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Abstract Owing to the maturity of complementary metal oxide semiconductor (CMOS) microelectronics, qubits realized with spins in silicon quantum dots (QDs) are considered among the most promising technologies for building scalable quantum computers. For this goal, ultra-low-power on-chip cryogenic CMOS (cryo-CMOS) electronics for control, read-out, and interfacing of the qubits is an important milestone. We report on-chip interfacing of tunable electron and hole QDs by a 64-channel cryo-CMOS multiplexer with less-than-detectable static power dissipation. We analyze charge noise and measure state-of-the-art addition energies and gate lever arm parameters in the QDs. We correlate low noise in QDs and sharp turn-on characteristics in cryogenic transistors, both fabricated with the same gate stack. Finally, we demonstrate that our hybrid quantum-CMOS technology provides a route to scalable interfacing of a large number of QD devices, enabling, for example, variability analysis and QD qubit geometry optimization, which are prerequisites for building large-scale silicon-based quantum computers.

Abstract Background Alzheimer’s disease (AD) is a complicated neurodegenerative disease. Neuron-glial cell interactions are an important but not fully understood process in the progression of AD. We used bioinformatic methods to analyze single-nucleus RNA sequencing (snRNA-seq) data to investigate the cellular and molecular biological processes of AD. Method snRNA-seq data were downloaded from Gene Expression Omnibus (GEO) datasets and reprocessed to identify 240,804 single nuclei from healthy controls and patients with AD. The cellular composition of AD was further explored using Uniform Manifold Approximation and Projection (UMAP). Enrichment analysis for the functions of the DEGs was conducted and cell development trajectory analyses were used to reveal underlying cell fate decisions. iTALK was performed to identify ligand-receptor pairs among various cell types in the pathological ecological microenvironment of AD. Results Six cell types and multiple subclusters were identified based on the snRNA-seq data. A subcluster of neuron and glial cells co-expressing lncRNA-SNHG14, myocardin-related transcription factor A (MRTFA), and MRTFB was found to be more abundant in the AD group. This subcluster was enriched in mitogen-activated protein kinase (MAPK)-, immune-, and apoptosis-related pathways. Through molecular docking, we found that lncRNA-SNHG14 may bind MRTFA and MRTFB, resulting in an interaction between neurons and glial cells. Conclusions The findings of this study describe a regulatory relationship between lncRNA-SNHG14, MRTFA, and MRTFB in the six main cell types of AD. This relationship may contribute to microenvironment remodeling in AD and provide a theoretical basis for a more in-depth analysis of AD.

We demonstrate ion irradiation by argon or gallium as a wafer-scale post-processing method to increase disorder in superconducting thin films. We study several widely used superconductors, both single-elements and compounds. We show that ion irradiation increases normal-state resistivity in all our films, which is expected to enable tuning their superconducting properties, for example, toward a higher kinetic inductance. We observe an increase in superconducting transition temperature for Al and MoSi and a decrease for Nb, NbN, and TiN. In MoSi, ion irradiation also improves the mixing of the two materials. We demonstrate the fabrication of an amorphous and homogeneous film of MoSi with uniform thickness, which is promising, for example, for superconducting nanowire single-photon detectors.

Abstract Low‐power nonvolatile memories operating down to deep cryogenic temperatures are important for a large spectrum of applications from high‐performance computing, electronics interfacing quantum computing hardware to space‐based electronics. Despite the potential of Hf0.5Zr0.5O2 (HZO), thanks to its compatibility with complementary metal‐oxide‐semiconductor (CMOS) back‐end‐of‐line processing, only few studies of HZO‐based memory devices down to cryogenic operation temperatures exist. Here, analog ferroelectric memory stack fabrication with 10 nm HZO and their detailed characterization under wide range of pulse amplitudes and frequencies down to 4 K are reported. When operated at temperatures below 100 K, HZO devices can support high amplitude voltage pulses, yielding record high Pr of up to 75µC cm−2 at ±7 Vp (14 Vpp) pulse amplitudes accompanied with frequency‐dependent memory window between 6 and 8 V. Devices show excellent endurance exceeding 109 cycles of ±5 Vp (10 Vpp) and Pr of 30 µC cm−2 without significant degradation of coercive voltages or loss of polarization at cryogenic temperatures. At least 20 reproducible analog states for temperatures below 100 K with almost ideal linearity of intermediate polarization states in both pulse directions is observed, demonstrating the high potential of analog cryogenic ferroelectric memories, essential for on‐line training in in‐memory‐computing architecture.

The integration of separate service systems, digitalisation, demographic changes, and staff shortages has increased the need for systematic and flexible skills development in social and health care services. In today’s working life, learning and development take place in ecosystems. This study aimed to evaluate and identify differences between students’ self-assessed competences and their beliefs about the importance of competence areas before and after professional specialisation education (PSE). The research questions were: 1) Was there any difference in students’ self-evaluated level of multidisciplinary competences before and after professional specialisation education? 2) Based on students’ self-evaluations, was there any difference between the multidisciplinary competences they considered important before and after professional specialisation education? Analysis of variance (ANOVA) test and paired t-tests were used to examine the differences in the subjects’ spontaneous responses about whether they had experienced a change in their competences after undertaking specialisation education. In the initial survey (N = 274), the student respondent group was 180, and the total number of student pairs was 65. The initial and final measurements of the 65 students who responded to the follow-up survey were therefore comparable. Four-point Likert scales were used in the questionnaires. The modified questionnaire was designed so that students answered each of the competences at two levels from their own perspectives. First, they described how important the acquisition of the skills described in this sentence would be for their own professional competence. Then, they assessed their current level of competence in relation to the sentence in question. There were no statistical differences (p>0.05) between measurements taken before and after education in most of the qualification statements describing importance. There were statistical differences (p

