Performance of 21 Early Warning System scores in predicting in-hospital deterioration among undifferentiated admitted patients managed by ambulance services.

BACKGROUND: The optimal Early Warning System (EWS) scores for identifying patients at risk of clinical deterioration among those transported by ambulance services remain uncertain. This retrospective study compared the performance of 21 EWS scores to predict clinical deterioration using vital signs (VS) measured in the prehospital or emergency department (ED) setting. METHODS: Adult patients transported to a single ED by ambulances and subsequently admitted to the hospital between 1 January 2019 and 18 April 2019 were eligible for inclusion. The primary outcome was 30-day mortality; secondary outcomes included 3-day mortality, admission to intensive care or coronary care units, length of hospital stay and emergency call activations. The discriminative ability of the EWS scores was assessed using the area under the receiver operating characteristic curve (AUROC). Subanalyses compared the performance of EWS scores between surgical and medical patient types. RESULTS: Of 1414 patients, 995 (70.4%) (53.1% male, mean age 68.7±17.5 years) were included. In the ED setting, 30-day mortality was best predicted by VitalPAC EWS (AUROC 0.71, 95% CI (0.65 to 0.77)) and National Early Warning Score (0.709 (0.65 to 0.77)). All EWS scores calculated in the prehospital setting had AUROC <0.70. Rapid Emergency Medicine Score (0.83 (0.73 to 0.92)) and New Zealand EWS (0.88 (0.81 to 0.95)) best predicted 3-day mortality in the prehospital and ED settings, respectively. EWS scores calculated using either prehospital or ED VS were more effective in predicting 3-day mortality in surgical patients, whereas 30-day mortality was best predicted in medical patients. Among the EWS scores that achieved AUROC ≥0.70, no statistically significant differences were detected in their discriminatory abilities to identify patients at risk of clinical deterioration. CONCLUSIONS: EWS scores better predict 3-day as opposed to 30-day mortality and are more accurate when estimated using VS measured in the ED. The discriminatory performance of EWS scores in identifying patients at higher risk of clinical deterioration may vary by patient type.

Mapping the differential impact of spontaneous and conversational laughter on brain and mind: an fMRI study in autism.

Spontaneous and conversational laughter are important socio-emotional communicative signals. Neuroimaging findings suggest that non-autistic people engage in mentalizing to understand the meaning behind conversational laughter. Autistic people may thus face specific challenges in processing conversational laughter, due to their mentalizing difficulties. Using fMRI, we explored neural differences during implicit processing of these two types of laughter. Autistic and non-autistic adults passively listened to funny words, followed by spontaneous laughter, conversational laughter, or noise-vocoded vocalizations. Behaviourally, words plus spontaneous laughter were rated as funnier than words plus conversational laughter, and the groups did not differ. However, neuroimaging results showed that non-autistic adults exhibited greater medial prefrontal cortex activation while listening to words plus conversational laughter, than words plus genuine laughter, while autistic adults showed no difference in medial prefrontal cortex activity between these two laughter types. Our findings suggest a crucial role for the medial prefrontal cortex in understanding socio-emotionally ambiguous laughter via mentalizing. Our study also highlights the possibility that autistic people may face challenges in understanding the essence of the laughter we frequently encounter in everyday life, especially in processing conversational laughter that carries complex meaning and social ambiguity, potentially leading to social vulnerability. Therefore, we advocate for clearer communication with autistic people.

Unraveling the Heat- and UV-Induced Degradation of Mixed Halide Perovskite Thin Films via Surface Analysis Techniques.

In recent years, organic-inorganic hybrid perovskite materials have become one of the most promising materials in the new generation of solar cells. These perovskites can provide excellent photoelectric properties after a simple fabrication process. Although perovskite solar cells have achieved high power conversion efficiency, instability concerns regarding material exposure to heat, moisture, air, and UV light present hindrances to commercialization. In this study, three kinds of perovskites (MAPbI3, MAPbI3-xBrx, and MAPbI3-xClx) were used to investigate the crystal stability upon exposure to heat and UV light. SEM, XRD, and FTIR were used to observe the surface morphology, crystal structure, and functional groups of the perovskite thin films. XPS was used to examine the surface composition and chemical state of the perovskite thin films under different conditions. Among these three types of perovskites, it was found that the MAPbI3-xBrx crystal demonstrated the best stability. ToF-SIMS was used to confirm the molecular distribution of the MAPbI3-xBrx films upon exposure to heat and UV light at different depths. ToF-SIMS revealed that [Pb]+ and [PbI]+ aggregated at the interface between the perovskite and ITO substrate after 14 days of thermal treatment. On the other hand, [Pb]+ and [PbI]+ were distributed uniformly after 3 days of UV exposure. This study systematically analyzed and revealed the thermal- and UV-induced degradation process of three perovskite films by using surface analysis techniques. It was concluded that bromine-doped perovskite films had better stability, and UV light caused more severe damage than heat.

