Ultraminiature Piezoelectric Implantable Acoustic Transducers for Biomedical Applications

Miniature piezoelectric acoustic transducers have been developed for numerous applications. Compared to other transduction mechanisms like capacitive or piezoresistive, piezoelectric transducers do not need direct current (DC) bias voltage and can work directly exposed to fluid. Hence, they are good candidates for biomedical applications that often require the transducer to work in water based fluid. Among all piezoelectric materials, aluminum nitride (AlN) is a great choice for implantable sensors because of the high electrical resistance, low dielectric loss, and biocompatibility for in vivo study. This thesis presents the design, modeling, fabrication, and testing of the AlN acoustic transducers, miniaturized to be implantable for biomedical applications like hearing or cardiovascular devices. To design and model the transducer in air and in water, a 3D finite element analysis (FEA) model was built to study the transducer in a viscous fluid environment. An array of AlN bimorph cantilevers were designed to create a multi-resonance transducer to increase the sensitivity in a broad band frequency range. A two-wafer process using microelectricalmechanical systems (MEMS) techniques was used to fabricate the xylophone transducer with flexible cable. Benchtop testing confirmed the transducer functionality and verified the FEA model experimentally. The transducer was then implanted inside a living cochlea of a guinea pig and tested in vivo. The piezoelectric voltage output from the transducer was measured in response to 80-95 dB sound pressure level (SPL) sinusoidal excitation spanning 1-14 kHz. The phases showed clear acoustic delay. The measured voltage responses were linear and above the noise level. These results demonstrated that the transducer can work as a sensor for a fully implantable cochlear implant. The second generation device, an ultraminiature diaphragm transducer, was designed to be smaller, and yet with an even lower noise floor. The transducer was designed and optimized using a 2D axial-symmetric FEA model for a better figure of merit (FOM), which considered both minimal detectable pressure (MDP) and the diaphragm area. The low-frequency sensitivity was increased significantly, because of the encapsulated back cavity. Because of this merit, cardiovascular applications, which focus on low frequency signals, were also investigated. The diaphragm transducers were fabricated using MEMS techniques. Benchtop tests for both actuating and sensing confirmed the transducer functionality, and verified the design and model experimentally. The transducer had a better FOM than other existing piezoelectric diaphragm transducers, and it had a much lower MDP than the other intracochlear acoustic sensors.PHDMechanical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/147673/1/chumingz_1.pd

Heterogenous profiles between primary lung cancers and paired brain metastases reveal tumor evolution

BackgroundBrain metastases (BMs) are the most common central nervous system (CNS) malignant tumors, with rapid disease progression and extremely poor prognosis. The heterogeneity between primary lung cancers and BMs leads to the divergent efficacy of the adjuvant therapy response to primary tumors and BMs. However, the extent of heterogeneity between primary lung cancers and BMs, and the evolutionary process remains little known.MethodsTo deeply insight into the extent of inter-tumor heterogeneity at a single-patient level and the process of these evolutions, we retrospectively analyzed a total of 26 tumor samples from 10 patients with matched primary lung cancers and BMs. One patient underwent four times brain metastatic lesion surgery with diverse locations and one operation for the primary lesion. The genomic and immune heterogeneity between primary lung cancers and BMs were evaluated by utilizing whole-exome sequencing (WESeq) and immunohistochemical analysis.ResultsIn addition to inheriting genomic phenotype and molecular phenotype from the primary lung cancers, massive unique genomic phenotype and molecular phenotype were also observed in BMs, which revealed unimaginable complexity of tumor evolution and extensive heterogeneity among lesions at a single-patient level. By analysis of a multi-metastases case (Case 3) of cancer cells’ subclonal composition, we found similar multiple subclonal clusters in the four spatial and temporal isolated brain metastatic focus, with the characteristics of polyclonal dissemination. Our study also verified that the expression level of immune checkpoints-related molecule Programmed Death-Ligand 1 (PD-L1) (P = 0.0002) and the density of tumor-infiltrating lymphocytes (TILs) (P = 0.0248) in BMs were significantly lower than that in paired primary lung cancers. Additionally, tumor microvascular density (MVD) also differed between primary tumors and paired BMs, indicating that temporal and spatial diversity profoundly contributes to the evolution of BMs heterogeneity.ConclusionOur study revealed the significance of temporal and spatial factors to the evolution of tumor heterogeneity by multi-dimensional analysis of matched primary lung cancers and BMs, which also provided novel insight for formulating individualized treatment strategies for BMs

