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The fifth generation (5G) of wireless networks promises to meet the stringent requirements of vehicular use cases that cannot be supported by previous technologies. However, the stakeholders of the automotive industry (e.g., car manufacturers and road operators) are still skeptical about the capability of the telecom industry to take the lead in a market that has been dominated by dedicated intelligent transport systems (ITS) deployments. In this context, this paper constructs a framework where the potential of 5G to support different vehicular use cases is thoroughly examined under a common format from both the technical and business perspectives. From the technical standpoint, a storyboard description is developed to explain when and how different use case scenarios may come into play (i.e., pre-conditions, service flows and post-conditions). Then, a methodology to trial each scenario is developed including a functional architecture, an analysis of the technical requirements and a set of target test cases. From the business viewpoint, an initial analysis of the qualitative value perspectives is conducted considering the stakeholders, identifying the pain points of the existing solutions, and highlighting the added value of 5G in overcoming them. The future evolution of the considered use cases is finally discussed.

5G enables the use of different types of services over the same physical infrastructure through the concepts and technologies of virtualization, softwarization, network slicing and cloud computing. Mobile Virtual Network Operators (MVNOs), using these concepts, provide an opportunity to share the same physical infrastructure among multiple operators. Each MVNO can have own distinct operating and support systems. However, the technologies used to enable such an environment have their own explicit security challenges and solutions. The integrated environment built upon these novel concepts and technologies, thus, will have complex security implications and requirements to be satisfied. In this vain, this article provides an overview of the security challenges and potential solutions for MVNOs.

The ongoing transition towards 5G technology expedites the emergence of a variety of mobile applications that pertain to different vertical industries. Delivering on the key commitment of 5G, these diverse service streams, along with their distinct requirements, should be facilitated under the same unified network infrastructure. Consequently, in order to unleash the benefits brought by 5G technology, a holistic approach towards the requirement analysis and the design, development, and evaluation of multiple concurrent vertical services should be followed. In this paper, we focus on the Transport vertical industry, and we study four novel vehicular service categories, each one consisting of one or more related specific scenarios, within the framework of the “5G Health, Aquaculture and Transport (5G-HEART)” 5G PPP ICT-19 (Phase 3) project. In contrast to the majority of the literature, we provide a holistic overview of the overall life-cycle management required for the realization of the examined vehicular use cases. This comprises the definition and analysis of the network Key Performance Indicators (KPIs) resulting from high-level user requirements and their interpretation in terms of the underlying network infrastructure tasked with meeting their conflicting or converging needs. Our approach is complemented by the experimental investigation of the real unified 5G pilot’s characteristics that enable the delivery of the considered vehicular services and the initial trialling results that verify the effectiveness and feasibility of the presented theoretical analysis.

Abstract Video Coding for Machines (VCM) is gaining momentum in applications like autonomous driving, industry manufacturing, and surveillance, where the robustness of machine learning algorithms against coding artifacts is one of the key success factors. This work complements the MPEG/JVET standardization efforts in improving the resilience of deep neural network (DNN)-based machine models against such coding artifacts by proposing the following three advanced fine-tuning procedures for their training: (1) the progressive increase of the distortion strength as the training proceeds; (2) the incorporation of a regularization term in the original loss function to minimize the distance between predictions on compressed and original content; and (3) a joint training procedure that combines the proposed two approaches. These proposals were evaluated against a conventional fine-tuning anchor on two different machine tasks and datasets: image classification on ImageNet and semantic segmentation on Cityscapes. Our joint training procedure is shown to reduce the training time in both cases and still obtain a 2.4% coding gain in image classification and 7.4% in semantic segmentation, whereas a slight increase in training time can bring up to 9.4% better coding efficiency for the segmentation. All these coding gains are obtained without any additional inference or encoding time. As these advanced fine-tuning procedures are standard-compliant, they offer the potential to have a significant impact on visual coding for machine applications.