Add-on astragalus in type 2 diabetes and chronic kidney disease: A multi-center, assessor-blind, randomized controlled trial.

BACKGROUND: Diabetes leads to chronic kidney disease (CKD) and kidney failure, requiring dialysis or transplantation. Astragalus, a common herbal medicine and US pharmacopeia-registered food ingredient, is shown kidney protective by retrospective and preclinical data but with limited long-term prospective clinical evidence. This trial aimed to assess the effectiveness of astragalus on kidney function decline in macroalbuminuric diabetic CKD patients. METHODS: This randomized, assessor-blind, standard care-controlled, multi-center clinical trial randomly assigned 118 patients with estimated glomerular filtration rate (eGFR) of 30-90 ml/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) of 300-5000 mg/g from 7 public outpatient clinics and the community in Hong Kong between July 2018 and April 2022 to add-on oral astragalus granules (15 gs of raw herbs daily equivalent) or to continue standard care alone as control for 48 weeks. Primary outcomes were the slope of change of eGFR (used for sample size calculation) and UACR of the intention-to-treat population. Secondary outcomes included endpoint blood pressures, biochemistry, biomarkers, concomitant drug change and adverse events. (ClinicalTrials.gov: NCT03535935) RESULTS: During the 48-week period, the estimated difference in the slope of eGFR decline was 4.6 ml/min/1.73m2 per year (95 %CI: 1.5 to 7.6, p = 0.003) slower with astragalus. For UACR, the estimated inter-group proportional difference in the slope of change was insignificant (1.14, 95 %CI: 0.85 to 1.52, p = 0.392). 117 adverse events from 31 astragalus-treated patients and 41 standard care-controlled patients were documented. The 48-week endpoint systolic blood pressure was 7.9 mmHg lower (95 %CI: -12.9 to -2.8, p = 0.003) in the astragalus-treated patients. 113 (96 %) and 107 (91 %) patients had post-randomization and endpoint primary outcome measures, respectively. CONCLUSION: In patients with type 2 diabetes, stage 2 to 3 CKD and macroalbuminuria, add-on astragalus for 48 weeks further stabilized kidney function on top of standard care.

APOE3-R136S mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition.

The Christchurch mutation (R136S) on the APOE3 (E3S/S) gene is associated with low tau pathology and slowdown of cognitive decline despite the causal PSEN1 mutation and high levels of amyloid beta pathology in the carrier1. However, the molecular effects enabling E3S/S mutation to confer protection remain unclear. Here, we replaced mouse Apoe with wild-type human E3 or E3S/S on a tauopathy background. The R136S mutation markedly mitigated tau load and protected against tau-induced synaptic loss, myelin loss, and spatial learning. Additionally, the R136S mutation reduced microglial interferon response to tau pathology both in vivo and in vitro, suppressing cGAS-STING activation. Treating tauopathy mice carrying wild-type E3 with cGAS inhibitor protected against tau-induced synaptic loss and induced similar transcriptomic alterations to those induced by the R136S mutation across brain cell types. Thus, cGAS-STING-IFN inhibition recapitulates the protective effects of R136S against tauopathy.

Removal, transformation and ecological risk assessment of pesticide in rural wastewater by field-scale horizontal flow constructed wetlands of treated effluent.

