients in hospital. These risks are dying, needing intensive care or having a cardiac arrest. We also looked at the risk that a patient’s condition would deteriorate significantly before their measurements were taken again. We identified early signs of deterioration and how changes in vital signs affected the risk of a patient’s condition becoming worse. From this we calculated a maximum risk of deterioration. We then calculated different monitoring schedules that keep individual patients below this risk level. Some of those would consume less staff time than current National Health Service guidelines suggest. We also watched staff record patients’ vital signs. We learnt it takes about 5 minutes to take these measurements from each patient. This information helped us calculate how costs would change if patients’ vital signs were taken more or less often. We found that patients with a low overall score could have their vital signs monitored less often without being in danger of serious harm. This frees up nursing time so that patients with a higher score can be monitored more often. Importantly, this can be achieved without employing more staff. Scientific summary Background The frequency that patients in hospital should have their vital signs (e.g. blood pressure, pulse, oxygen saturations) measured is currently unknown. Current monitoring protocols (from NHS England) are based on expert opinion supported by little empirical evidence. The challenge is to find the balance between insufficient monitoring of patients (which risks missing early signs of deterioration and delays in treatment) and over-observation of stable patients (which wastes resources needed in other aspects of patient care). Guidance suggests monitoring frequency should be determined by a patient’s severity of illness – often measured using risk scores. One such score is the National Early Warning Score (NEWS), which provides a simple integer value showing how much a patient’s vital signs are outside normal ranges. A high NEWS score means the patient is at high risk of deterioration, prompting a range of responses from increasing observations to review by a doctor and changes to treatment. While there is evidence that NEWS can predict patient risk of adverse outcomes [such as death or transfer to the intensive care unit (ICU)], there is no evidence to suggest the appropriate monitoring frequency based on that risk. With so much discussion about pressures on NHS resources, especially workforce issues, this is an important topic. Objectives This study aimed to fill the evidence gap and guide development of future monitoring protocols taking into account the risk of deterioration and the impact on nursing workload and associated cost. We addressed the following research questions: What is the current practice for recording a patient’s vital signs? Who typically takes vital sign observations? How long does it take to record a set of vital signs required to calculate a NEWS score? And how do nursing staff fit observation in alongside other clinical work? Can we predict a patient’s risk of deterioration over time based on their NEWS score? Can we use these risk predictions to identify acceptable monitoring frequencies for each NEWS value? Can we estimate the economic impact and cost-effectiveness of new monitoring protocols to identify whether these are feasible for use in practice? Methods Our study consisted of two parts: (1) an observational study of nursing staff to ascertain the time it takes to perform vital sign observations; and (2) a retrospective study of historic data on patient admissions to explore the relationships between NEWS and risk of outcome over time. These were underpinned by opinions and experiences from stakeholders. Observational study We observed nursing staff on 16 randomly selected adult general wards at 4 acute general NHS hospitals. All wards included in this study used NEWS2, the 2017 update to NEWS. Three hospitals used electronic systems to record vital signs and automate NEWS2 calculation. In one hospital, vital signs were recorded on paper charts at the patient’s bedside and NEWS2 was calculated manually. We observed each ward for a total of 8 hours, spread across four sessions, with a total of 715 sets of vital sign measurements observed. Data were collected in real time by non-participating observers using bespoke software on a tablet computer. They also collected contextual data, including the total number of patients on the ward and the numbers of registered nurses (RNs), healthcare assistants (HCAs) and student nurses on shift during the observation session. Further, they recorded factors influencing the measurement and recording of vital signs, including reasons for, and the nature of, interruptions. After each observation session, data were uploaded onto a server managed by the raters’ institution. We did not store any personal data. We quantified the time it took to record a set of vital signs using three different estimates: (1) length of the round per number of vital signs observation sets, (2) time at the patient’s bedside and (3) variants of (1) and (2) removing interruptions. We used an iterative approach and thematic coding to group the different activities that delayed or interrupted vital sign observations. Retrospective study We extracted, linked and analysed routinely collected data from two large NHS trusts providing acute care: Portsmouth Hospitals University NHS Trust (PHU) and Oxford University Hospitals NHS Foundation Trust (OUH). Data sets included information on: patient demographics; vital sign observations; admission-specific data including admission specialty, whether the patient died, had a cardiac arrest or was