Monitoring the diversity and distribution of species in an ecosystem is essential to assess the success of restoration strategies. Implementing biomonitoring methods, which provide a comprehensive assessment of species diversity and mitigate biases in data collection, holds significant importance in biodiversity research. Additionally, ensuring that these methods are cost-efficient and require minimal effort is crucial for effective environmental monitoring. In this study we compare the efficiency of species detection, the cost and the effort of two non-destructive sampling techniques: Baited Remote Underwater Video (BRUV) and environmental DNA (eDNA) metabarcoding to survey marine vertebrate species. Comparisons were conducted along the Sussex coast upon the introduction of the Nearshore Trawling Byelaw. This Byelaw aims to boost the recovery of the dense kelp beds and the associated biodiversity that existed in the 1980s. We show that overall BRUV surveys are more affordable than eDNA, however, eDNA detects almost three times as many species as BRUV. eDNA and BRUV surveys are comparable in terms of effort required for each method, unless eDNA analysis is carried out externally, in which case eDNA requires less effort for the lead researchers. Furthermore, we show that increased eDNA replication yields more informative results on community structure. We found that using both methods in conjunction provides a more complete view of biodiversity, with BRUV data supplementing eDNA monitoring by recording species missed by eDNA and by providing additional environmental and life history metrics. The results from this study will serve as a baseline of the marine vertebrate community in Sussex Bay allowing future biodiversity monitoring research projects to understand community structure as the ecosystem recovers following the removal of trawling fishing pressure. Although this study was regional, the findings presented herein have relevance to marine biodiversity and conservation monitoring programs around the globe.

Generally, alkali activated materials (AAMs) are prepared by curing an alkaline paste via conventional methods such as at room temperature for weeks, even months, or in oven for days to achieve the required properties. In this paper, fast electromagnetic radiation (microwaves) was investigated in detail as an alternative to conventional methods to produce environmentally friendly porous metakaolin-based AAMs as supports for catalysts (MK-AAMs). Hydrogen peroxide was used as a foaming agent to achieve porosity of the porous MK-AAMs. The non-porous MK-AAMs without a foaming agent were used as reference for the porous MK-AAMs. Curing of the MK-AAMs were conducted at room temperature (CU1), in an oven (CU2), and by microwaves (CU3). The specific surface area (SSA) of porous and non-porous MK-AAMs cured via CU1–3 was 36, 49, 90 m2/g and 9.0, 23, 24 m2/g, respectively. The average compressive strength (MPa) was 3.8, 2.7, 2.1 and 8.9, 6.4, 5.2, respectively. The catalytical performance of porous and non- porous MK-AAMs with Cu-catalyst (i.e., Cu-composites) were tested with an aqueous solution of bisphenol A (BPA) in catalytic wet air oxidation (CWAO). After 5 h of oxidation, the highest BPA conversion of 97 % was achieved with the porous Cu-composites. A slight mass loss of 1.5 wt % was observed in the Cu composites due to erosion caused by strong fluid flow in the CWAO experiments. Based on the various analyzes performed, no significant structural or chemical changes were observed in porous and non-porous MK-AAMs regardless of the curing method of CU1–3, which also confirmed that MK-AAMs can be produced by microwaves without losing the desired properties of the materials, such as porosity and mechanical durability.

From 2007 in US and from 2022 in EU it is mandatory to use TPMS monitoring in new cars. Sensors mounted in tires require a continuous power supply, which currently only is from batteries. Piezoelectric energy harvesting is a promising technology to harvest energy from tire movement and deformation to prolong usage of batteries and even avoid them inside tires.This study presents a simpler method to simultaneous model the tire deformation and piezoelectric harvester performance by using a new simulation approach - dynamic bending zone. For this, angular and initial velocities were used for rolling motion, while angled polarization was introduced in the model for the piezoelectric material to generate correct voltage from tire deformation. We combined this numerical simulation in COMSOL Multiphysics with real-life measurements of electrical output of a piezoelectric energy harvester that was mounted onto a tire. This modelling approach allowed for 10 times decrease in simulation time as well as simpler investigation of systems parameters influencing the output power. By using experimental data, the simulation could be fine-tuned for material properties and for easier extrapolation of tire deformation with output harvested energy from simulations done at low velocity to the high velocity experimental data.

Neuronal death is one of the key pathologies in Alzheimer's disease (AD). How neuronal death begins in AD is far from clear, so clarifying this process may help develop effective therapies. This study collected single-cell RNA sequencing data of 85 AD samples and 83 control samples, covering the prefrontal cortex, internal olfactory cortex, superior parietal lobe, superior frontal gyrus, caudal internal olfactory cortex, somatosensory cortex, hippocampus, superior frontal cortex and peripheral blood mononuclear cells. Additionally, spatial transcriptomic data of coronal sections from 6 AppNL-G-F AD mice and 6 control C57Bl/6 J mice were acquired. The main single-cell and spatial transcriptomics results were experimentally validated in wild type and 5 × FAD mice. We found that the microglia subpopulation Mic_PTPRG can communicate with specific types of neurons (especially excitatory ExNeu_PRKN_VIRMA and inhibitory InNeu_PRKN_VIRMA neuronal subpopulations) and cause them to express PTPRG during AD progression. Within neurons, PTPRG binds and upregulates the m6A methyltransferase VIRMA, thus inhibiting translation of PRKN mRNA to prevent the clearance of damaged mitochondria in neurons through suppressing mitophagy. As the disease progresses, the energy and nutrient metabolic pathways in neurons are reprogrammed, leading to their death. Consistently, we determined that PTPTRG can physically interact with VIRMA in mouse brains and PRKN is significantly upregulated in 5 × FAD mouse brain. Altogether, our findings demonstrate that PTPRG activates the m6A methyltransferase VIRMA to block mitophagy-mediated neuronal death in AD, which is a potential pathway, through which microglia and neuronal PTPRG modify neuronal connections in the brain during AD progression.