Constructed wetlands (CWs) are widely used in sewage treatment in rural areas, but there are only a few studies on field-scale CWs in treating wastewater-borne pesticides. In this study, the treatment and metabolic transformation of 29 pesticides in rural domestic sewage by 10 field-scale horizontal flow CWs (HF-CWs), each with a treatment scale of 36‒5000 m3/d and operated for 2‒10 years, in Guangzhou, Southern China was investigated. The risk of pesticides in treated effluent and main factors influencing such risk were evaluated. Results demonstrated that HF-CWs could remove pesticides in sewage and reduce their ecological risk in effluent, but the degree varied among types of pesticides. Herbicides had the highest mean removal rate (67.35 %) followed by insecticides (60.13 %), and the least was fungicides (53.22 %). In terms of single pesticide compounds, the mean removal rate of butachlor was the highest (73.32 %), then acetochlor (69.41 %), atrazine (68.28 %), metolachlor (58.40 %), and oxadixyl (53.28 %). The overall removal rates of targeted pesticides in each HF-CWs ranged from 11 %‒57 %, excluding two HF-CWs showing increases in pesticides in treated effluent. Residues of malathion, phorate, and endosulfan in effluent had high-risks (RQ > 5). The pesticide concentration in effluent was mainly affected by that in influent (P = 0.042), and source control was the key to reducing risk. The main metabolic pathways of pesticide in HF-CWs were oxidation, with hydroxyl group to carbonyl group or to form sulfones, the second pathways by hydrolysis, aerobic condition was conducive to the transformation of pesticides. Sulfones were generally more toxic than the metabolites produced by hydrolytic pathways. The present study provides a reference on pesticides for the purification performance improvement, long-term maintenance, and practical sustainable application of field-scale HF-CWs.

Human iPSC 4R tauopathy model uncovers modifiers of tau propagation.

Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer's Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.

Hormone replacement therapy and periodontitis progression in postmenopausal women: A prospective cohort study.

OBJECTIVE: This study aimed to investigate the responses of periodontal environment to hormone replacement therapy (HRT) in postmenopausal women with or without periodontitis. BACKGROUND: HRT is a common and effective strategy for controlling menopausal symptoms, while the changes of periodontal environment under it, particularly in postmenopausal women with periodontitis, remain unclear. METHODS: As a prospective cohort study, a total of 97 postmenopausal women receiving HRT were screened, including 47 with and 50 without periodontitis. Correspondingly, 97 women did not receiving HRT were screened as controls during the same period. The full-mouth sulcus bleeding index (SBI), bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment level (CAL) were measured using periodontal probes. The levels of interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α) in the gingival crevicular fluid were measured using enzyme-linked immunosorbent assay. In addition, cone beam computed tomography was performed to measure the alveolar bone height (ABH) and bone mineral density (BMD). RESULTS: In postmenopausal women without periodontitis, no significantly changes on periodontal parameters were observed after HRT. In women with stage II periodontitis, SBI, BOP, IL-6, and TNF-α were significant decreased after one year and two years of HRT. Compared to the controls, women with stage II periodontitis who underwent HRT had significantly lower CAL and ABH and higher BMD in the second year. The incidence of at least one site with CAL increase ≥1 mm between baseline and 2 years was significantly lower in the HRT group than in the control group in women with stage II periodontitis. In addition, HRT was significantly associated with a decrease in SBI, BOP, IL-6, and TNF-α in the first year and with a decrease in CAL, SBI, BOP, IL-6, and ABH and an increase in BMD in the second year. CONCLUSIONS: In postmenopausal women with stage II periodontitis, HRT is associated with the alleviation of inflammation within two years and the remission of alveolar bone loss in the second year. HRT appears to decrease the incidence of CAL increase ≥1 mm within 2 years in women with periodontitis by inhibiting inflammation and alveolar bone loss.

Use of tryptic peptide MALDI mass spectrometry imaging to identify the spatial proteomic landscape of colorectal cancer liver metastases.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. CRC liver metastases (CRLM) are often resistant to conventional treatments, with high rates of recurrence. Therefore, it is crucial to identify biomarkers for CRLM patients that predict cancer progression. This study utilised matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to spatially map the CRLM tumour proteome. CRLM tissue microarrays (TMAs) of 84 patients were analysed using tryptic peptide MALDI-MSI to spatially monitor peptide abundances across CRLM tissues. Abundance of peptides was compared between tumour vs stroma, male vs female and across three groups of patients based on overall survival (0-3 years, 4-6 years, and 7+ years). Peptides were then characterised and matched using LC-MS/MS. A total of 471 potential peptides were identified by MALDI-MSI. Our results show that two unidentified m/z values (1589.876 and 1092.727) had significantly higher intensities in tumours compared to stroma. Ten m/z values were identified to have correlation with biological sex. Survival analysis identified three peptides (Histone H4, Haemoglobin subunit alpha, and Inosine-5'-monophosphate dehydrogenase 2) and two unidentified m/z values (1305.840 and 1661.060) that were significantly higher in patients with shorter survival (0-3 years relative to 4-6 years and 7+ years). This is the first study using MALDI-MSI, combined with LC-MS/MS, on a large cohort of CRLM patients to identify the spatial proteome in this malignancy. Further, we identify several protein candidates that may be suitable for drug targeting or for future prognostic biomarker development.