transferred to ICU; information on treatment such as visit to operating theatre, receiving blood transfusions or chemotherapy. Data were extracted by each trust’s data team and pseudonymised prior to transfer to the research team. Patient records were filtered to remove people who had registered with the NHS national opt-out. In both hospitals, vital signs were monitored electronically. At PHU, NEWS was automatically calculated at the bedside, while OUH used a different score and NEWS values were calculated retrospectively. Monitoring protocols also varied across the different sites. For analysis and modelling, three study cohorts were created: Development data set: admissions to PHU 1 January 2014 to 30 June 2017 Internal validation data set: admissions to PHU 1 July 2017 to 30 June 2019 External validation data set: admissions to OUH 1 July 2017 to 30 June 2019 We excluded data from vital sign observations outside recorded admission and discharge periods, incomplete vital sign sets, surgical day admissions and admissions to maternity or paediatric specialties. We analysed patient subgroups separately to identify whether these patients had different monitoring requirements: admissions to medical, surgical and ‘elderly medicine’ specialties, admissions with and without visit to operating theatre, elective admissions, emergency admissions, admissions with and without an observation in the last 24 hours, patients aged 80 or older, patients aged 30 or younger. We considered the following adverse events as outcomes: DEATH: in-hospital death. COMB: combined outcome of either in-hospital death or cardiac arrest or unexpected admission to a high-care ward, whichever comes first. NEWS7: any of the events included in COMB or a NEWS value greater than 6. NEWSINC: combined outcome or NEWS > 6 or a NEWS increase of 2 or more. For each data set and patient subgroup, we summarised patient demographics, admission characteristics, observation frequency, average NEWS values and outcomes. We further investigated changes in NEWS over the course of a hospital admission, by tracking the mean NEWS in the days following admission and the days leading up to an event. Using the development data set, we created survival models to predict the risk of each outcome at 15-minute intervals over a 24-hour period based on NEWS from the time of observation. We randomly sampled each data set 2000 times to avoid bias towards admissions that had more vital sign observations, and then calculated average predicted risk. The model was validated internally (including patient subgroups) and externally by assessing model calibration and discrimination. Monitoring protocols were created by setting a consistent risk threshold before which the next observation should be taken, based on predicted risk for a given NEWS value. In generating alternative monitoring schedules, we considered relative workloads and the proportion of observations that will be missed. We explored the effect of three alternative monitoring regimes on risk thresholds, nursing workload and associated cost. Possible observation intervals were limited to integer hour (1 hour, 2 hour, 4 hour, 6 hour, 8 hour, 12 hour) values. Combining the expected number of observations and the average time taken to complete each, we calculated the nursing time required and the nursing cost per patient-day under each alternative protocol. Staffing costs were estimated by applying representative unit costs for RNs and HCAs, weighted to reflect the proportion of vital signs observations undertaken by each, based on observational study data. Stakeholder involvement and engagement We organised stakeholder events to identify factors relevant to the selection of an optimal monitoring protocol. Stakeholders included patients and their carers, and healthcare staff who were responsible for taking vital signs, escalating patients for more senior clinical review or introducing monitoring systems into one or more institutions. Their experiences of current practices influenced decisions made in the retrospective study, particularly when considering the practicalities of alternative observation frequencies. Results Observational study Across the four hospitals we studied, we found a variety of practices, with two hospitals having RNs take the majority of vital sign observations, while the other two hospitals favoured HCAs or student nurses. However, whoever took the observations spent roughly the same length of time. The average of 5:01 minutes per observation over a ‘round’ included the preparation time associated with locating and preparing the equipment and travelling to the patient’s area. An average of 3:45 was spent at each patient’s bedside (excluding interruptions not related to the vital sign taking), rising to 4:24 at the bedside with all interruptions included. Interruptions included jobs needing to be done at a set time of day, jobs convenient to do at the same time as vital sign observations, communication with other health professionals, emergencies, work prompted by the proximity to the patient, and absence or unavailability of patient. Other clinical work seemed to take priority during core time (9 a.m.