Association of social health with all-cause mortality and cause-specific mortality: A population-based cohort study.

BACKGROUND: Previous studies only focused on the individual social factors, without considering the overall social health patterns. The present study aimed to develop an integrated social health score (SHS) and investigate its associations with all-cause, cardiovascular disease (CVD), cancer mortality. METHODS: A total of 330,716 participants (mean age 56.3 years; 52.4 % female) from UK Biobank was included between 2006 and 2010, and thereafter followed up to 2021. SHS was calculated by using information on social connections, social engagement and social support. Cox proportional hazards models was used to estimate the hazard ratios and 95 % confidence intervals (CIs) of the association between SHS and all-cause and cause-specific mortality and the 4-way decomposition was used to quantify the mediating effect of lifestyle factors. RESULTS: During a median follow-up period of 12.4 years, 37,897 death cases were recorded, including 4347 CVD and 10,380 cancer cases. The SHS was inversely associated with the risks of all-cause, CVD and cancer mortality in a dose-dependent manner (P for trend <0.001). The association between SHS with all-cause mortality was mediated by lifestyle factors including diet score, smoking status and alcohol consumption. CONCLUSION: Integrated SHS was inversely associated with risks of all-cause, CVD and cancer mortality, and the associations were partially mediated by lifestyle factors. Our study highlights the importance of maintaining high levels of social health by jointly enhancing social involvement, expanding social networks, and cultivating enduring intimate relationships across the life course.

Trajectories of depressive symptoms and risk of cardiovascular disease, cancer and mortality: a prospective cohort study.

Background: Depressive symptoms are established risk factors for various health outcomes. However, previous studies assessed depressive symptoms at a single time point, neglecting individual variations over time. Aims: To identify depressive symptoms trajectories through repeated measures and examine their associations with cardiovascular disease (CVD), cancer and mortality. Methods: This study included 20 634 UK Biobank participants free of CVD and cancer at baseline with two or more assessments of depressive symptoms during 2006-2016. Group-based trajectory modelling identified depressive symptoms trajectories. Incident CVD, cancer and mortality were followed up until 2021 through linked registries. Results: Six depressive symptoms trajectories were identified: no symptoms (n=6407), mild-stable (n=11 539), moderate-stable (n=2183), severe-decreasing (n=206), moderate-increasing (n=177) and severe-stable (n=122). During a median follow-up of 5.5 years, 1471 CVD cases, 1275 cancer cases and 503 deaths were documented. Compared with the no symptoms trajectory, the mild-stable, moderate-stable and severe-stable trajectories exhibited higher CVD risk, with hazard ratios (HRs) (95% CIs) of 1.19 (1.06 to 1.34), 1.32 (1.08 to 1.34) and 2.99 (1.85 to 4.84), respectively. Moderate-increasing and severe-stable trajectories were associated with higher mortality risks, with HRs (95% CIs) of 2.27 (1.04 to 4.93) and 3.26 (1.55 to 6.88), respectively. However, the severe-decreasing trajectory was not associated with higher risks of adverse outcomes. We did not find significant associations between any trajectory and cancer. Conclusions: Trajectories related to stable and increasing depressive symptoms, but not the trajectory associated with severe depressive symptoms at the initial assessment but decreasing at the follow-up, were associated with higher risks of CVD and mortality. Alleviating severe depressive symptoms at the initial onset may mitigate CVD and mortality risks.

Healthy lifestyle and the risk of depression recurrence requiring hospitalisation and mortality among adults with pre-existing depression: a prospective cohort study.