Abstract Biosensors based on graphene and bio‐graphene interfaces have gained momentum in recent years due to graphene's outstanding electronic and mechanical properties. By introducing the patterning of a single‐layer graphene surface by two‐photon oxidation (2PO), the surface hydrophobicity/hydrophilicity and doping can be varied at the nanoscale while preserving the carbon network, thus opening possibilities to design new devices. In this study, the effect of 2PO on the catalytic activity of the noncovalently immobilized enzyme horseradish peroxidase (HRP) on single‐layer graphene‐coated Si/SiO2 chips is presented. To monitor the activity continuously, a simple well‐plate setup is introduced. Upon controllable 1–2‐layer immobilization, the catalytic activity decreases to a maximum value of 7.5% of the free enzyme. Interestingly, the activity decreases with increasing 2PO area on the samples. Hence, the HRP catalytic activity on the graphene surface is locally controlled. This approach can enable the development of graphene‐bio interfaces with locally varying enzyme activity.

There has been a rising interest in the iron and steel industry in replacing fossil-based carbon carriers in their processes because they are the main origin of the anthropogenic carbon emissions within the industry. The use of bio-based carbon carriers could be one solution to partly tackle this challenge. Conventionally, biocarbon is produced by pyrolysis with fixed heating rate, pyrolysis temperature, and retention time. Although the mechanisms behind the formation of biocarbon and the decomposition temperatures of the main compounds of biomass-based materials are known, this knowledge is rarely being utilized in the design of commercial pyrolysis reactors, even though the pyrolysis mechanism-based approach increases the biocarbon yield. In this study, the mechanistic pathway of carbonization of lignocellulosic biomass is taken into account to produce biocarbon with higher yield and quality than conventional pyrolysis with the same process time. Results show that when the process time is the same in both methods, segmented pyrolysis increases biocarbon yield up to 5.4% within a pyrolysis temperature range from 300 °C to 900 °C. Also, fixed carbon yield increased 1.5% in this temperature area. When using segmented pyrolysis, the most suitable pyrolysis temperature is 700 °C based on the characteristics of the produced biocarbon.

Abstract Background As an adult tumor with the most invasion and the highest mortality rate, the inherent heterogeneity of glioblastoma (GBM) is the main factor that causes treatment failure. Therefore, it is important to have a deeper understanding of the pathology of GBM. Some studies have shown that Eukaryotic Initiation Factor 4A-3 (EIF4A3) can promote the growth of many people’s tumors, and the role of specific molecules in GBM remains unclear. Methods The correlation between the expression of EIF4A3 gene and its prognosis was studied in 94 GBM patients using survival analysis. Further in vitro and in vivo experiments, the effect of EIF4A3 on GBM cells proliferation, migration, and the mechanism of EIF4A3 on GBM was explored. In addition, combined with bioinformatics analysis, we further confirmed that EIF4A3 contributes to the progress of GBM. Results The expression of EIF4A3 was upregulated in GBM tissues, and high expression of EIF4A3 is associated with poor prognosis in GBM. In vitro, knockdown of EIF4A3 significantly reduced the proliferation, migration, and invasion abilities of GBM cells, whereas overexpression of EIF4A3 led to the opposite effect. The analysis of differentially expressed genes related to EIF4A3 indicates that it is involved in many cancer-related pathways, such as Notch and JAK-STAT3 signal pathway. In Besides, we demonstrated the interaction between EIF4A3 and Notch1 by RNA immunoprecipitation. Finally, the biological function of EIF4A3-promoted GBM was confirmed in living organisms. Conclusion The results of this study suggest that EIF4A3 may be a potential prognostic factor, and Notch1 participates in the proliferation and metastasis of GBM cells mediated by EIF4A3.

Introduction Shoulder pain is a substantial medical and socioeconomic problem in most societies, affecting the ability to work or carry out leisure time activities as well as subsequently influencing physical and psychological well-being. According to a nationwide survey in Finland, 27% of the population reported shoulder pain within the last 30 days. In clinical practice, imaging findings of structural abnormalities are typically thought to explain symptoms, even though such findings are also prevalent in asymptomatic individuals, particularly with increasing age. Overall, there is a paucity of high-quality evidence on the prevalence, clinical relevance and prognosis of ‘abnormal’ imaging findings of the shoulder.The aim of the Finnish Imaging of Shoulder (FIMAGE) study is fourfold: to assess (1) the prevalence of shoulder symptoms and the most common anatomical variants and imaging abnormalities of the shoulder; (2) the concordance between shoulder symptoms, function and imaging abnormalities; (3) the most important determinants of symptoms, function and imaging abnormalities; and (4) the course of shoulder complaints over 5 years.Methods The FIMAGE target population of 600 participants, aged 40–75 years, will be randomly selected from a nationally representative general population sample of 9922 individuals originally recruited for the Finnish Health 2000 Survey. On giving informed consent, the participants will be invited to a clinical visit that includes assessment of general health, shoulder symptoms, bilateral shoulder examination and imaging of both shoulders with plain radiography and MRI.Ethics and dissemination The study has been approved by the Institutional Review Board of the Helsinki and Uusimaa Hospital District. The findings will be published according to the Strengthening the Reporting of Observational Studies in Epidemiology criteria.Trial registration number NCT05641415.