–5 p.m.) but staff made up for this by scheduling the main rounds of observations around the main shift-change times (early morning and early evening) when there were fewer competing tasks. Any future protocol reducing the frequency of observations might support timely recording during core times, though they would probably still be prioritised below fixed-time activities. Any change to existing protocols might have knock-on effects on proximity-related care. For example, reducing the frequency of observations would reduce the opportunities for the patient to ask a question or benefit from other interaction with the nurse. Correspondingly, increasing the frequency could improve the quality of care provided. Our stakeholders proposed that ‘social interaction’ could be separated from vital sign observations, with a short ‘check-in’ approach adopted for lower-risk patients. In conclusion, while individual components of observation work are quite small, when aggregated over many patients and multiple observations per patient per day, they add up to a substantial amount of daily nursing workload that has to be integrated, prioritised and resourced. Retrospective study Our analysis included data from over 400,000 patient admissions and 9,000,000 vital sign observations. Differences in the distribution of NEWS values suggested there was a difference in case-mix between the two hospital trusts in the study. While patient demographics were broadly comparable, length of stay and mortality rates were higher at PHU (mortality 3.9%) than at OUH (2.6%). Rates for outcomes NEWS7 and NEWSINC were more consistent across the two sites. Elective patients, admissions without an observation in the last 24 hours and patients receiving blood transfusions or chemotherapy were identified as patient subgroups where outcomes and/or monitoring frequency were different to others. Daily patterns of observations showed peak activity at four different times: 06:00, 11:00, 16:00 and 20:00, with more distinct peaks at OUH than PHU. This is consistent with findings from the observational study that showed staff batch observations to avoid meal times and fit observations in with other regular activities. As expected, average NEWS values increased in the days prior to adverse outcome, with trends of deterioration starting up to 9 days prior to the event. Patients with the worst outcomes (death, unanticipated ICU admission) averaged the highest NEWS scores and had the earliest increases. Patients who were discharged without an adverse outcome had higher initial average NEWS values compared to those with outcomes NEWS7 or NEWSINC but showed a steady reduction in the last 5 days prior to discharge. Consistent with previous studies, breathing rate and oxygen saturation were identified as the vital signs most predictive of deterioration. We created survival models that predicted the risk of outcomes over time since the patient was last observed. For low-risk patients, there was not much difference in risk between 4 hours and 24 hours post observation. Model validation showed acceptable performance in both PHU and OUH validation cohorts. The tendency of the model to overestimate risk of outcome in the OUH cohort can be explained by lower observed outcome rates. These results suggest that a single monitoring protocol might be appropriate for the general adult hospital population, offering significant operational advantages. We explored a number of different scenarios with our stakeholders, based on how ‘risk’ could be managed in different ways. Vital sign observations are often done more frequently than necessary from a bald assessment of the patient’s risk. A changed protocol could redeploy existing resources to achieve better outcomes for some patients without compromising the safety of the rest. However, reducing the risk to some patients (by observing them more frequently) is offset by a theoretical increase in risk to others (by observing them less frequently). We cannot be certain that the net effect is positive (though it is likely). Stakeholders felt an increased risk for patients at low risk was acceptable to reduce the risk for high-risk patients. As an observational study, our analysis could not evaluate the actual impact of new monitoring protocols on outcomes. Nevertheless, our approach did assess protocol cost-effectiveness, allowing us to rule out any protocols that would require unfeasible changes in outcomes or costs and so help identify plausible candidate protocols whose performance could be assessed in clinical trials. For example, theoretically a 61% reduction in nursing resource could be achieved without raising any patient’s risk above the current maximum. A 34% saving could be achieved while halving the maximum risk, but both scenarios increase the risk for all low-risk patients (the majority). A 65% increase in resource would reduce the patient risk threshold by a factor of 10. Conclusions We developed a framework using clinical data to propose new observation protocols and a way of evaluating them both clinically (in terms of patient outcome) and economically (possible cost-effectiveness). Our work supports the approach of the current monitoring protocol, whereby patients’ NEWS2 scores guide observation frequency. Existing practice is to observe higher-risk patients more frequently and our findings have shown that this is objectively justified. It is worth noting that important nurse–patient interactions take place during vital sign monitoring and should not be eliminated under new monitoring processes. Our study contributes to the existing evidence on scheduling vital sign observations, but our retrospective design did not allow us to take into account all factors impacting monitoring frequency. Ultimately, it is for relevant professionals to collectively decide how our work should be used: nationally this could be the Royal College of Physicians reviewing NEWS; locally, it could be clinicians/managers determining local practice. Study registration This study is registered as ISRCTN10863045. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 17/05/03) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 6. See the NIHR Funding and Awards website for further award information.

