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To achieve the mission of personalized medicine, centering on delivering the right drug to the right patient at the right dose, therapeutic drug monitoring solutions are necessary. In that regard, wearable biosensing technologies, capable of tracking drug pharmacokinetics in noninvasively retrievable biofluids (e.g., sweat), play a critical role, because they can be deployed at a large scale to monitor the individuals’ drug transcourse profiles (semi) continuously and longitudinally. To this end, voltammetry-based sensing modalities are suitable, as in principle they can detect and quantify electroactive drugs on the basis of the target’s redox signature. However, the target’s redox signature in complex biofluid matrices can be confounded by the immediate biofouling effects and distorted/buried by the interfering voltammetric responses of endogenous electroactive species. Here, we devise a wearable voltammetric sensor development strategy—centering on engineering the molecule–surface interactions—to simultaneously mitigate biofouling and create an “undistorted potential window” within which the target drug’s voltammetric response is dominant and interference is eliminated. To inform its clinical utility, our strategy was adopted to track the temporal profile of circulating acetaminophen (a widely used analgesic and antipyretic) in saliva and sweat, using a surface-modified boron-doped diamond sensing interface (cross-validated with laboratory-based assays, R² ∼ 0.94). Through integration of the engineered sensing interface within a custom-developed smartwatch, and augmentation with a dedicated analytical framework (for redox peak extraction), we realized a wearable solution to seamlessly render drug readouts with minute-level temporal resolution. Leveraging this solution, we demonstrated the pharmacokinetic correlation and significance of sweat readings.

Active biofluid management is central to the realization of wearable bioanalytical platforms that are poised to autonomously provide frequent, real-time, and accurate measures of biomarkers in epidermally-retrievable biofluids (e.g., sweat). Accordingly, here, a programmable epidermal microfluidic valving system is devised, which is capable of biofluid sampling, routing, and compartmentalization for biomarker analysis. At its core, the system is a network of individually-addressable microheater-controlled thermo-responsive hydrogel valves, augmented with a pressure regulation mechanism to accommodate pressure built-up, when interfacing sweat glands. The active biofluid control achieved by this system is harnessed to create unprecedented wearable bioanalytical capabilities at both the sensor level (decoupling the confounding influence of flow rate variability on sensor response) and the system level (facilitating context-based sensor selection/protection). Through integration with a wireless flexible printed circuit board and seamless bilateral communication with consumer electronics (e.g., smartwatch), contextually-relevant (scheduled/on-demand) on-body biomarker data acquisition/display was achieved. Wearable biosensors have been used successfully for biomarker analysis, however, a lack of control over sampling limits applications. Here, the authors report a programmable microfluidic valve to control flow rate, sampling times and allow for biofluid routing and compartmentalisation.

Background China is becoming an aging society at the fastest pace in history, and there are a large number of empty nesters in the country. With economic and social development, internal support systems among families are gradually weakening. Supporting the elderly is thus emerging as a significant issue, and promoting digital health technologies is an effective way to help address it. Encouraging the application of Internet to elderly care and Internet use among the elderly are important means of promoting digital health technologies. This paper examines the current state of the use of the Internet by the elderly and factors influencing it (including physical, psychological, and social) as well as demand among the elderly for smart services. Methods A total of 669 subjects over the age of 60 years were randomly selected from 13 cities in Heilongjiang province and surveyed using questionnaires from May 1 to July 31, 2018. The questionnaires were collected for descriptive statistics, the chi-square test, and the analysis of influential factors. Results Of the people surveyed, 38.6% used the Internet. Their favorite online activity was online dating (74.2%), and the health information they obtained through the Internet was mainly related to diet (63.1%) and exercise (47.1%). The subjects demanded smart bracelets (MD = 2.80) and emergency callers (MD = 2.77). Gender, age, education, monthly income, quality of life, number of friends, and social participation were found to have an impact on Internet use. Conclusions More measures are needed to reduce barriers to the use of the Internet and promote digital health technologies. The society, equipment manufacturers, and family members of the elderly should work together to enable them to reap the benefits of online technologies.