BACKGROUND: Although lifestyle-based treatment approaches are recommended as important aspects of depression care, the quantitative influence of aggregated healthy lifestyles on depression recurrence and mortality remains unknown. OBJECTIVE: To investigate the association between healthy lifestyle and the risks of first-time hospitalisation for recurrent depression and mortality. METHODS: 26 164 adults with depression (mean (SD) age, 56.0 (7.9) years) were included from UK Biobank between 2006 and 2010 and followed up until 2022. Depression was defined as a physician's diagnosis in hospital admissions or the use of prescribed antidepressant medication. A weighted healthy lifestyle score (HLS) was calculated based on smoking, alcohol consumption, diet, sleep pattern, physical activity, social health, employment status and greenspace interaction. FINDINGS: Over a 13.3-year follow-up, 9740 cases of first-time hospitalisation due to depression recurrence and 1527 deaths were documented. Compared with the lowest HLS tertile, the highest tertile was associated with a 27% lower risk (HR=0.73, 95% CI 0.69 to 0.77) of first-time hospitalisation for depression recurrence and a 22% (HR=0.78, 95% CI 0.68 to 0.91) lower risk of mortality among adults with depression. Lower risks of first-time hospitalisation for depression recurrence were observed among those who smoked less, drank more alcohol, followed healthier diets and sleep patterns, spent more time employed in current job or had greater exposure to greenspace. CONCLUSION AND IMPLICATIONS: Greater adherence to healthy lifestyle was associated with a lower risk of hospitalisation and mortality among adults with pre-existing depression. Incorporating behaviour modification as an essential part of clinical practice for depressed patients could complement medication-based therapies.

Associations between Recreational Screen Time and Brain Health in Middle-Aged and Older Adults: A Large Prospective Cohort Study.

OBJECTIVES: To investigate the associations of recreational screen time with risks of brain-related disorders (dementia, stroke, and Parkinson's disease) and neuroimaging features. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: A total of 407,792 participants from the UK Biobank who were free of dementia, stroke, or Parkinson's disease at enrollment (2006-2010). METHODS: TV viewing and time spent using the computer were self-reported at baseline. Among a subsample of 40,692 participants, neuroimaging features were measured by magnetic resonance imaging in 2014. Data were analyzed using Cox proportional hazard models, restricted cubic spline models, and general linear regression models. RESULTS: During a median follow-up of 12.6 years, 5227 incident dementia, 6822 stroke, and 2308 Parkinson's disease cases were identified. Compared with TV viewing >0-1 h/day, watching TV ≥5 h/day was associated with higher risks of dementia [hazard ratio (HR), 1.44; 95% confidence interval (CI), 1.28-1.62], stroke (HR, 1.12; 95% CI, 1.01-1.25), and Parkinson's disease (HR, 1.28; 95% CI, 1.06-1.54). Moreover, we observed inverse associations between TV viewing time and both gray matter volume and hippocampus volume (Ptrend <.001). However, we did not observe the significant associations between discretional computer use and brain-related disorders or neuroimaging features. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that high TV viewing time is associated with increased risk of various brain-related disorders, highlighting recreational TV viewing could have an important impact on brain-related health.

Translation and Validation of the Chinese Language Version of the Control of Allergic Rhinitis and Asthma Test in Patients with Allergic Rhinitis.

Objective: Due to the escalating global prevalence of allergic rhinitis (AR) and its status as an independent risk factor for asthma, timely and effective control of AR is crucial. Achieving this often involves the accurate assessment of AR. Currently, the Control of Allergic Rhinitis and Asthma Test (CARAT) is widely used as an assessment tool, but its measurement effectiveness in Chinese AR patients remains unclear. Therefore, this study aims to evaluate the reliability and validity of the Chinese version of the CARAT10 scale (CARAT10-C) and analyze its application value in the assessment of allergic rhinitis and asthma control trials. Methods: The study enrolled 130 patients with AR from the Ear, Nose, and Throat (ENT) outpatient department of a comprehensive teaching hospital from March to May 2022 as participants. The reliability and validity of the CARAT10-C scale were assessed using Cronbach's alpha coefficient (CAC), Kaiser-Meyer-Olkin (KMO), and Bartlett's sphericity test. Additionally, the study analyzed the effectiveness of the CARAT10-C scale in its application within the Control of Allergic Rhinitis and Asthma Test (CARAT). Results: The Cronbach's alpha coefficient ranges between 0 and 1, with higher values indicating better reliability. Significant differences in exploratory factor analysis suggest good validity. The Cronbach's alpha coefficient of the CARAT10-C scale was 0.806. Exploratory factor analysis revealed that the eigenvalues of Component 1 (3.851) and Component 2 (2.193) were both greater than 1, with a cumulative variance contribution rate (CVCR) of 60.436%. Items 6-10 were primarily loaded on Component 1 (Asthma), while items 1-4 were mainly influenced by Component 2 (AR), with loading ranges of 0.508-0.874, all significant at P < .001. The composite reliability (CAC) of the CARAT10-C scale was 0.806, exceeding 0.8, indicating high reliability. Component 1 had a CAC of 0.834, and Component 2 had a CACs of 0.807, both exceeding 0.8, indicating high reliability for both components. Conclusion: The CARAT10-C scale demonstrates good reliability and validity in the preliminary assessment of AR. It holds potential value in the evaluation and management of AR in China, although the specific application effects still require further investigation.