In this paper, we experimentally illustrate the effectiveness of neural networks (NNs) as non-linear equalisers for multilevel pulse amplitude modulation (PAM-M) transmission over an optical wireless communication (OWC) link. In our study, we compare the bit-error-rate (BER) performances of two decision feedback equalisers (DFEs)—a multilayer-perceptron-based DFE (MLPDFE), which is the NN equaliser, and a transversal DFE (TRDFE)—under two degrees of non-linear distortion using an eye-safe 850 nm single-mode vertical-cavity surface-emitting laser (SM-VCSEL). Our results consistently show that the MLPDFE delivers superior performance in comparison to the TRDFE, particularly in scenarios involving high non-linear distortion and PAM constellations with eight or more levels. At a forward error correction (FEC) threshold BER of 0.0038, we achieve bit rates of ~28 Gbps, ~29 Gbps, ~22.5 Gbps, and ~5 Gbps using PAM schemes with 2, 4, 8, and 16 levels, respectively, with the MLPDFE. Comparably, the TRDFE yields bit rates of ~28 Gbps and ~29 Gbps with PAM-2 and PAM-4, respectively. Higher PAM levels with the TRDFE result in BERs greater than 0.0038 for bit rates above 2 Gbps. These results highlight the effectiveness of the MLPDFE in optimising the performance of SM-VCSEL-based OWC systems across different modulation schemes and non-linear distortion levels.

CT angiography has become, in recent years, a main evaluating modality for patients with coronary artery disease (CAD). Recent advancements in the field have allowed us to identity not only the presence of obstructive disease but also the characteristics of identified lesions. High-risk coronary atherosclerotic plaques are identified in CT angiographies via a number of specific characteristics and may provide prognostic and therapeutic implications, aiming to prevent future ischemic events via optimizing medical treatment or providing coronary interventions. In light of new evidence evaluating the safety and efficacy of intervening in high-risk plaques, even in non-flow-limiting disease, we aim to provide a comprehensive review of the diagnostic algorithms and implications of plaque vulnerability in CT angiography, identify any differences with invasive imaging, analyze prognostic factors and potential future therapeutic options in such patients, as well as discuss new frontiers, including intervening in non-flow-limiting stenoses and the role of CT angiography in patient stratification.