Due to seasonally appearing viruses and several outbreaks and present pandemic, we are surrounded by viruses in our everyday life. In order to reduce viral transmission, functionalized surfaces that inactivate viruses are in large demand. Here the endeavor was to functionalize cellulose-based materials with tannic acid (TA) and tannin-rich extracts by using different binding polymers to prevent viral infectivity of both non-enveloped coxsackievirus B3 (CVB3) and enveloped human coronavirus OC43 (HCoV-OC43). Direct antiviral efficacy of TA and spruce bark extract in solution was measured: EC50 for CVB3 was 0.12 and 8.41 μg/ml and for HCoV-OC43, 78.16 and 95.49 μg/ml, respectively. TA also led to an excellent 5.8- to 7-log reduction of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infectivity. TA functionalized materials reduced infectivity already after 5-min treatment at room temperature. All the tested methods to bind TA showed efficacy on paperboard with 0.1 to 1% (w/v) TA concentrations against CVB3 whereas material hydrophobicity decreased activities. Specific signatures for TA and HCoV-OC43 were discovered by Raman spectroscopy and showed clear co-localization on the material. qPCR study suggested efficient binding of CVB3 to the TA functionalized cellulose whereas HCoV-OC43 was flushed out from the surfaces more readily. In conclusion, the produced TA-materials showed efficient and broadly acting antiviral efficacy. Additionally, the co-localization of TA and HCoV-OC43 and strong binding of CVB3 to the functionalized cellulose demonstrates an interaction with the surfaces. The produced antiviral surfaces thus show promise for future use to increase biosafety and biosecurity by reducing pathogen persistence.

Summary: Epithelial-mesenchymal transition (EMT) empowers epithelial cells with mesenchymal and stem-like attributes, facilitating metastasis, a leading cause of cancer-related mortality. Hybrid epithelial-mesenchymal (E/M) cells, retaining both epithelial and mesenchymal traits, exhibit heightened metastatic potential and stemness. The mesenchymal intermediate filament, vimentin, is upregulated during EMT, enhancing the resilience and invasiveness of carcinoma cells. The phosphorylation of vimentin is critical to its structure and function. Here, we identify that stabilizing vimentin phosphorylation at serine 56 induces multinucleation, specifically in hybrid E/M cells with stemness properties but not epithelial or mesenchymal cells. Cancer stem-like cells are especially susceptible to vimentin-induced multinucleation relative to differentiated cells, leading to a reduction in self-renewal and stemness. As a result, vimentin-induced multinucleation leads to sustained inhibition of stemness properties, tumor initiation, and metastasis. These observations indicate that a single, targetable phosphorylation event in vimentin is critical for stemness and metastasis in carcinomas with hybrid E/M properties.

Objectives Determine community needs and perspectives as part of planning health service incorporation into Wanang Conservation Area, in support of locally driven sustainable development.Design Clinical and rapid anthropological assessment (individual primary care assessments, key informant (KI) interviews, focus groups (FGs), ethnography) with treatment of urgent cases.Setting Wanang (pop. c189), a rainforest community in Madang province, Papua New Guinea.Participants 129 villagers provided medical histories (54 females (f), 75 males (m); median 19 years, range 1 month to 73 years), 113 had clinical assessments (51f, 62m; median 18 years, range 1 month to 73 years). 26 ≥18 years participated in sex-stratified and age-stratified FGs (f40 years; m>40 years). Five KIs were interviewed (1f, 4m). Daily ethnographic fieldnotes were recorded.Results Of 113 examined, 11 were ‘well’ (a clinical impression based on declarations of no current illness, medical histories, conversation, no observed disease signs), 62 (30f, 32m) were treated urgently, 31 referred (15f, 16m), indicating considerable unmet need. FGs top-4 ranked health issues concorded with KI views, medical histories and clinical examinations. For example, ethnoclassifications of three ((A) ‘malaria’, (B) ‘sotwin’, (C) ‘grile’) translated to the five biomedical conditions diagnosed most ((A) malaria, 9 villagers; (B) upper respiratory infection, 25; lower respiratory infection, 10; tuberculosis, 9; (C) tinea imbricata, 15) and were highly represented in declared medical histories ((A) 75 participants, (B) 23, (C) 35). However, 29.2% of diagnoses (49/168) were limited to one or two people. Treatment approaches included plant medicines, stored pharmaceuticals, occasionally rituals. Travel to hospital/pharmacy was sometimes undertaken for severe/refractory disease. Service barriers included: no health patrols/accessible aid post, remote hospital, unfamiliarity with institutions and medicine costs. Service introduction priorities were: aid post, vaccinations, transport, perinatal/birth care and family planning.Conclusions This study enabled service planning and demonstrated a need sufficient to acquire funding to establish primary care. In doing so, it aided Wanang’s community to develop sustainably, without sacrificing their forest home.

Although there is general agreement that global change will influence low-lying atoll islands, considerable uncertainty remains concerning the nature, rates, and causes of morphological change (or, conversely, the stability) of islands. As the net geomorphical product of sediment erosion, transport, and accumulation, islands are intimately tied to reef flat sedimentological processes. Recognizing the morphodynamical linkages between reef flats and islands, the purpose of this study is to examine the nature and controls on spatial and temporal variations in sediment transport pathways on reef flats and their relation to island planform changes or stability on atolls of Tokelau and Kiribati. GIS analysis of historical aerial images and high-resolution remote-sensing data capture patterns of reef flat change up to 72 years in duration with up to weekly temporal resolution. Data reveal how granular materials that make up bars and islands on reef flats respond to physical oceanographic processes via sedimentary-geomorphical change across temporal scales, from “instantaneous” impacts of cyclones or swell events to seasonal to multi-decadal shifts. Each of these shifts is manifest as migration of sediment of island beaches and bar forms, but the character varies markedly—bars form new islands, others erode and disappear; some changes are cyclic, others are directional, still others are hybrid; sediment can be transported lagoonward, oceanward, along the reef flat, or in combinations thereof; and migration rates reach up to 10 s of m/month. Although sea-level change likely plays a modulating role, much of the considerable spatial and temporal variability relates to differences in energy controlled by seasonal change in swell direction and climate shifts. Nonetheless, sedimentary response to these external forcings at any specific location also is shaped by local factors, such as trade wind-generated lagoonal waves and currents, atoll lagoon size and depth, margin width and orientation relative to waves, and autogenic processes such as attachment of migrating bars. Collectively, these influences shape the spatially and temporally heterogeneous sediment flux to and from islands, and thus the variable response of islands to ongoing sea-level change. Understanding such local influences is requisite to predictive understanding of how global change might impact these sensitive seascapes.