Topical Delivery of microRNA-125b by Framework Nucleic Acids for Psoriasis Treatment.

Purpose: Psoriasis is a chronic and recurrent inflammatory dermatitis characterized by T cell imbalance and abnormal keratinocyte proliferation. MicroRNAs (miRNAs) hold promise as therapeutic agents for this disease; however, their clinical application is hindered by poor stability and limited skin penetration. This study demonstrates the utilization of Framework Nucleic Acid (FNA) for the topical delivery of miRNAs in psoriasis treatment. Methods: By utilizing miRNA-125b as the model drug, FNA-miR-125b was synthesized via self-assembly. The successful synthesis and stability of FNA-miR-125b in bovine fetal serum (FBS) were verified through gel electrophoresis. Subsequently, flow cytometry was employed to investigate the cell internalization on HaCaT cells, while qPCR determined the effects of FNA-miR-125b on cellular functions. Additionally, the skin penetration ability of FNA-miR-125b was assessed. Finally, a topical administration study involving FNA-miR-125b cream on imiquimod (IMQ)-induced psoriasis mice was conducted to evaluate its therapeutic efficacy. Results: The FNA-miR-125b exhibited excellent stability, efficient cellular internalization, and potent inhibition of keratinocyte proliferation. In the psoriasis mouse model, FNA-miR-125b effectively penetrated the skin tissue, resulting in reduced epidermal thickness and PASI score, as well as decreased levels of inflammatory cytokines.

Immune-mediated diseases are associated with a higher risk of ALS incidence: a prospective cohort study from the UK Biobank.

Objective: The occurrence of immune-mediated diseases (IMDs) in amyotrophic lateral sclerosis (ALS) patients is widely reported. However, whether IMDs and ALS is a simple coexistence or if there exists causal relationships between the two has been a subject of great interest to researchers. Methods: A total of 454,444 participants from the prospective cohort of UK Biobank were recruited to investigate the longitudinal association between IMDs and ALS. Previously any IMDs and organ specific IMDs were analyzed in relation to the following incident ALS by Cox-proportional hazard models. Subgroup analyses were performed to explore the covariates of these relationships. Results: After adjusting for potential covariates, the multivariate analysis showed that any IMDs were associated with an increased risk of ALS incidence (HR:1.42, 95%CI:1.03-1.94). IMDs of the endocrine-system and the intestinal-system were associated with increased risk of ALS incidence (endocrine-system IMDs: HR:3.01, 95%CI:1.49-6.06; intestinal system IMDs: HR:2.07, 95%CI: 1.14-3.77). Subgroup analyses revealed that immune burden, including IMD duration and the severity of inflammation had specific effects on the IMD-ALS association. In participants with IMD duration≥10 years or CRP≥1.3mg/L or females, previous IMDs increased the risk of incident ALS; however, in participants with IMD duration <10 years or CRP<1.3mg/L or males, IMDs had no effect on incident ALS. Interpretation: Our study provides evidence that previous any IMDs and endocrine-system and the intestinal-system specific IMDs are associated with an increased risk of developing ALS in females, but not in males.

Physical Activity, Mental Activity, and Risk of Incident Stroke: A Prospective Cohort Study.