Isolation, identification and whole-genome analysis of an Achromobacter strain with a novel sulfamethazine resistance gene and sulfamethazine degradation gene cluster.

A sulfamethazine (SM2) degrading strain, Achromobacter mucicolens JD417, was isolated from sulfonamide-contaminated sludge using gradient acclimation. Optimal SM2 degradation conditions were pH 7, 36 °C, and 5 % inoculum, achieving a theoretical maximum degradation rate of 48 % at 50 ppm SM2. Cell growth followed the Haldane equation across different SM2 concentrations. Whole-genome sequencing of the strain revealed novel functional annotations, including a sulfonamide resistance gene (sul4) encoding dihydropteroate synthase, two flavin-dependent monooxygenase genes (sadA and sadB) crucial for SM2 degradation, and unique genomic islands related to metabolism, pathogenicity, and resistance. Comparative genomics analysis showed good collinearity and homology with other Achromobacter species exhibiting organics resistance or degradation capabilities. This study reveals the novel molecular resistance and degradation mechanisms and genetic evolution of an SM2-degrading strain, providing insights into the bioremediation of sulfonamide-contaminated environments.

Do Scholars Respond Faster Than Google Trends in Discussing COVID-19 Issues? An Approach to Textual Big Data.

Background: The COVID-19 pandemic has posed various difficulties for policymakers, such as the identification of health issues, establishment of policy priorities, formulation of regulations, and promotion of economic competitiveness. Evidence-based practices and data-driven decision-making have been recognized as valuable tools for improving the policymaking process. Nevertheless, due to the abundance of data, there is a need to develop sophisticated analytical techniques and tools to efficiently extract and analyze the data. Methods: Using Oxford COVID-19 Government Response Tracker, we categorize the policy responses into 6 different categories: (a) containment and closure, (b) health systems, (c) vaccines, (d) economic, (e) country, and (f) others. We proposed a novel research framework to compare the response times of the scholars and the general public. To achieve this, we analyzed more than 400,000 research abstracts published over the past 2.5 years, along with text information from Google Trends as a proxy for topics of public concern. We introduced an innovative text-mining method: coherent topic clustering to analyze the huge number of abstracts. Results: Our results show that the research abstracts not only discussed almost all of the COVID-19 issues earlier than Google Trends did, but they also provided more in-depth coverage. This should help policymakers identify core COVID-19 issues and act earlier. Besides, our clustering method can better reflect the main messages of the abstracts than a recent advanced deep learning-based topic modeling tool. Conclusion: Scholars generally have a faster response in discussing COVID-19 issues than Google Trends.

A framework to quantitatively assess the influence of land use and land cover on coastal wetland hydrological connectivity from a landscape resistance perspective.

Land use and land cover (LULC) change is one of the dominant factors contributing to coastal wetland degradation and loss. Most studies focused on LULC changes or whether they influenced on ecosystems. However, few studies quantitatively assessed the impact of different LULCs on hydrological connectivity. This study aimed to understand how LULC affected hydrological connectivity in the coastal wetlands in the Yellow River Delta (YRD), China, from 1985 to 2020. A framework from a landscape resistance perspective was used to evaluate the LULC's influence. LULCs were converted into a series of resistance surfaces whose values represent the degree to which LULC facilitated or restricted hydrological connectivity. The LULC's influence was evaluated by parameterizing the resistance surfaces using observed hydrological connectivity. The results showed that human-related LULC had more influence on hydrological connectivity. The critical time of LULC's influence on hydrological connectivity was 1985-1990 and 2010-2015. The critical areas were Zone II, Zone I, and Zone VI. The LULCs of agriculture, industry, town/city, and river had the most significant impact on the hydrological connectivity of the YRD coastal wetland. The result could direct LULC planning to mitigate the negative effect on coastal wetlands and provide support for the environmental impact assessment of coastal development practices. This paper advances the study by assessing LULCs' impact on hydrological connectivity and providing a quantitative method. The framework of this study enriches the coastal wetland conservation theory and policy-making of coastal management.

Optofluidic tunable filters using ionic liquid electrolyte capacitors.