Abstract Background Two common ways of assessing the clinical relevance of treatment outcomes are the minimal important difference (MID) and the patient acceptable symptom state (PASS). The former represents the smallest change in the given outcome that makes people feel better, while the latter is the symptom level at which patients feel well. Methods We recruited 124 patients with a humeral shaft fracture to a randomised controlled trial comparing surgery to nonsurgical care. Outcome instruments included the Disabilities of Arm, Shoulder, and Hand (DASH) score, the Constant-Murley score, and two numerical rating scales (NRS) for pain (at rest and on activities). A reduction in DASH and pain scores, and increase in the Constant-Murley score represents improvement. We used four methods (receiver operating characteristic [ROC] curve, the mean difference of change, the mean change, and predictive modelling methods) to determine the MID, and two methods (the ROC and 75th percentile) for the PASS. As an anchor for the analyses, we assessed patients’ satisfaction regarding the injured arm using a 7-item Likert-scale. Results The change in the anchor question was strongly correlated with the change in DASH, moderately correlated with the change of the Constant-Murley score and pain on activities, and poorly correlated with the change in pain at rest (Spearman’s rho 0.51, -0.40, 0.36, and 0.15, respectively). Depending on the method, the MID estimates for DASH ranged from -6.7 to -11.2, pain on activities from -0.5 to -1.3, and the Constant-Murley score from 6.3 to 13.5. The ROC method provided reliable estimates for DASH (-6.7 points, Area Under Curve [AUC] 0.77), the Constant-Murley Score (7.6 points, AUC 0.71), and pain on activities (-0.5 points, AUC 0.68). The PASS estimates were 14 and 10 for DASH, 2.5 and 2 for pain on activities, and 68 and 74 for the Constant-Murley score with the ROC and 75th percentile methods, respectively. Conclusion Our study provides credible estimates for the MID and PASS values of DASH, pain on activities and the Constant-Murley score, but not for pain at rest. The suggested cut-offs can be used in future studies and for assessing treatment success in patients with humeral shaft fracture. Trial registration ClinicalTrials.gov NCT01719887, first registration 01/11/2012.

Exposure notification applications (ENAs) or digital proximity tracing apps were used in several countries during the COVID-19 pandemic. In this viewpoint, we share our experience of implementing and running the Finnish ENA (Koronavilkku), one of the national ENAs with the highest proportion of users during the pandemic. With the aim of strengthening public trust and increasing app uptake, there was a strong prioritization of privacy and data security for the end user throughout the ENA development. This, in turn, limited the use of the app as a tool for health care professionals and deeper insight into its potential effectiveness. The ENA was designed to supplement conventional contact tracing, rather than replace it, and to serve as an early warning system and a trigger for action for the user in case of potential exposure. The predefined target of 40% uptake in the population was achieved within 3 months of the ENA launch. We consider easy-to-understand information produced together with communication experts crucial during the changing pandemic situation. This information educated people about the app as one component in mitigating the pandemic. As the pandemic and its mitigation evolved, the ENA also needed adapting and updating. A few months after its launch, Finland joined European interoperability, which allowed the ENA to share information with ENAs of other countries. We added automatic token issuing to the ENA as of mid-2021. If added earlier and more comprehensively, automatization could have more effectively saved resources in health care services and prevented overburdening contact tracing teams, while also notifying potentially exposed individuals quicker and more reliably. In the spring of 2021, the number of active apps started to gradually decline. Quarantine and testing practices for asymptomatic vaccinated individuals following exposure to the virus were eased and home tests became more common, eventually replacing laboratory testing for much of the population. Taken together, this led to decreased token issuance, which weakened the potential public health usefulness of the app. A self-service option for token issuance would likely have prolonged the lifespan of the app. The ENA was discontinued in mid-2022. Regularly conducted surveys would have helped gain timely knowledge on the use and effectiveness of the app for better responding to the changing needs during the pandemic.

The destructive Sir Ivan Dougherty fire burned 55,000 hectares around 250 km northwest of Sydney in New South Wales on 12 February 2017. Record hot temperatures were recorded in the area during the lead-in days and the fire conditions at the time were described as the ‘worst ever seen in NSW’. The observed weather conditions were hot, dry and very windy ahead of a synoptic frontal wind change during the afternoon. ‘Extreme’ to ‘catastrophic’ fire weather was predicted, and the potential for extreme fire behaviour was identified several days in advance. The Australian coupled fire–atmosphere model ACCESS-Fire has been run to explore the characteristics of the Sir Ivan fire. Several features resulting from fire–atmosphere interaction are produced in the simulations. Simulated heat flux along the fire perimeter shows increased intensity on the northern fire flank in response to gradual backing winds ahead of the main frontal wind change. Temporal and spatial variability in fire activity, seen as pulses in fire intensity and fireline wind speed, develop in response to boundary layer rolls in the wind fields. Deep moist convection consistent with the observed pyrocumulonimbus (pyroCb) cloud is simulated over the fire at around the time of the frontal wind change, and matches guidance from the ‘PyroCb Firepower Threshold’ tool, which showed transient favourable conditions. After the wind change, short-lived near-surface and elevated vortices suggest organised rotating features on the northern flank of the fire. The coupled model captures processes that cannot be produced in uncoupled fire predictions and that are not captured in current operational meteorological forecast products provided to Australian fire agencies. This paper links the features from coupled simulations to available observations and suggests pathways to embed the learnings in operational practice.

Pääkirjoitus numeroon 1/2023.