BACKGROUND: Cumulative evidence suggests a correlation between physical or mental activity and the risk of stroke. However, the combined impact of these activities on stroke onset remains unexplored. This study identified physical and mental activity patterns using principal component analysis and investigated their associations with risk of incident stroke in the general population. METHODS: Our study was sourced from the UK Biobank cohort between 2006 and 2010. Information on physical and mental-related activities were obtained through a touch-screen questionnaire. The incident stroke was diagnosed by physicians and subsequently verified through linkage to Hospital Episode Statistics. Principal component analysis was used to identify potential physical and mental activity patterns. Cox proportional hazard regression models were performed to calculate hazard ratios (HRs) and 95% CIs of incident stroke, adjusting for potential confounders. RESULTS: The initial UK Biobank cohort originally consisted of 502 411 individuals, of whom a total of 386 902 participants (aged 38-79 years) without any history of stroke at baseline were included in our study. During a median follow-up of 7.7 years, 6983 (1.8%) cases of stroke were documented. The mean age of the included participants was 55.9 years, and the proportion of women was 55.1%. We found that multiple individual items related to physical and mental activity showed significant associations with risk of stroke. We identified 4 patterns of physical activity and 3 patterns of mental activity using principal component analysis. The adherence to activity patterns of vigorous exercise, housework, and walking predominant patterns were associated with a lower risk of stroke by 17% (HR, 0.83 [95% CI, 0.78-0.89]; 20% (HR, 0.80 [95% CI, 0.75-0.85]; and 20% (HR, 0.80 [95% CI, 0.75-0.86), respectively. Additionally, the transportation predominant pattern (HR, 1.36 [95% CI, 1.28-1.45) and watching TV pattern (HR, 1.43 [95% CI, 1.33-1.53) were found to be significantly associated with a higher risk of stroke. These associations remained consistent across all subtypes of stroke. CONCLUSIONS: Activity patterns mainly related to frequent vigorous exercise, housework, and walking were associated with lower risks of stroke and all its subtypes. Our findings provide new insights for promoting suitable patterns of physical and mental activity for primary prevention of stroke.

Accelerometer-measured physical activity, sedentary behavior, and risk of incident pelvic organ prolapse: a prospective cohort study in the UK Biobank.

BACKGROUND: Previous studies on physical activity (PA) and pelvic organ prolapse (POP) were largely limited to self-reported PA in athletes, soldiers, and women in postpartum. We aimed to investigate the association of accelerometer-measured PA and sedentary behavior with the risk of POP in middle-aged and elderly women. METHODS: In this prospective cohort derived from the UK Biobank, the intensity and duration of PA and sedentary behavior were measured with wrist-worn accelerometers over a 7-day period in 2013-2015 for 47,674 participants (aged 42.8-77.9 years) without pre-existing POP. Participants were followed up until the end of 2022, during which incident POP was ascertained mainly by the electronic health records. Multivariable-adjusted Cox proportional hazards models and restricted cubic splines were used to assess the associations of interest. Isotemporal substitution models were applied to test the effects of substituting a type of activity with equivalent duration of others. RESULTS: During a median follow-up of 8.0 years, 779 cases of POP were recorded. The duration of light-intensity PA (LPA) was positively whereas sedentary time was negatively associated with the risk of POP. Every additional 1 h/day of LPA elevated the risk of POP by 18% (95% confidence interval [CI], 10%-26%). In contrast, the risk decreased by 5% (95% CI, 0-8%) per 1 h/day increment in sedentary behavior. No associations were found between moderate-intensity PA (MPA) or vigorous-intensity PA (VPA) and POP, except that women who had a history of hysterectomy were more likely to develop POP when performing more VPA (53% higher risk for every additional 15 min/day). Substituting 1 h/day of LPA with equivalent sedentary time was associated with a 18% (95% CI, 11%-24%) lower risk of POP. The risk can also be reduced by 17% (95% CI, 7%-25%) through substituting 30 min/day of LPA with MPA. CONCLUSIONS: More time spent in LPA or less sedentary time was linked to an elevated risk of POP in middle-aged and elderly women, while MPA or VPA was not. Substituting LPA with equivalent duration of sedentary behavior or MPA may lower the risk of POP.

On-Site Melanoma Diagnosis Utilizing a Swellable Microneedle-Assisted Skin Interstitial Fluid Sampling and a Microfluidic Particle Dam for Visual Quantification of S100A1.