Identification of heterogeneous subtypes and a prognostic model for gliomas based on mitochondrial dysfunction and oxidative stress-related genes

ObjectiveMitochondrial dysfunction and oxidative stress are known to involved in tumor occurrence and progression. This study aimed to explore the molecular subtypes of lower-grade gliomas (LGGs) based on oxidative stress-related and mitochondrial-related genes (OMRGs) and construct a prognostic model for predicting prognosis and therapeutic response in LGG patients.MethodsA total of 223 OMRGs were identified by the overlap of oxidative stress-related genes (ORGs) and mitochondrial-related genes (MRGs). Using consensus clustering analysis, we identified molecular subtypes of LGG samples from TCGA database and confirmed the differentially expressed genes (DEGs) between clusters. We constructed a risk score model using LASSO regression and analyzed the immune-related profiles and drug sensitivity of different risk groups. The prognostic role of the risk score was confirmed using Cox regression and Kaplan-Meier curves, and a nomogram model was constructed to predict OS rates. We validated the prognostic role of OMRG-related risk score in three external datasets. Quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) staining confirmed the expression of selected genes. Furthermore, wound healing and transwell assays were performed to confirm the gene function in glioma.ResultsWe identified two OMRG-related clusters and cluster 1 was significantly associated with poor outcomes (P<0.001). The mutant frequencies of IDH were significantly lower in cluster 1 (P<0.05). We found that the OMRG-related risk scores were significantly correlated to the levels of immune infiltration and immune checkpoint expression. High-risk samples were more sensitive to most chemotherapeutic agents. We identified the prognostic role of OMRG-related risk score in LGG patients (HR=2.665, 95%CI=1.626-4.369, P<0.001) and observed that patients with high-risk scores were significantly associated with poor prognosis (P<0.001). We validated our findings in three external datasets. The results of qRT-PCR and IHC staining verified the expression levels of the selected genes. The functional experiments showed a significant decrease in the migration of glioma after knockdown of SCNN1B.ConclusionWe identified two molecular subtypes and constructed a prognostic model, which provided a novel insight into the potential biological function and prognostic significance of mitochondrial dysfunction and oxidative stress in LGG. Our study might help in the development of more precise treatments for gliomas

Association between methionine sulfoxide and risk of moyamoya disease

ObjectiveMethionine sulfoxide (MetO) has been identified as a risk factor for vascular diseases and was considered as an important indicator of oxidative stress. However, the effects of MetO and its association with moyamoya disease (MMD) remained unclear. Therefore, we performed this study to evaluate the association between serum MetO levels and the risk of MMD and its subtypes.MethodsWe eventually included consecutive 353 MMD patients and 88 healthy controls (HCs) with complete data from September 2020 to December 2021 in our analyzes. Serum levels of MetO were quantified using liquid chromatography-mass spectrometry (LC–MS) analysis. We evaluated the role of MetO in MMD using logistic regression models and confirmed by receiver-operating characteristic (ROC) curves and area under curve (AUC) values.ResultsWe found that the levels of MetO were significantly higher in MMD and its subtypes than in HCs (p < 0.001 for all). After adjusting for traditional risk factors, serum MetO levels were significantly associated with the risk of MMD and its subtypes (p < 0.001 for all). We further divided the MetO levels into low and high groups, and the high MetO level was significantly associated with the risk of MMD and its subtypes (p < 0.05 for all). When MetO levels were assessed as quartiles, we found that the third (Q3) and fourth (Q4) MetO quartiles had a significantly increased risk of MMD compared with the lowest quartile (Q3, OR: 2.323, 95%CI: 1.088–4.959, p = 0.029; Q4, OR: 5.559, 95%CI: 2.088–14.805, p = 0.001).ConclusionIn this study, we found that a high level of serum MetO was associated with an increased risk of MMD and its subtypes. Our study raised a novel perspective on the pathogenesis of MMD and suggested potential therapeutic targets

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial

Background: Previous cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes. Methods: We conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment. Results: Forty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference − 0.40 [95% CI − 0.71 to − 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference − 1.6% [95% CI − 4.3% to 1.2%]; P = 0.42) between groups. Conclusions: In this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness. Trial registration: ISRCTN, ISRCTN12233792. Registered November 20th, 2017

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial.