BackgroundDespite tremendous progress in diagnosis and prediction of Alzheimer’s disease (AD), the absence of treatments implies the need for further research. In this study, we screened AD biomarkers by comparing expression profiles of AD and control tissue samples and used various models to identify potential biomarkers. We further explored immune cells associated with these biomarkers that are involved in the brain microenvironment.MethodsBy differential expression analysis, we identified differentially expressed genes (DEGs) of four datasets (GSE125583, GSE118553, GSE5281, GSE122063), and common expression direction of genes of four datasets were considered as intersecting DEGs, which were used to perform enrichment analysis. We then screened the intersecting pathways between the pathways identified by enrichment analysis. DEGs in intersecting pathways that had an area under the curve (AUC) > 0.7 constructed random forest, least absolute shrinkage and selection operator (LASSO), logistic regression, and gradient boosting machine models. Subsequently, using receiver operating characteristic curve (ROC) and decision curve analysis (DCA) to select an optimal diagnostic model, we obtained the feature genes. Feature genes that were regulated by differentially expressed miRNAs (AUC > 0.85) were explored further. Furthermore, using single-sample GSEA to calculate infiltration of immune cells in AD patients.ResultsScreened 1855 intersecting DEGs that were involved in RAS and AMPK signaling. The LASSO model performed best among the four models. Thus, it was used as the optimal diagnostic model for ROC and DCA analyses. This obtained eight feature genes, including ATP2B3, BDNF, DVL2, ITGA10, SLC6A12, SMAD4, SST, and TPI1. SLC6A12 is regulated by miR-3176. Finally, the results of ssGSEA indicated dendritic cells and plasmacytoid dendritic cells were highly infiltrated in AD patients.ConclusionThe LASSO model is the optimal diagnostic model for identifying feature genes as potential AD biomarkers, which can supply new strategies for the treatment of patients with AD.

Abstract Background Microglia, the resident immune cells of the brain, play a critical role in numerous diseases, but are a minority cell type and difficult to genetically manipulate in vivo with viral vectors and other approaches. Primary cultures allow a more controlled setting to investigate these cells, but morphological and transcriptional changes upon removal from their normal brain environment raise many caveats from in vitro studies. Methods To investigate whether cultured microglia recapitulate in vivo microglial signatures, we used single-cell RNA sequencing (scRNAseq) to compare microglia freshly isolated from the brain to primary microglial cultures. We performed cell population discovery, differential expression analysis, and gene co-expression module analysis to compare signatures between in vitro and in vivo microglia. We constructed causal predictive network models of transcriptional regulators from the scRNAseq data and identified a set of potential key drivers of the cultured phenotype. To validate this network analysis, we knocked down two of these key drivers, C1qc and Prdx1, in primary cultured microglia and quantified changes in microglial activation markers. Results We found that, although often assumed to be a relatively homogenous population of cells in culture, in vitro microglia are a highly heterogeneous population consisting of distinct subpopulations of cells with transcriptional profiles reminiscent of macrophages and monocytes, and are marked by transcriptional programs active in neurodegeneration and other disease states. We found that microglia in vitro presented transcriptional activation of a set of “culture shock genes” not found in freshly isolated microglia, characterized by strong upregulation of disease-associated genes including Apoe, Lyz2, and Spp1, and downregulation of homeostatic microglial markers, including Cx3cr1, P2ry12, and Tmem119. Finally, we found that cultured microglia prominently alter their transcriptional machinery modulated by key drivers from the homeostatic to activated phenotype. Knockdown of one of these drivers, C1qc, resulted in downregulation of microglial activation genes Lpl, Lyz2, and Ccl4. Conclusions Overall, our data suggest that when removed from their in vivo home environment, microglia suffer a severe case of “culture shock”, drastically modulating their transcriptional regulatory network state from homeostatic to activated through upregulation of modules of culture-specific genes. Consequently, cultured microglia behave as a disparate cell type that does not recapitulate the homeostatic signatures of microglia in vivo. Finally, our predictive network model discovered potential key drivers that may convert activated microglia back to their homeostatic state, allowing for more accurate representation of in vivo states in culture. Knockdown of key driver C1qc partially attenuated microglial activation in vitro, despite C1qc being only weakly upregulated in culture. This suggests that even genes that are not strongly differentially expressed across treatments or preparations may drive downstream transcriptional changes in culture.

Kindergarten teachers optimize manipulatives in teaching young children. These manipulatives can be tools in developing essential skills needed to meet the demands of 21st century society. A descriptive mixed method design was employed in this study. Qualitative data were gathered using interviews and classroom observations, while quantitative data were extracted from questionnaire and classroom inventory checklist. Quantitative data were analyzed using descriptive statistics, whereas qualitative data were transcribed, coded, and categorized by themes. Research respondents were the 25 kindergarten teachers from public schools (n=8) and private schools (n=3) in Pulilan, Bulacan. Results showed that teachers use manipulatives in the teaching and learning process as these provide many opportunities for children to learn and acquire different skills. Several manipulatives develop more than one skill, depending on their characteristics and nature. Moreover, skill development varies depending on the activity and type of manipulatives used. The research finds that manipulatives continue to be relevant and can be used to develop 21st century skills in kindergarten. However, teachers need to undergo training on the optimization of manipulatives that are readily available in the kindergarten classroom. Furthermore, there is a need for schools to invest in different manipulatives for use in kindergarten.

Biomass-based solutions have been discussed as having the potential to replace fossil-based solutions in the iron and steel industry. To produce the biocarbon required in these processes, thermochemical treatment, pyrolysis, typically takes place. There are various ways to produce biocarbon, alongside other products, which are called pyrolysis oil and pyrolysis gas. These conversion methods can be divided into conventional and non-conventional methods. In this paper, those techniques and technologies to produce biocarbon are summarized and reviewed. Additionally, the effect of different process parameters and their effect on biocarbon yield and properties are summarized. The process parameters considered were final pyrolysis temperature, heating rate, reaction atmosphere, pressure, catalyst, use of binders, and particle size. Finally, the effect of different reactor configurations is discussed. Understanding the combination of these methods, technology parameters, and reactor configurations will help to produce biocarbon with the desired quality and highest yield possible.