Malignant melanoma (MM) is the most aggressive form of skin cancer. The delay in treatment will induce metastasis, resulting in a poor prognosis and even death. Here, a two-step strategy for on-site diagnosis of MM is developed based on the extraction and direct visual quantification of S100A1, a biomarker for melanoma. First, a swellable microneedle is utilized to extract S100A1 in skin interstitial fluid (ISF) with minimal invasion. After elution, antibody-conjugated magnetic microparticles (MMPs) and polystyrene microparticles (PMPs) are introduced. A high expression level of S100A1 gives rise to a robust binding between MMPs and PMPs and reduces the number of free PMPs. By loading the reacted solution into the device with a microfluidic particle dam, the quantity of free PMPs after magnetic separation is displayed with their accumulation length inversely proportional to S100A1 levels. A limit of detection of 18.7 ng mL-1 for S100A1 is achieved. The animal experiment indicates that ISF-based S100A1 quantification using the proposed strategy exhibits a significantly higher sensitivity compared with conventional serum-based detection. In addition, the result is highly comparable with the gold standard enzyme-linked immunosorbent assay based on Lin's concordance correlation coefficient, suggesting the high practicality for routine monitoring of melanoma.

Ozone alleviates MSU-induced acute gout pain via upregulating AMPK/GAS6/MerTK/SOCS3 signaling pathway.

BACKGROUND: Gout pain seriously affects the quality of patients' life. There is still no effective treatment. The inflammatory response is the main mechanism of gout. Here, we found that ozone can reduce the inflammatory reaction in the joints of gouty mice and relieve gout pain, and we further explore its protective mechanism. METHODS: MSU was used to establish the gouty mice model. Nociception was assessed by Von Frey hairs. Cell signaling assays were performed by western blotting and immunohistochemistry. The mouse leukemia cells of monocyte macrophage line RAW264.7 were cultured to investigate the effects of ozone administration on macrophage. RESULTS: Ozone reduced inflammation, relieved gout pain and improved the paw mean intensity and duty cycle of the gouty mice. Ozone increased the phosphorylation of AMP-activated protein kinase (AMPK), induced suppressor of cytokine signaling 3 (SOCS3) expression and inhibited metallopeptidase 9 (MMP9) expression. In vivo, ozone activated AMPK to induce Gas6 release, and upregulated MerTK/SOCS3 signaling pathway to reduce inflammation in mouse macrophage line RAW264.7. Inhibitors of AMPK and MerTK, respectively abolished the analgesic and anti-inflammatory effects of ozone in vivo and in vitro. Gas6 knockout cancelled the protectively effects of ozone on gout pain and the paw mean intensity and duty cycle of gouty mice. Additionally, the level of Gas6 and protein S in plasma of patients with hyperuricemia was significantly higher than that of healthy contrast group. CONCLUSION: Ozone reduces inflammation and alleviates gout pain by activating AMPK to up-regulate Gas6/MerTK/SOCS3 signaling pathway.

Wireless, battery-free, multifunctional integrated bioelectronics for respiratory pathogens monitoring and severity evaluation.

The rapid diagnosis of respiratory virus infection through breath and blow remains challenging. Here we develop a wireless, battery-free, multifunctional pathogenic infection diagnosis system (PIDS) for diagnosing SARS-CoV-2 infection and symptom severity by blow and breath within 110 s and 350 s, respectively. The accuracies reach to 100% and 92% for evaluating the infection and symptom severity of 42 participants, respectively. PIDS realizes simultaneous gaseous sample collection, biomarker identification, abnormal physical signs recording and machine learning analysis. We transform PIDS into other miniaturized wearable or portable electronic platforms that may widen the diagnostic modes at home, outdoors and public places. Collectively, we demonstrate a general-purpose technology for rapidly diagnosing respiratory pathogenic infection by breath and blow, alleviating the technical bottleneck of saliva and nasopharyngeal secretions. PIDS may serve as a complementary diagnostic tool for other point-of-care techniques and guide the symptomatic treatment of viral infections.

Study of 2,881 Nasal Bone Fractures using Multivariate Analysis.