Purpose: Syncope remains a common medical problem. Recently, the role of dedicated syncope units and implantable loop recorders has emerged in the investigation of unexplained syncope. This study aims to investigate the possibilities for a more rational and targeted use of various diagnostic tools. Methods: In this retrospective single-center study, 196 patients with unexplained syncope were included between March 2019 and February 2023. Various diagnostic tools were utilized during the investigation, according to clinical judgement. Patients were retrospectively allocated into Group A (including those who, among other tests, underwent loop recorder insertion) and Group B (including patients investigated without loop recorder implantation). Data were compared with Group C, including patients assessed prior to syncope unit establishment. Results: There was no difference between Group A (n = 133) and Group B (n = 63) in the diagnostic yield (74% vs. 76%, p = 0.22). There were significant differences between Groups A and B regarding age (67.3 ± 16.9 years vs. 48.3 ± 19.1 years, p < 0.001) and cause of syncope (cardiogenic in 69% of Group A, reflex syncope in 77% of Group B, p < 0.001). Electrocardiography-based diagnosis occurred in 55% and 19% of Groups A and B, respectively (p < 0.001). The time to diagnosis was 4.2 ± 2.7 months in Group A and 7.5 ± 5.6 months in Group B (p < 0.001). In Group C, the diagnostic yield was 57.9% and the electrocardiography-based diagnostic yield was 18.3%. Conclusions: A selective use of loop recorders according to clinical and electrocardiographic characteristics increases the effectiveness of the structured syncope unit approach and further preserves financial resources.

Abstract With the current massive increases in drug-resistant microbial infection as well as the significant role of fungal infections in the death toll of COVID-19, discovering new antifungals is extremely important. Natural and synthetic xanthones are promising derivatives, although only few reports have demonstrated their antifungal mechanism of action in detail. Newly synthetized by us xanthone derivative 44 exhibited strong antifungal activity against reference and fluconazole resistant C. albicans strains. Our results indicate that the most active compounds 42 and 44 are not substrates for fungal ABC transporters (Cdr1p and Cdr2p) and Mdr1p, the main representative of the major facilitator superfamily efflux pumps, membrane proteins that are responsible for the development of resistance. Moreover, fungicidal mode of action reduces the probability of persistent or recurrent infections and resistance development. In this light, the demonstrated killing activity of the examined derivatives is their undoubted advantage. Novel synthesized compounds exhibited moderate cytotoxicity against human cell lines, although the selectivity index value for human pathogenic strains remained favourable. Our results also indicate that novel synthetized compounds 42 and 44 with antifungal activity target yeast topoisomerase II activity. In summary, further validation of xanthones applicability as antifungals is highly valuable.

Abstract Background Urothelial bladder cancer is most frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact the quality of life. Biomarkers for patient stratification could help to avoid unnecessary interventions whilst indicating aggressive measures when required. Methods In this study, immuno-oncology focused, multiplexed proximity extension assays were utilised to analyse plasma (n = 90) and urine (n = 40) samples from 90 newly-diagnosed and treatment-naïve bladder cancer patients. Public single-cell RNA-sequencing and microarray data from patient tumour tissues and murine OH-BBN-induced urothelial carcinomas were also explored to further corroborate the proteomic findings. Results Plasma from muscle-invasive, urothelial bladder cancer patients displayed higher levels of MMP7 (p = 0.028) and CCL23 (p = 0.03) compared to NMIBC patients, whereas urine displayed higher levels of CD27 (p = 0.044) and CD40 (p = 0.04) in the NMIBC group by two-sided Wilcoxon rank-sum tests. Random forest survival and multivariable regression analyses identified increased MMP12 plasma levels as an independent marker (p

Background: Breastfeeding is proposed to play a role in reducing the risk of obesity throughout life. Kuwait has an extremely high prevalence of childhood obesity (45% of adolescents are overweight/obese) and extremely low breastfeeding indicators, particularly exclusive breastfeeding. In fact, little is known about the association between breastfeeding and obesity from Kuwait and the broader Middle East. Aims: To estimate the prevalence of overweight/obesity in female adolescents in Kuwait and assess its association with breastfeeding during infancy. Methods: This is a cross-sectional study that included 775 girls randomly selected from public and private high schools in Kuwait. The primary exposure was breastfeeding in the first four months of life, and the outcome was overweight/obesity during adolescence. Multivariable logistic regression was used to assess the association between breastfeeding and overweight/obesity while adjusting for potential confounders. Results: Approximately 45% of adolescent girls were either overweight/obese. We found no significant association between breastfeeding (exclusive/mixed breastfeeding and formula feeding/no breastfeeding) and overweight/obesity neither in univariable analysis (Crude Prevalence Ratio: 1.14, 95%CI [0.92–1.36] & Crude Prevalence Ratio: 1.29, 95%CI [0.86–1.68]; p = 0.293) for mixed feeding and no breastfeeding respectively, nor in multivariable analysis (Adjusted Prevalence Ratio: 1.14, 95%CI [0.85–1.42] & Adjusted Prevalence Ratio: 1.20, 95%CI [0.68–1.68]; p = 0.589) for mixed feeding and no breastfeeding respectively. Conclusion: Breastfeeding during infancy was not significantly associated with overweight/obesity during adolescence. However, breastfeeding should be encouraged for its indisputable benefits for infants and their mothers alike. Further prospective studies are needed to assess the association.