Artikkelissa pohditaan minkälaisiin lähtökohtiin ja filosofisiin olettamuksiin steinerkasvatuksen toiminta ja sivistyskäsitys perustuu. Keskustelemme sivistyksen monimuotoisuudesta ja avaamme steinerkasvatuksen ihmiskäsitystä vertailemalla Rudolf Steinerin ja Wilhelm Diltheyn käsitteitä hengentieteestä (Geisteswissenshaft). Dilthey näki luonnon- ja henkitieteiden välisen laadullisen eron perustavanlaatuisena. Steinerin Geisteswissenschaft taas ei ole erillinen tieteellinen alue suhteessa muihin alueisiin, vaan pyrkimys sovittaa tieteellinen toiminta monistiseen ja idealistiseen katsantokantaan, jossa ihminen ja maailma (kuten myös tietoisuus ja luonto) ovat osa samaa holistista kokonaisuutta. Näkemys ihmisen henkisestä kehityksestä – jossa henki viittaa maailman ontologiseen rakenteeseen – on keskeinen teoreettinen olettamus steinerkasvatuksen taustalla. Nostamme steinerkoulun sivistyskäsityksen korostuksina esiin yksilöllisyyden tukemisen, esteettisyyden ja luontosuhteen. Steinerkasvatuksen idealistinen sivistyskäsitys näyttäytyy hyvin kokonaisvaltaisena, jossa on piirteitä klassisesta sivistysperinteestä. Se on sopusointua, yhteyden löytämistä itseen, toisiin ihmisiin ja luontoon. Se asettuu omalta osaltaan vastavoimaksi suuntauksille, jotka korostavat kilpailuyhteiskunnan arvoja koulun kehittämisen lähtökohtana. Kilpailua ja tehokkuusajattelua pyritään korvaamaan painottamalla eettistä vapautta, yhteisöllisyyttä, mielikuvitusta, esteettisyyttä ja luontosuhdetta. Kognitiivisten taitojen rinnalle nostetaan tunteen ja tahdon kehitys. Tavoitteena on eettinen persoonallisuus eli vapaa yksilö, joka toimii epäitsekkäästi laajemman kokonaisuuden hyväksi.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Upconversion luminescence (UCL) has great potential for highly sensitive biosensing due to its unique wavelength shift properties. The main limitation of UCL is its low quantum efficiency, which is typically compensated using low-noise detectors and high-intensity excitation. In this work, we demonstrate surface plasmon polariton (SPP)-enhanced UCL for biosensing applications. SPPs are excited by using a gold grating. The gold grating is optimized to match the SPP resonance with the absorption wavelength of upconverting nanoparticles (UCNPs). Functionalized UCNPs conjugated with antibodies are immobilized on the surface of the fabricated gold grating. We achieve an UCL enhancement up to 65 times at low excitation power density. This enhancement results from the increase in the absorption cross section of UCNPs caused by the SPP coupling on the grating surface. Computationally, we investigated a slight quenching effect in the emission process with UCNPs near gold surfaces. The experimental observations were in good agreement with the simulation results. The work enables UCL-based assays with reduced excitation intensity that are needed, for example, in scanning-free imaging.

Abstract Background Beta-cell monogenic forms of diabetes have strong support for precision medicine. We systematically analyzed evidence for precision treatments for GCK-related hyperglycemia, HNF1A-, HNF4A- and HNF1B-diabetes, and mitochondrial diabetes (MD) due to m.3243 A > G variant, 6q24-transient neonatal diabetes mellitus (TND) and SLC19A2-diabetes. Methods The search of PubMed, MEDLINE, and Embase for individual and group level data for glycemic outcomes using inclusion (English, original articles written after 1992) and exclusion (VUS, multiple diabetes types, absent/aggregated treatment effect measures) criteria. The risk of bias was assessed using NHLBI study-quality assessment tools. Data extracted from Covidence were summarized and presented as descriptive statistics in tables and text. Results There are 146 studies included, with only six being experimental studies. For GCK-related hyperglycemia, the six studies (35 individuals) assessing therapy discontinuation show no HbA1c deterioration. A randomized trial (18 individuals per group) shows that sulfonylureas (SU) were more effective in HNF1A-diabetes than in type 2 diabetes. Cohort and case studies support SU’s effectiveness in lowering HbA1c. Two cross-over trials (each with 15–16 individuals) suggest glinides and GLP-1 receptor agonists might be used in place of SU. Evidence for HNF4A-diabetes is limited. Most reported patients with HNF1B-diabetes (N = 293) and MD (N = 233) are on insulin without treatment studies. Limited data support oral agents after relapse in 6q24-TND and for thiamine improving glycemic control and reducing/eliminating insulin requirement in SLC19A2-diabetes. Conclusion There is limited evidence, and with moderate or serious risk of bias, to guide monogenic diabetes treatment. Further evidence is needed to examine the optimum treatment in monogenic subtypes.