Objective: This retrospective cohort study is aimed to provide a certain reference for the clinical prevention and treatment of nasal bone fracture, and further formulated a more perfect diagnosis and treatment plan. Methods: In detailed cases, 2881 patients with nasal bone fracture were recorded. Its general clinical data, cause of injury, fracture site, and fracture typing were collected through the database. All hospitalized patients admitted to the Ninth People's Hospital Affiliated to the School of Medicine of Shanghai Jiao Tong University with integrated medical records could be retrospectively included from June 2013 to July 2018 and comprehensively analyzed for their gender, age, fracture type and cause of injury. Results: The sex ratio of nasal bone fracture was 2.44:1. The most patients with nasal bone fracture were 19-29 years old (35.6%). The injury rate of traffic accidents was the highest, 33.8%, followed by violent strikes, 24.1%. Statistical analysis showed that the number of patients with nasal bone combined with maxillary frontal bone fracture and type II nasal bone fracture was significantly higher than other fracture types. Logistic multiple regression analysis showed that the relative risk of nasal bone fracture in men was lower (odds ratio, OR = 0.807, P < .05), and the risk of nasal bone fracture decreased with age (OR = 0.978, P < .001). Compared with car accident injury, the relative risk of simple nasal bone fracture comes from violence, exercise or collision [OR = 1.244, P < .05; OR = 1.410, P < .05; OR = 1.453, P < .05]). Conclusion: Given these findings, it's evident that nasal bone fractures exhibit distinct patterns based on individual characteristics, causes of trauma, and injury site, and relevant strategy research should be conducted.

Development of hyaluronic acid-silica composites via in situ precipitation for improved penetration efficiency in fast-dissolving microneedle systems.

Fast-dissolving microneedles (DMNs) hold significant promise for transdermal drug delivery, offering improved patient compliance, biocompatibility, and functional adaptability for various therapeutic purposes. However, the mechanical strength of the biodegradable polymers used in DMNs often proves insufficient for effective penetration into human skin, especially under high humidity conditions. While many composite strategies have been developed to reinforce polymer-based DMNs, simple mixing of the reinforcements with polymers often results in ineffective penetration due to inhomogeneous dispersion of the reinforcements and the formation of undesired micropores. In response to this challenge, this study aimed to enhance the mechanical performance of hyaluronic acid (HA)-based microneedles (MNs), one of the most commonly used DMN systems. We introduced in situ precipitation of silica nanoparticles (Si) into the HA matrix in conjunction with conventional micromolding. The precipitated silica nanoparticles were uniformly distributed, forming an interconnected network within the HA matrix. Experimental results demonstrated that the mechanical properties of the HA-Si composite MNs with up to 20 vol% Si significantly improved, leading to higher penetration efficiency compared to pure HA MNs, while maintaining structural integrity without any critical defects. The composite MNs also showed reduced degradation rates and preserved their drug delivery capabilities and biocompatibility. Thus, the developed HA-Si composite MNs present a promising solution for efficient transdermal drug delivery and address the mechanical limitations inherent in DMN systems. STATEMENT OF SIGNIFICANCE: HA-Si composite dissolving microneedle (DMN) systems were successfully fabricated through in situ precipitation and conventional micromolding processes. The precipitated silica nanoparticles formed an interconnected network within the HA matrix, ranging in size from 25 to 230 nm. The optimal silica content for HA-Si composite MN systems should be up to 20 % by volume to maintain structural integrity and mechanical properties. HA-Si composite MNs with up to 20 % Si showed improved penetration efficiency and reduced degradation rates compared to pure HA MNs, thereby expanding the operational window. The HA-Si composite MNs retained good drug delivery capabilities and biocompatibility.

A nanometallic conductive composite-hydrogel core-shell microneedle skin patch for real-time monitoring of interstitial glucose levels.

A microneedle-based skin patch system allows the minimally invasive extraction of skin interstitial fluid, which offers hope for the realization of quantitative and non-invasive diagnosis/monitoring of biological/physiological signals (biomarkers) in the human body. This work describes a nanometallic conductive composite-hydrogel core-shell microneedle skin patch that can realize minimally invasive real-time monitoring of physiological signals. The microneedle sensing system contains an inner conductive silver paste core and an outer bioactive hydrogel layer. The inner core is coated with biomarker-specific enzymes while the outer hydrogel layer extracts the biomarkers from the skin interstitial fluid. This patch can be integrated with the commercial signal processing and transmission modules and enable real-time monitoring. Taking glucose as a model biomarker, we confirm the function and potential application of this core-shell microneedle patch for transdermal diagnosis. It is proven that the core-shell microneedle patch can quickly extract skin interstitial fluid within 30 seconds and has a fast and linear response to glucose concentrations from 0 to 21 mM with a correlation coefficient of 0.9970, which may pave the way for the future development of smart wearable devices with minimally invasive transdermal biosensors.

A skin patch integrating swellable microneedles and electrochemical test strips for glucose and alcohol measurement in skin interstitial fluid.