BackgroundThe peroxisome proliferator-activated receptor γ (PPAR-γ)-dependent upregulation of fatty acid oxidation (FAO) mediates protumor (also known as M2-like) polarization of tumor-associated macrophages (TAMs). However, upstream factors determining PPAR-γ upregulation in TAM protumor polarization are not fully identified. S100A4 plays crucial roles in promotion of cancer malignancy and mitochondrial metabolism. The fact that macrophage-derived S100A4 is major source of extracellular S100A4 suggests that macrophages contain a high abundance of intracellular S100A4. However, whether intracellular S100A4 in macrophages also contributes to cancer malignancy by enabling TAMs to acquire M2-like protumor activity remains unknown.MethodsGrowth of tumor cells was evaluated in murine tumor models. TAMs were isolated from the tumor grafts in whole-body S100A4-knockout (KO), macrophage-specific S100A4-KO and transgenic S100A4WT−EGFP mice (expressing enhanced green fluorescent protein (EGFP) under the control of the S100A4 promoter). In vitro induction of macrophage M2 polarization was conducted by interleukin 4 (IL-4) stimulation. RNA-sequencing, real-time quantitative PCR, flow cytometry, western blotting, immunofluorescence staining and mass spectrometry were used to determine macrophage phenotype. Exogenous and endogenous FAO, FA uptake and measurement of lipid content were used to analyze macrophage metabolism.ResultsTAMs contain two subsets based on whether they express S100A4 or not and that S100A4+ subsets display protumor phenotypes. S100A4 can be induced by IL-4, an M2 activator of macrophage polarization. Mechanistically, S100A4 controls the upregulation of PPAR-γ, a transcription factor required for FAO induction during TAM protumor polarization. In S100A4+ TAMs, PPAR-γ mainly upregulates CD36, a FA transporter, to enhance FA absorption as well as FAO. In contrast, S100A4-deficient TAMs exhibited decreased protumor activity because of failure in PPAR-γ upregulation-dependent FAO induction.ConclusionsWe find that macrophagic S100A4 enhances protumor macrophage polarization as a determinant of PPAR-γ-dependent FAO induction. Accordingly, our findings provide an insight into the general mechanisms of TAM polarization toward protumor phenotypes. Therefore, our results strongly suggest that targeting macrophagic S100A4 may be a potential strategy to prevent TAMs from re-differentiation toward a protumor phenotype.

The shared steering control (SSC) system is a solution for safe driving before achieving fully autonomous driving, however, its overall stability is easily affected by the driver characteristics. This paper investigates the problem of the design method for the SSC system to improve the overall stability of the system. The design method consists of three core contents: the SSC overall stability condition analysis, the drivers’ driving characteristic analysis, and the design condition of the controller obtaining. On this basis, a nonlinear controller is designed considering the control objectives comprehensively. The effectiveness of the proposed method is verified by simulation and experiment. The results show that the designed SSC system based on the proposed method can remain stable when the driver characteristics are poor. In addition, the designed system can effectively improve the path-tracking performance and stability of the vehicle, reduce human–machine conflict, and reduce the operating load of the driver and the workload of the controller. This research can improve SSC system stability, thereby contributing to the enhancement of system reliability and driving safety.

CD146 was originally identified as a melanoma cell adhesion molecule (MCAM) and highly expressed in many tumors and endothelial cells. However, the evidence that CD146 acts as an adhesion molecule to mediate a homophilic adhesion through the direct interactions between CD146 and itself is still lacking. Recent evidence revealed that CD146 is not merely an adhesion molecule, but also a cellular surface receptor of miscellaneous ligands, including some growth factors and extracellular matrixes. Through the bidirectional interactions with its ligands, CD146 is actively involved in numerous physiological and pathological processes of cells. Overexpression of CD146 can be observed in most of malignancies and is implicated in nearly every step of the development and progression of cancers, especially vascular and lymphatic metastasis. Thus, immunotherapy against CD146 would provide a promising strategy to inhibit metastasis, which accounts for the majority of cancer-associated deaths. Therefore, to deepen the understanding of CD146, we review the reports describing the newly identified ligands of CD146 and discuss the implications of these findings in establishing novel strategies for cancer therapy.

Milvexian (BMS‐986177/JNJ‐70033093) is a small molecule, active‐site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of milvexian were assessed in a two‐part, double‐blind, placebo‐controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200‐ and 500‐mg panels investigated the pharmacokinetic impact of a high‐fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive milvexian (once‐ or twice‐daily) or placebo for 14 days. All milvexian dosing regimens were safe and well‐tolerated, with only mild treatment‐emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half‐life (T1/2) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose‐proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased milvexian bioavailability in a dose‐dependent fashion. In MAD panels, steady‐state milvexian plasma concentration was reached within 3 and 6 dosing days with once‐ and twice‐daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development.