Abstract Due to its involvement in physiological and pathological processes, histone deacetylase 6 (HDAC6) is considered a promising pharmaceutical target for several neurological manifestations. However, the exact regulatory role of HDAC6 in the central nervous system (CNS) is still not fully understood. Hence, using a semi-automated literature screening technique, we systematically collected HDAC6-protein interactions that are experimentally validated and reported in the CNS. The resulting HDAC6 network encompassed 115 HDAC6-protein interactions divided over five subnetworks: (de)acetylation, phosphorylation, protein complexes, regulatory, and aggresome-autophagy subnetworks. In addition, 132 indirect interactions identified through HDAC6 inhibition were collected and categorized. Finally, to display the application of our HDAC6 network, we mapped transcriptomics data of Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis on the network and highlighted that in the case of Alzheimer’s disease, alterations predominantly affect the HDAC6 phosphorylation subnetwork, whereas differential expression within the deacetylation subnetwork is observed across all three neurological disorders. In conclusion, the HDAC6 network created in the present study is a novel and valuable resource for the understanding of the HDAC6 regulatory mechanisms, thereby providing a framework for the integration and interpretation of omics data from neurological disorders and pharmacodynamic assessments.

Objective The collection of comprehensive data from post-authorisation trials for conditionally authorised anticancer medicines is frequently delayed. This raises questions about the feasibility of post-authorisation randomised controlled trials (RCTs) that aim to address remaining uncertainties. Therefore, this study explored factors that facilitate or impede the feasibility of post-authorisation RCTs from the perspective of stakeholders directly involved in the design, medical-ethical approval, and conduct of these RCTs.Design We conducted four qualitative focus groups (FGs).Setting FG discussions focused on the oncology setting in European context.Participants Twenty-eight European patients, physicians, medical ethicists and pharmaceutical industry representatives participated in the FGs.Intervention Respondents were informed about the topic and the purpose of the FGs before and at the start of FG discussions. An FG script was used to guide the discussion, which was informed by 14 semi-structured interviews with various stakeholders.Results We identified factors with the potential to impact feasibility related to trial design, trial conduct, factors external to a trial and post-authorisation interaction with regulators. Factors that may be particularly relevant for the post-authorisation setting include the choice of relevant endpoints and the inclusion of a fair comparator (trial design), strategies to increase patients’ and physicians’ willingness to participate (trial conduct), and external factors relating to a medicine’s commercial availability, the presence of competing medicines and trials and the perceptions about clinical equipoise. Post-authorisation interaction with regulators about how to obtain comprehensive data was deemed necessary in cases where a post-authorisation RCT seems infeasible.Conclusions Based on the identified factors, our findings suggest that patient recruitment and retention could be assessed more in-depth during regulatory feasibility assessments at the time of granting conditional marketing authorisation and that sponsors and regulators should better inform patients and physicians about the remaining uncertainties for conditionally authorised medicines and the necessity for post-authorisation RCTs. By enhancing the evaluation of trial feasibility, timely completion of post-authorisation RCTs may be facilitated to resolve the remaining uncertainties within a reasonable timeframe.

In this article, we aim to study how astrocytes control electrophysiological activity during neuronal network formation. We used a combination of spike/burst analysis, classification of spike waveforms based on various signal properties and tools from information theory to demonstrate how astrocytes modulate the electrical activity of neurons using microelectrode array (MEA) signals. We cultured rat primary cortical neurons and astrocytes on 60-electrode MEAs with different neuron/astrocyte ratios ranging from ‘pure’ neuronal cultures to co-cultures containing 50% neurons and 50% astrocytes. Our results show that astrocytes desynchronize the network and reduce predictability in the signals and affect the repolarization phase of the action potentials. Our work highlights that it is crucial to go beyond standard MEA analysis to assess how astrocytes control neuronal cultures and investigate any dysfunction that could potentially result in neuronal hyperactivity.