The Waroona fire burned 69000ha south of Perth in January 2016. There were two fatalities and 170 homes were lost. Two evening ember storms were reported and pyrocumulonimbus (pyroCb) cloud developed on consecutive days. The extreme fire behaviour did not reconcile with the near-surface conditions customarily used to assess fire danger. A case study of the fire (Peace et al. 2017) presented the hypothesis that the evening ember storms resulted from interactions between the above-surface wind fields, local topography and the fire plume. The coupled fire–atmosphere model ACCESS-Fire has been run in order to explore this hypothesis and other aspects of the fire activity, including the pyroCb development. ACCESS-Fire incorporates the numerical weather prediction model ACCESS (Australian Community Climate and Earth System Simulator, described by Puri et al. 2013) and a fire spread component. In these simulations, the Dry Eucalypt Forest Fire (Vesta) fire spread model is used. In this study we first show that the reconstruction of surface fire spread and simulated fire spread are a good match for the first day; second, we show that the model produces deep moist convection as an indicator of pyrocumulonimbus cloud and, third, we show the fire–atmosphere interactions surrounding the ember showers provided an environment conducive to the observed mass spotting. The simulation results demonstrate that ACCESS-Fire is a tool that may be used to further explore the complex processes and potential impacts surrounding pyroCb development and short-distance ember transport.

In breast cancer, the currently approved anti‐receptor tyrosine‐protein kinase erbB‐2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2‐related therapeutic targets could offer a means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin‐related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2‐targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti‐SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumab in vitro and in ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cell density in a mouse xenograft model of HER2‐positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient‐derived explant three‐dimensional cultures. These results provide, for the first time, proof of principle that SorLA is a druggable target in breast cancer.

Abstract Aim To examine how work community factors are related to occupational well‐being and work ability, and how occupational well‐being is related to work ability. Design A cross‐sectional study was conducted among home care workers in one municipality in Finland. Methods A self‐administered survey on work and well‐being was filled out by 167 employees working two shifts in 2019. Structural equation modelling was used to analyse the association between work community factors, occupational well‐being and work ability. Results The only work community factor directly affecting Occupational well‐being was Information and work organization; the effect of the other two factors, Social support and Influence on work shifts, was indirect. All work community factors indirectly affected Work ability. Home care should emphasize information provision and work organization with optimal time use. This requires social support, a well‐functioning work atmosphere and providing employees with opportunities for influence and participation.

Abstract Background Arthroscopic subacromial decompression is one of the most commonly performed shoulder surgeries in the world. It is performed to treat patients with suspected shoulder impingement syndrome, i.e., subacromial pain syndrome. Only few studies have specifically assessed return-to-work rates after subacromial decompression surgery. All existing evidence comes from open, unblinded study designs and this lack of blinding introduces the potential for bias. We assessed return to work and its predictors in patients with shoulder impingement syndrome in a secondary analysis of a placebo-surgery controlled trial. Methods One hundred eighty-four patients in a randomised trial had undergone arthroscopic subacromial decompression (n = 57), diagnostic arthroscopy, a placebo surgical intervention, (n = 59), or exercise therapy (n = 68). We assessed return to work, defined as having returned to work for at least two follow-up visits by the primary 24-month time point, work status at 24 and 60 months, and trajectories of return to work per follow-up time point. Patients and outcome assessors were blinded to the assignment regarding the arthroscopic subacromial decompression vs. diagnostic arthroscopy comparison. We assessed the treatment effect on the full analysis set as the difference between the groups in return-to-work rates and work status at 24 months and at 60 months using Chi-square test and the predictors of return to work with logistic regression analysis. Results There was no difference in the trajectories of return to work between the study groups. By 24 months, 50 of 57 patients (88%) had returned to work in the arthroscopic subacromial decompression group, while the respective figures were 52 of 59 (88%) in the diagnostic arthroscopy group and 61 of 68 (90%) in the exercise therapy group. No clinically relevant predictors of return to work were found. The proportion of patients at work was 80% (147/184) at 24 months and 73% (124/184) at 60 months, with no difference between the treatment groups (p-values 0.842 and 0.943, respectively). Conclusions Arthroscopic subacromial decompression provided no benefit over diagnostic arthroscopy or exercise therapy on return to work in patients with shoulder impingement syndrome. We did not find clinically relevant predictors of return to work either. Trial registration ClinicalTrials.gov identifier NCT00428870 .

BackgroundCerebral small vessel disease (CSVD) is associated with the pathogenesis of Alzheimer’s disease (AD). Effective treatments to alleviate AD are still not currently available. Hence, we explored markers and underlying molecular mechanisms associated with AD by utilizing gene expression profiles of AD and CSVD patients from public databases, providing more options for early diagnosis and its treatment.MethodsGene expression profiles were collected from GSE63060 (for AD) and GSE162790 (for CSVD). Differential analysis was performed between AD and mild cognitive impairment (MCI) or CSVD progression and CSVD no-progression. In both datasets, differentially expressed genes (DEGs) with the same expression direction were identified as common DEGs. Then protein-protein interaction (PPI) network was constructed for common DEGs. Differential immune cells and checkpoints were calculated between AD and MCI.ResultsA total of 146 common DEGs were identified. Common DEGs were mainly enriched in endocytosis and oxytocin signaling pathways. Interestingly, endocytosis and metabolic pathways were shown both from MCI to AD and from CSVD no-progression to CSVD progression. Moreover, SIRT1 was identified as a key gene by ranking degree of connectivity in the PPI network. SIRT1 was associated with obesity-related genes and metabolic disorders. Additionally, SIRT1 showed correlations with CD8 T cells, NK CD56 bright cells, and checkpoints in AD.ConclusionThe study revealed that the progression of AD is associated with abnormalities in gene expression and metabolism and that the SIRT1 gene may serve as a promising therapeutic target for the treatment of AD.