Physical and chemical soil properties are affected by wildfires. Post-wildfire runoff may contain nutrient loads and particulate matter that negatively impact soil, surface water, and groundwater. According to data from the Copernicus Emergency Management Service, devastating wildfires on Northern Euboea Island, Greece, in August 2021 destroyed more than 50,910 ha. Coniferous and broad-leaved forests mostly covered the affected area, according to CORINE. Topsoil and subsoil samples were collected from burned areas and analyzed for physicochemical parameters: pH, electrical conductivity, and organic carbon. After digestion with aqua regia, the Pb, Zn, Cd, Cu, Mn, Fe, Cr, Ni, Co, and As ‘pseudo total’ contents were determined. Leaching experiments were conducted to evaluate the levels of potentially toxic elements leaching from soils and the impact of environmental conditions. The leachates were analyzed for Pb, Zn, Cd, Cu, Mn, Fe, Cr, Ni, Co, As, Ca, Mg, Na, and K. Overall, most of the concentrations of the studied elements were higher in fire-affected soils than in unburned ones. Similar findings for element concentrations have been confirmed between topsoils and subsoils, with the latter exhibiting lower values. The increased ‘pseudo total’ values of Cr, Ni, Fe, Co, and Mn in all the soil samples, along with the medium to high positive correlations between them, indicate that geogenic factors play a major role in controlling element enrichment. High concentrations of Mn, Ni, and As in soil leachates exceeded the EU maximum permissible limits, indicating a potential ecological risk to natural water quality and, subsequently, to human health. The correlation coefficients between elements in fire-affected and unburned soils suggested that their geogenic origins were mainly associated with the ultramafic rocks and related ores of the study area. The elements’ concentrations in the leachates were significantly lower than their ‘pseudo total’ contents in soil, with no correlation between them. The reducing order of elements leachability did not coincide with the decreasing order of elements ‘pseudo total’ median values in soils. The decreasing order of element abundance in soil leachates coincides with their relative extractability and differs from the decreasing order of their ‘pseudo total’ median values in soils. Neutral to alkaline, soil pH conditions and organic carbon content, which substantially influence the retention and mobility of elements, presented different patterns among the studied elements, with only Mn, Cr, and Co showing correlations. The increased content of organic matter in fire-affected soils suggests that the combustion of vegetation was incomplete.

The concentrations of Co were determined in the hydrological cycle (in maquis and fir forests), litterfall and soils in maquis, oak, beech and fir forests. The concentrations in the hydrological cycle were characterized by high variability. The concentrations in soil solution were much higher than those in the bulk deposition and throughfall. The contribution of the earth’s’ crust in the bulk deposition enrichment with Co was not high but some minor quantities of Co can be considered to be transported in long distances. The concentrations of Co in litterfall were high in the fraction composed of lichens, flowers and mosses, especially in the fir forest. The total content of Co was significantly higher in the soils derived from mica schist than those in the flysch. The residence time of Co in the forest floor was rather long. This is an indication that weathering in the mineral layers plays an important role in providing Co for plant uptake.