Introduction Inadequate treatment of enlarged lateral lymph nodes (LLNs) in rectal cancer patients is associated with an increased lateral local recurrence (LLR) risk, despite neoadjuvant treatment and total mesorectal excision (TME) surgery. There is a promising role for LLN dissection (LLND) to lower this risk, but this challenging procedure requires appropriate training. This study protocol describes a prospective evaluation of oncological outcomes after standardised treatment based on multidisciplinary training, thereby aiming for a 50% reduction in LLR rate.Methods and analysis A prospective registration study will be opened in hospitals in which the involved multidisciplinary team members (radiologists, radiation oncologists, surgeons and pathologists) have received dedicated training to enhance knowledge and awareness of LLNs and in which standardised treatment including LLND has been implemented. Patients with rectal cancer and at least one enlarged LLN (short-axis ≥7.0 mm), or intermediate LLN (short-axis 5.0–6.9 mm) with at least one malignant feature on primary MRI, evaluated by a trained radiologist, are eligible. Patients will undergo neoadjuvant treatment by trained radiation oncologists, followed by TME surgery in combination with a minimally invasive, nerve-sparing LLND performed by trained surgeons. LLND specimens are evaluated by trained pathologists or grossing assistants. The primary outcome is LLR rate 3 years postoperatively. Secondary outcomes are morbidity, disease-free survival, overall survival and quality of life. To demonstrate a significant reduction in LLR rate from 13% (based on historical control data) to 6% after optimised treatment, 200 patients with enlarged LLNs are required.Ethics and dissemination The medical ethics board of the Vrije Universiteit Medical Centre (VUMC), the Netherlands, approved the study on 23 November 2022 (reference: 2021.0524). Participating centres must obtain local approval and participants are required to provide written informed consent. Results obtained from this study will be communicated via peer-reviewed medical journals and presentations at conferences.Trail registration number NCT04486131, 24 July 2020, https://clinicaltrials.gov/ct2/show/NCT04486131.

Metabolic rewiring is a defining characteristic of cancer cells, driving their ability to proliferate. Leveraging these metabolic vulnerabilities for therapeutic purposes has a long and impactful history, with the advent of antimetabolites marking a significant breakthrough in cancer treatment. Despite this, only a few in vitro metabolic discoveries have been successfully translated into effective clinical therapies. This limited translatability is partially due to the use of simplistic in vitro models that do not accurately reflect the tumor microenvironment. This Review examines the effects of current cell culture practices on cancer cell metabolism and highlights recent advancements in establishing more physiologically relevant in vitro culture conditions and technologies, such as organoids. Applying these improvements may bridge the gap between in vitro and in vivo findings, facilitating the development of innovative metabolic therapies for cancer.

Abstract Wearable long-term monitoring applications are becoming more and more popular in both the consumer and the medical market. In wearable ECG monitoring, the data quality depends on the properties of the electrodes and on how they interface with the skin. Dry electrodes do not require any action from the user. They usually do not irritate the skin, and they provide sufficiently high-quality data for ECG monitoring purposes during low-intensity user activity. We investigated prospective motion artifact–resistant dry electrode materials for wearable ECG monitoring. The tested materials were (1) porous: conductive polymer, conductive silver fabric; and (2) solid: stainless steel, silver, and platinum. ECG was acquired from test subjects in a 10-min continuous settling test and in a 48-h intermittent long-term test. In the settling test, the electrodes were stationary, whereas both stationary and controlled motion artifact tests were included in the long-term test. The signal-to-noise ratio (SNR) was used as the figure of merit to quantify the results. Skin–electrode interface impedance was measured to quantify its effect on the ECG, as well as to leverage the dry electrode ECG amplifier design. The SNR of all electrode types increased during the settling test. In the long-term test, the SNR was generally elevated further. The introduction of electrode movement reduced the SNR markedly. Solid electrodes had a higher SNR and lower skin–electrode impedance than porous electrodes. In the stationary testing, stainless steel showed the highest SNR, followed by platinum, silver, conductive polymer, and conductive fabric. In the movement testing, the order was platinum, stainless steel, silver, conductive polymer, and conductive fabric.

Abstract Aims Approximately half of patients with heart failure and a reduced ejection fraction (HeFREF) are discharged from hospital on triple therapy [angiotensin‐converting enzyme inhibitors (ACE‐Is) or angiotensin receptor blockers (ARBs), beta‐blockers (BBs), and mineralocorticoid receptor antagonists (MRAs)]. We investigated what proportion of patients are on optimal doses prior to discharge and how many might be eligible for initiation of sacubitril–valsartan or sodium‐glucose co‐transporter‐2 inhibitors (SGLT2Is). Methods and results Between 2012 and 2017, 1277 patients admitted with suspected heart failure were enrolled at a single hospital serving a local community around Kingston upon Hull, UK. Eligibility for sacubitril–valsartan or SGLT2I was based on entry criteria for the PIONEER‐HF, DAPA‐HF, and EMPEROR‐Reduced trials. Four hundred fifty‐five patients had HeFREF with complete data on renal function, heart rate, and systolic blood pressure (SBP) prior to discharge. Eighty‐three per cent of patients were taking an ACE‐I or ARB, 85% a BB, and 63% an MRA at discharge. More than 60% of patients were eligible for sacubitril–valsartan and >70% for SGLT2I. Among those not already receiving a prescription, 37%, 28%, and 49% were eligible to start ACE‐I or ARB, BB, and MRA, respectively. Low SBP (≤105 mmHg) was the most frequent explanation for failure to initiate or up‐titrate therapy. Conclusions Most patients admitted for heart failure are eligible for initiation of life‐prolonging medications prior to discharge. A hospital admission may be a common missed opportunity to improve treatment for patients with HeFREF.