Tunable optical filter is a basic component for most optical systems. This study reports a unique design of Fabry-Pérot (FP) tunable filter by using an ionic liquid solution. The tunable filter consists of two neighboring regions: capacitor region and FP region. The former is in the form of electrolyte capacitor and the latter remains transparent as an FP cavity for light transmission. When the capacitor region is applied with a bias voltage, it attracts the ions from the FP region and thus reduces the ion concentration of the FP region, resulting in a change of the refractive index and eventually a shift of transmission peak of the FP cavity. Among four electrolyte solutions studied, 1-butyl-3-methylimidazolium hexafluorophosphate (BMIM-PF6) exhibits the best overall performance, such as low insertion loss (3.2 dB), large side mode suppression ratio (23 dB) and high stability (drift <0.2 nm). Additionally, a wavelength tuning of 0.17 nm/V is achieved over 0-17 V, providing a tunable range of 3 nm. This device features low bias voltage, no mechanical movement, easy fabrication and seamless integration with microfluidics systems, and may find potential applications in spectral analyzers and lab-on-a-chip biosensing systems.

Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model.

The strongest risk factors for Alzheimer's disease (AD) include the χ4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H ( R47H ) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting disease-causing mechanisms. We find that the R47H variant induces neurodegeneration in female APOE4 mice without impacting hippocampal tau load. The combination of APOE4 and R47H amplified tauopathy-induced cell-autonomous microglial cGAS-STING signaling and type-I interferon response, and interferon signaling converged across glial cell types in the hippocampus. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.

Bowel Stiffness Assessed by Shear-Wave Ultrasound Elastography Predicts Disease Behavior Progression in Patients With Crohn's Disease.

INTRODUCTION: There is a lack of reliable predictors of disease behavior progression in patients with Crohn's disease (CD). Real-time shear-wave elastography (SWE) is a novel method for evaluating tissue stiffness. However, its value for assessing CD has not yet been investigated. We aimed to explore the value of SWE and other ultrasound parameters at diagnosis in predicting CD behavior progression. METHODS: We retrospectively collected data from patients with CD with the nonstenotic nonpenetrating disease (B1 phenotype based on the Montreal classification). All patients underwent intestinal ultrasound at baseline and were followed up. The end point was defined as disease behavior progression to stricturing (B2) or penetrating (B3) disease. Cox regression analysis was performed for the association between baseline characteristics and subsequent end points. In addition, a multivariate nomogram was established to predict the risk of disease behavior progression quantitatively. RESULTS: A total of 130 patients with CD with B1 phenotype were enrolled. Twenty-seven patients (20.8%) developed B2 or B3 disease, with a median follow-up of 33 months. Multivariate analysis identified that SWE was the only independent predictor of disease behavior progression (hazard ratio 1.08, 95% confidence interval 1.03-1.12, P = 0.001). A reverse of the HR appeared at the cutoff 12.75 kPa. The nomogram incorporating SWE and other clinical characteristics showed a good prediction performance (area under the curve = 0.792). DISCUSSION: Intestinal stiffness assessed using SWE is an independent predictor of disease behavior progression in patients with CD. Patients with CD with SWE >12.75 kPa at diagnosis are prone to progress toward stricturing or penetrating diseases.

Generation and assessment of cytokine-induced killer cells for the treatment of colorectal cancer liver metastases.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Cytokine-induced killer (CIK) cells are an adoptive immunotherapy reported to have strong anti-tumour activity across a range of cancers. They are a heterogeneous mix of lymphoid cells generated by culturing human peripheral blood mononuclear cells with cytokines and monoclonal antibodies in vitro. In this study, we investigated the yield and function of CIK cells generated from patients with CRC liver metastases. We first showed that CIK cells generated in serum free medium X-VIVO 15 were comparable to those from RPMI medium with 10% FBS in terms of the number and percentages of the main subsets of cells in the CIK culture, and the intracellular levels of granzyme B and perforin, and the pro-inflammatory cytokines IL-2, IFN-γ and TNF-α. The CIK cells were cytotoxic to CRC cell lines grown in 2D cultures or as spheroids, and against autologous patient-derived tumour organoids. Donor attributes such as age, sex, or prior chemotherapy exposure had no significant impact on CIK cell numbers or function. These results suggest that functional CIK cells can be generated from patients with CRC liver metastatic disease, and support further investigations into the therapeutic application of autologous CIK cells in the management of patients with CRC liver metastases.