ObjectiveThis study investigated the effects of a school-based skill-training intervention in attention control and executive functions for pupils with hyperactivity-impulsivity (H-I) and cognitive control (CC) deficits. The main aim was to examine whether the intervention differently influenced H-I and CC, and whether cognitive abilities or conduct problems moderated response to the intervention.MethodElementary school pupils from 41 schools participated the study and were divided into an intervention group (n = 71) and a waitlist control group (n = 77). Intervention outcomes were assessed with an inventory assessing executive function difficulties (including H-I and CC) completed by classroom teachers.ResultsSignificant intervention effects and positive changes were detected in CC but not in H-I. Significant intervention effects were found mainly among pupils with low levels of conduct problems.ConclusionsThe results suggest that a skill-training intervention has specific positive effects on CC, but conduct problems may diminish response to intervention.

BackgroundAlzheimer’s disease (AD) and sleep disorders are both neurodegenerative conditions characterized by impaired or absent sleep. However, potential common pathogenetic mechanisms of these diseases are not well characterized.MethodsDifferentially expressed genes (DEGs) were identified using publicly available human gene expression profiles GSE5281 for AD and GSE40562 for sleep disorder. DEGs common to the two datasets were used for enrichment analysis, and we performed multi-scale embedded gene co-expression network analysis (MEGENA) for common DEGs. Fast gene set enrichment analysis (fGSEA) was used to obtain common pathways, while gene set variation analysis (GSVA) was applied to quantify those pathways. Subsequently, we extracted the common genes between module genes identified by MEGENA and genes of the common pathways, and we constructed protein-protein interaction (PPI) networks. The top 10 genes with the highest degree of connectivity were classified as hub genes. Common genes were used to perform Metascape enrichment analysis for functional enrichment. Furthermore, we quantified infiltrating immune cells in patients with AD or sleep disorder and in controls.ResultsDEGs common to the two disorders were involved in the citrate cycle and the HIF-1 signaling pathway, and several common DEGs were related to signaling pathways regulating the pluripotency of stem cells, as well as 10 other pathways. Using MEGENA, we identified 29 modules and 1,498 module genes in GSE5281, and 55 modules and 1,791 module genes in GSE40562. Hub genes involved in AD and sleep disorder were ATP5A1, ATP5B, COX5A, GAPDH, NDUFA9, NDUFS3, NDUFV2, SOD1, UQCRC1, and UQCRC2. Plasmacytoid dendritic cells and T helper 17 cells had the most extensive infiltration in both AD and sleep disorder.ConclusionAD pathology and pathways of neurodegeneration participate in processes contributing in AD and sleep disorder. Hub genes may be worth exploring as potential candidates for targeted therapy of AD and sleep disorder.

Abstract Graphene has exceptionally high in-plane strength, which makes it ideal for various nanomechanical applications. At the same time, its exceptionally low out-of-plane stiffness makes it also flimsy and hard to handle, rendering out-of-plane structures unstable and difficult to fabricate. Therefore, from an application point of view, a method to stiffen graphene would be highly beneficial. Here we demonstrate that graphene can be significantly stiffened by using a laser writing technique called optical forging. We fabricate suspended graphene membranes and use optical forging to create stable corrugations. Nanoindentation experiments show that the corrugations increase graphene bending stiffness up to 0.8 MeV, five orders of magnitude larger than pristine graphene and corresponding to some 35 layers of bulk graphite. Simulations demonstrate that, in addition to stiffening by micron-scale corrugations, optical forging stiffens graphene also at the nanoscale. This magnitude of stiffening of an atomically thin membrane will open avenues for a plethora of new applications, such as GHz resonators and 3D scaffolds.

BackgroundThe detection of atrial fibrillation (AF) is a major clinical challenge as AF is often paroxysmal and asymptomatic. Novel mobile health (mHealth) technologies could provide a cost-effective and reliable solution for AF screening. However, many of these techniques have not been clinically validated. ObjectiveThe purpose of this study is to evaluate the feasibility and reliability of artificial intelligence (AI) arrhythmia analysis for AF detection with an mHealth patch device designed for personal well-being. MethodsPatients (N=178) with an AF (n=79, 44%) or sinus rhythm (n=99, 56%) were recruited from the emergency care department. A single-lead, 24-hour, electrocardiogram-based heart rate variability (HRV) measurement was recorded with the mHealth patch device and analyzed with a novel AI arrhythmia analysis software. Simultaneously registered 3-lead electrocardiograms (Holter) served as the gold standard for the final rhythm diagnostics. ResultsOf the HRV data produced by the single-lead mHealth patch, 81.5% (3099/3802 hours) were interpretable, and the subject-based median for interpretable HRV data was 99% (25th percentile=77% and 75th percentile=100%). The AI arrhythmia detection algorithm detected AF correctly in all patients in the AF group and suggested the presence of AF in 5 patients in the control group, resulting in a subject-based AF detection accuracy of 97.2%, a sensitivity of 100%, and a specificity of 94.9%. The time-based AF detection accuracy, sensitivity, and specificity of the AI arrhythmia detection algorithm were 98.7%, 99.6%, and 98.0%, respectively. ConclusionsThe 24-hour HRV monitoring by the mHealth patch device enabled accurate automatic AF detection. Thus, the wearable mHealth patch device with AI arrhythmia analysis is a novel method for AF screening. Trial RegistrationClinicalTrials.gov NCT03507335; https://clinicaltrials.gov/ct2/show/NCT03507335