This commentary examines the resilience of primary health care in Ukraine amidst the ongoing war, drawing a few reflections relevant for other fragile and conflict-affected situations. Using personal observations and various published and unpublished reports, this article outlines five reflections on the strengths, challenges, and necessary adaptations of Primary Health Care (PHC) in Ukraine. It underscores the concerted efforts of the government to maintain public financing of PHC, thereby averting system collapse. The research also highlights the role of strategic adaptations during the COVID-19 pandemic in fostering resilience during the war, including the widespread use of digital communication and skills training. The commentary emphasizes the role of managerial and financial autonomy in facilitating quick and efficient organizational response to crisis. It also recognizes emerging challenges, including better access to PHC services among the internally displaced persons, shifting patient profiles and service needs, and challenges related to reliance on local government financing. Finally, the authors advocate for a coordinated approach in humanitarian response, recovery efforts, and development programs to ensure the sustainability and effectiveness of PHC in Ukraine.

Objective Appendicoliths are associated with a more complicated course of acute appendicitis and failure of non-operative treatment. We aimed to update the appendicolith classification originally described in 1966 and to assess the association of appendicolith characteristics with appendicitis severity.Design This prospective predefined MAPPAC-trial (ClinicalTrials.gov NCT03257423) substudy included patients with CT diagnosed appendicitis presenting with an appendicolith. CT visible appendicoliths were harvested at surgery, measured and characterised by morphological examination complemented with micro-CT and micro-X-ray fluorescence spectroscopy. Patients were categorised into two groups: appendicolith appendicitis without other complications and appendicolith appendicitis with complications (appendiceal gangrene, perforation and/or abscess). The association of appendicolith classification and characteristics with appendicitis severity was evaluated.Results Of 78 patients with a CT appendicolith, 41 appendicoliths were collected and classified based on the degree of hardness into three classes. The hardest appendicoliths (class 3) were less common (19.5%) presenting with a stone-hard outer layer and concentrically layered inner structure around a core. The layered inner structure was also observed in class 2 appendicoliths, but was absent in soft, class 1 appendicoliths. Appendicolith hardness or measures (maximum length, diameter and weight) were not associated with appendicitis severity. The spatial distribution of the main inorganic elements of calcium and phosphorus varied within most appendicoliths.Conclusion This updated classification confirms categorisation of CT visible appendicoliths into three classes based on their physical and chemical characteristics. The data on clinical and aetiopathological characteristics of appendicoliths is scarce and using this systematic classification would add to this understanding.

ABSTRACT Background Colorectal cancer is identified as a lifestyle‐related type of cancer. There is an increasing emphasis on lifestyle interventions targeting pivotal lifestyle factors such as excess weight, cigarette smoking, alcohol consumption, poor diet and physical inactivity as primary and tertiary prevention. Furthermore, modifying these lifestyle factors has the potential to improve quality of life for cancer patients. We aim to identify, appraise and synthesise the available evidence regarding the effect of combined lifestyle interventions on quality of life in colorectal cancer survivors. Methods Pubmed, Ovid Embase and the Cochrane Library were searched for studies reporting on quality of life in post‐treatment colorectal cancer patients. The systematic literature search was performed according to the Preferred Reporting Items for systematic reviews and meta‐analysis (PRISMA) guidelines. Results Five articles reporting on 719 individual patients were included. Two studies reported significantly better results in (cancer‐specific) quality‐of‐life questionnaires for patients after combined lifestyle interventions. Conclusion We conclude that there is some evidence that combined lifestyle interventions could have beneficial effects on the quality of life of colorectal cancer survivors. Future randomised controlled trials reporting on quality of life of combined lifestyle interventions in colorectal cancer survivors are warranted.