Public preference on sharing health data to inform research, health policy and clinical practice in Australia: A stated preference experiment.

OBJECTIVE: To investigate public willingness to share sensitive health information for research, health policy and clinical practice. METHODS: A total of 1,003 Australian respondents answered an online, attribute-driven, survey in which participants were asked to accept or reject hypothetical choice sets based on a willingness to share their health data for research and frontline-medical support as part of an integrated health system. The survey consisted of 5 attributes: Stakeholder access for analysis (Analysing group); Type of information collected; Purpose of data collection; Information governance; and Anticipated benefit; the results of which were analysed using logistic regression. RESULTS: When asked about their preference for sharing their health data, respondents had no preference between data collection for the purposes of clinical practice, health policy or research, with a slight preference for having government organisations manage, govern and curate the integrated datasets from which the analysis was being conducted. The least preferred option was for personal health records to be integrated with insurance records or for their data collected by privately owned corporate organisations. Individuals preferred their data to be analysed by a public healthcare provider or government staff and expressed a dislike for any private company involvement. CONCLUSIONS: The findings from this study suggest that Australian consumers prefer to share their health data when there is government oversight, and have concerns about sharing their anonymised health data for clinical practice, health policy or research purposes unless clarity is provided pertaining to its intended purpose, limitations of use and restrictions to access. Similar findings have been observed in the limited set of existing international studies utilising a stated preference approach. Evident from this study, and supported by national and international research, is that the establishment and preservation of a social license for data linkage in health research will require routine public engagement as a result of continuously evolving technological advancements and fluctuating risk tolerance. Without more work to understand and address stakeholder concerns, consumers risk being reluctant to participate in data-sharing and linkage programmes.

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity.

Pathogenic tau accumulation fuels neurodegeneration in Alzheimer's disease (AD). Enhancing aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses. Previous studies have showed that mice lacking DAP12 in tauopathy mice exhibit higher tau pathology but are protected from tau-induced cognitive deficits. However, the exact mechanism remains elusive. Our current study uncovers a novel resilience mechanism via microglial interaction with oligodendrocytes. Despite higher tau inclusions, Dap12 deletion curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Specifically, removal of Dap12 abolished tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli), which are spatially correlated with tau pathology in AD brains. Our study highlights the critical role of interactions between microglia and oligodendrocytes in tau toxicity and DAP12 signaling as a promising target for enhancing resilience in AD.

DAP12 deficiency alters microglia-oligodendrocyte communication and enhances resilience against tau toxicity.

Pathogenic tau accumulation fuels neurodegeneration in Alzheimer's disease (AD). Enhancing aging brain's resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12) is critically involved in microglial immune responses. Previous studies have showed that mice lacking DAP12 in tauopathy mice exhibit higher tau pathology but are protected from tau-induced cognitive deficits. However, the exact mechanism remains elusive. Our current study uncovers a novel resilience mechanism via microglial interaction with oligodendrocytes. Despite higher tau inclusions, Dap12 deletion curbs tau-induced brain inflammation and ameliorates myelin and synapse loss. Specifically, removal of Dap12 abolished tau-induced disease-associated clusters in microglia (MG) and intermediate oligodendrocytes (iOli), which are spatially correlated with tau pathology in AD brains. Our study highlights the critical role of interactions between microglia and oligodendrocytes in tau toxicity and DAP12 signaling as a promising target for enhancing resilience in AD.

Sex Chromosomes and Gonads Shape the Sex-Biased Transcriptomic Landscape in Tlr7-Mediated Demyelination During Aging.

Demyelination occurs in aging and associated diseases, including Alzheimer's disease. Several of these diseases exhibit sex differences in prevalence and severity. Biological sex primarily stems from sex chromosomes and gonads releasing sex hormones. To dissect mechanisms underlying sex differences in demyelination of aging brains, we constructed a transcriptomic atlas of cell type-specific responses to illustrate how sex chromosomes, gonads, and their interaction shape responses to demyelination. We found that sex-biased oligodendrocyte and microglial responses are driven by interaction of sex chromosomes and gonads prior to myelin loss. Post demyelination, sex chromosomes mainly guide microglial responses, while gonadal composition influences oligodendrocyte signaling. Significantly, ablation of the X-linked gene Toll-like receptor 7 (Tlr7), which exhibited sex-biased expression during demyelination, abolished the sex-biased responses and protected against demyelination.