ObjectiveTo investigate the effects of the willingness to live in elder care institutions associated with individual factors, family environment and the community environment in the elderly in China.DesignCross-sectional survey.SettingHeilongjiang Province, China.ParticipantsA total of 1003 elderly people were selected through multistage sampling in Heilongjiang Province.Primary and secondary outcome measuresA multistage, stratified sampling design was employed. Differences in health status, family environment and community environment of the respondents were compared with the t-test and χ2 test. Logistic regression analysis was performed to assess key determinants of willingness to live in institutions.ResultsThis study showed that 45.4% of respondents were willing to live in elder care institutions in the future. Factors influencing willingness to live in elder care institutions were age, house ownership, living with spouse and children, disease caregivers and availability of home healthcare services. The elders who had no property (OR=2.37, 95% CI 1.750 to 3.200, p<0.01) and those aged 80 or above (OR=2.25, 95% CI 1.490 to 3.400, p<0.01) were, respectively, 2.370 and 2.250 times more receptive to living in elder care institutions than their control groups. However, those living with a spouse (OR=0.47, 95% CI 0.287 to 0.762, p<0.01), living with children (OR=0.25, 95% CI 0.158 to 0.402, p<0.01) or living with a spouse and children (OR=0.29, 95% CI 0.160 to 0.509, p<0.01) were less willing to live in elder care institutions.ConclusionsThese results suggest that the willingness to enter elder care institutions is affected by individual, family environmental and community environmental factors. We should vigorously develop community-centred intensive home-based elder care services by improving the quality and availability of home health services by expanding investment in the community.

Milvexian (BMS-986177/JNJ-70033093) is a potent, oral small molecule that inhibits the active form of factor XI with high affinity and selectivity. This study assessed the single-dose pharmacokinetic and pharmacodynamic properties of milvexian co-administered with rifampin, an organic anion transport protein (OATP) inhibitor and potent cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp) inducer. In this open-label, nonrandomized, single-sequence study, healthy participants ( N  = 16) received single doses of milvexian on Day 1 (100 mg), milvexian and rifampin (600 mg) on Day 4, rifampin on Days 5–11, milvexian and rifampin on Day 12, and rifampin on Days 13–14. Pharmacokinetic data were summarized using descriptive statistics. Administration of milvexian, alone or in combination with rifampin, was generally safe and well tolerated. Single-dose co-administration of rifampin and milvexian demonstrated no meaningful changes in milvexian exposure versus milvexian alone (C max , 110%; AUC [0–T] , 102%; AUC [INF] , 101%). After multiple doses of rifampin and milvexian, peak and total milvexian exposure substantially decreased versus milvexian alone (C max , 22%; AUC [0–T] , 15%; AUC [INF] , 15%). Results were consistent with preclinical data, indicating that milvexian is a substrate for CYP3A4/5 and P-gp but not OATP. The implications of these results on the need for dose adjustment of milvexian will be further elucidated following the completion of phase 2 and 3 trials. Trial registration The study was registered with ClinicalTrials.gov (NCT02959060; submitted 7/11/2016, first posted 8/11/2016).

Background Antiphospholipid syndrome (APS) is notably linked to thrombotic events, particularly cardiovascular disease (CVD). The role of remnant cholesterol (RC) in predicting CVD risk is established, yet its relationship with thrombotic risk in APS patients remains to be elucidated. This study aims to assess the association between RC and recurrent thrombotic risk in patients with APS. Methods A prospective analysis was conducted based on a cohort of APS patients who met the 2006 Sydney revised classification criteria. Thrombotic risks associated with varying levels of RC were evaluated using Kaplan–Meier survival analysis and Cox proportional hazards regression models. Mendelian randomization (MR) was applied to examine the causal link between RC and different types of thrombotic events. Results A total of 325 patients with APS were enrolled in this study. Over a median follow-up of 35 months, 51 patients experienced thrombotic events, including 24 venous, 19 arterial, and 16 microvascular incidents. Patients with RC levels above 0.60 mmol/L exhibited significantly higher risks, with multivariable-adjusted hazard ratio (and 95% confidence interval) for all-cause, venous, arterial thrombosis, and microvascular disease being 5.05 (2.23–11.41), 6.34 (1.71–23.54), 3.79 (1.00–14.32), and 4.36 (1.08–17.58), respectively. Notably, elevated RC remained a significant thrombotic risk factor even in patients with normal conventional lipid profiles. MR analysis revealed a significant causal association between RC and arterial thrombosis, but not venous thrombosis. Conclusions Elevated RC is linked to a substantial increase in the risk of thrombotic events in APS patients. These findings suggest that RC could be a valuable marker for thrombotic risk in this population and a potential target for therapeutic intervention. Highlights A more than 5-fold increase in thrombotic risk, including arterial, venous, and microvascular events, is linked to individuals with RC levels >0.60 mmol/L in APS. Elevated RC remains a significant risk factor even in patients with normal conventional lipid indices (LDL-C, TC, TG, and non-HDL-C). Through MR analysis, there was a significant causal relationship between RC and AT in the general population, but not with VT, suggesting the complexity of the pathogenesis of VT in patients with APS. Patients with APS treated with hydroxychloroquine have lower RC levels, and hydroxychloroquine may have the potential to reduce RC. Graphical Abstract