Microneedle (MN)-based diagnostic devices can efficiently access skin interstitial fluid (ISF) for accurate and minimally invasive detection of health-related biomarkers. This work reports a biomarker (i.e., glucose or alcohol) monitoring MN device that is composed of swellable MNs and electrochemical test strip. This device is constructed by adhering MN patch on the electrochemical strips using the chitosan as the connecting layer. The MNs penetrate the skin for extraction of ISF that flows to the backing layer of MNs and is analyzed by the test strip. In the in vitro skin models, this device accurately detects the glucose from 0 mM to 12 mM and alcohol from 0 mM to 20 mM. In vivo experiment shows this MN device is capable of minimally invasive sampling of ISF and analysis of glucose levels to determine the glycemic status of mice.

Co-delivery of dendritic cell vaccine and anti-PD-1 antibody with cryomicroneedles for combinational immunotherapy.

Combinational immunotherapy of dendritic cell (DC) vaccines and anti-programmed cell death protein 1 antibodies (aPD1) has been regarded as a promising strategy for cancer treatment because it not only induces tumor-specific T cell immune responses, but also prevents failure of T cell functions by the immune suppressive milieu of tumors. Microneedles have emerged as an innovative platform for efficient transdermal immunotherapies. However, co-delivery of DC vaccines and aPD1 via microneedles has not been studied since conventional microneedle platforms are unsuitable for fragile therapeutics like living cells and antibodies. This study employs our newly invented cryomicroneedles (cryoMNs) to co-deliver DC vaccines and aPD1 for the combinational immunotherapy. CryoMNs are fabricated by stepwise cryogenic micromoulding of cryogenic medium with pre-suspended DCs and aPD1, which are further integrated with a homemade handle for convenient application. The viability of DCs in cryoMNs remains above 85%. CryoMNs are mechanically strong enough to insert into porcine and mouse skin, successfully releasing DCs and aPD1 inside skin tissue after melting. Co-delivery of ovalbumin (OVA)-pulsed DCs (OVA-DCs) and aPD1 via cryoMNs induced higher antigen-specific cellular immune responses compared with the mono-delivery of OVA-DCs or aPD1. Finally, administration with cryoMNs co-encapsulated with OVA-DCs and aPD1 increases the infiltration of effector T cells in the tumor, resulting in stronger anti-tumor therapeutic efficacy in both prophylactic and therapeutic melanoma models compared with administration with cryoMNs loaded with OVA-DCs or aPD1. This study demonstrates the great potential of cryoMNs as a co-delivery system of therapeutic cells and biomacromolecules for combinational therapies.

Leucocyte telomere length, brain volume and risk of dementia: a prospective cohort study.

Background: The evidence regarding the association between leucocyte telomere length (LTL) and brain health is sparse and inconclusive. Aims: To investigate the associations of LTL with brain structure and the risk of dementia based on a large-scale prospective study. Methods: LTL in the peripheral blood was measured by the quantitative polymerase chain reaction (qPCR) assay from 439 961 individuals in the UK Biobank recruited between 2006 and 2010 and followed up until 2020. Electronic health records were used to record the incidence of dementia, including Alzheimer's disease (AD) and vascular dementia (VD). The brain structure, including total and regional brain volume, of 38 740 participants was then assessed by magnetic resonance imaging (MRI). Results: During a median follow-up of 11.6 years, a total of 5 820 (1.3%) dementia cases were documented. The restricted cubic spline model showed significant overall associations between LTL and the risk of dementia and AD (p for overall <0.05). The multivariable adjusted hazard ratios (HRs) for the lowest LTL tertile compared with the highest LTL tertile were 1.14 (95% confidence interval (CI): 1.06 to 1.21) for dementia, 1.28 (95% CI: 1.12 to 1.46) for AD and 1.18 (95% CI: 0.98 to 1.42) for VD. Furthermore, we found that shorter LTL was associated with smaller total brain volume (ß=-0.012 8, p=0.003), white matter volume (ß=-0.022 4, p<0.001), hippocampus volume (ß=-0.017 2, p<0.001), thalamus volume (ß=-0.023 9, p<0.001) and accumbens (ß=-0.015 5, p=0.001). Conclusions: Shorter LTL is associated with total and regional brain structure and a higher risk of incident dementia and AD, implying the potential of telomere length as a predictive biomarker of brain health.