BackgroundPrevious cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes.MethodsWe conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment.ResultsForty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference - 0.40 [95% CI - 0.71 to - 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference - 1.6% [95% CI - 4.3% to 1.2%]; P = 0.42) between groups.ConclusionsIn this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness.Trial registrationISRCTN, ISRCTN12233792 . Registered November 20th, 2017

Actively implementing an evidence-based feeding guideline for critically ill patients (NEED): a multicenter, cluster-randomized, controlled trial (vol 26, 46, 2022)

BackgroundPrevious cluster-randomized controlled trials evaluating the impact of implementing evidence-based guidelines for nutrition therapy in critical illness do not consistently demonstrate patient benefits. A large-scale, sufficiently powered study is therefore warranted to ascertain the effects of guideline implementation on patient-centered outcomes.MethodsWe conducted a multicenter, cluster-randomized, parallel-controlled trial in intensive care units (ICUs) across China. We developed an evidence-based feeding guideline. ICUs randomly allocated to the guideline group formed a local "intervention team", which actively implemented the guideline using standardized educational materials, a graphical feeding protocol, and live online education outreach meetings conducted by members of the study management committee. ICUs assigned to the control group remained unaware of the guideline content. All ICUs enrolled patients who were expected to stay in the ICU longer than seven days. The primary outcome was all-cause mortality within 28 days of enrollment.ResultsForty-eight ICUs were randomized to the guideline group and 49 to the control group. From March 2018 to July 2019, the guideline ICUs enrolled 1399 patients, and the control ICUs enrolled 1373 patients. Implementation of the guideline resulted in significantly earlier EN initiation (1.20 vs. 1.55 mean days to initiation of EN; difference - 0.40 [95% CI - 0.71 to - 0.09]; P = 0.01) and delayed PN initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI 0.44 to 1.67]; P = 0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference - 1.6% [95% CI - 4.3% to 1.2%]; P = 0.42) between groups.ConclusionsIn this large-scale, multicenter trial, active implementation of an evidence-based feeding guideline reduced the time to commencement of EN and overall PN use but did not translate to a reduction in mortality from critical illness.Trial registrationISRCTN, ISRCTN12233792 . Registered November 20th, 2017

Performance of a free-space-optical relay-assisted hybrid RF/FSO system in generalized M-distributed channels

This paper investigates the average symbol error rate (ASER) performance of a dual-hop hybrid relaying system relying on both radio frequency (RF) and free-space optical (FSO) links. Specifically, an RF link is used for supporting mobile communication, whereas an FSO link is adopted as the backhaul of the cellular infrastructure. Considering nonline-of-sight RF transmissions and a generalized atmospheric turbulence (AT) channel, the associated statistical features constituted of both exact and asymptotic moment-generating functions are derived in the closed form. They are then used for calculating the ASER of M -ary phase-shift keying (PSK), differentially encoded noncoherent PSK (DPSK), and noncoherent frequency-shift keying. A range of additional asymptotic expressions is also derived for all the modulation schemes under high signal-to-noise ratios (SNR). It is observed from the asymptotic analysis that the ASERs of all the modulation schemes are dominated by the average SNR of the RF link in the hybrid relaying system using a fixed relay gain, whereas in the relaying system using a dynamic channel-dependent relay gain, the ASERs of all the modulation schemes depend both on the average SNR and the AT condition of the FSO path. We also find that the fixed-gain relaying strategy achieves twice the diversity order of the channel-dependent relaying strategy, albeit at the cost of requiring a high power amplifier dynamic range at the relay node. Furthermore, by comparing the asymptotic ASERs, we calculate the SNR differences between the different modulation schemes in both the fixed-gain and channel-dependent relaying systems. Finally, simulation results are presented for confirming the accuracy of our expressions and observation

Pulmonary embolism induces pneumonia‐like lung injury beyond pulmonary infarction

Abstract Patients with pulmonary embolism (PE) commonly manifest concomitant “pneumonia,” which is generally believed to be either a cause (infection) or a consequence (infarction) of PE. This study aimed to clarify the relationship between PE and “pneumonia‐like” lesions beyond pulmonary infection and infarction. Chest computed tomography (CT) images of patients with PE and deep vein thrombosis (DVT) were retrospectively analyzed to compare the incidence of pneumonia lesions. The pathological damage and wet/dry ratio of lung tissues were observed in PE rats and PE plasma‐injected rats. In total, 793 and 914 inpatients were enrolled in the PE and DVT groups, respectively. Pneumonia lesions were observed in 36.9% and 26.3% of patients in the PE and DVT groups, respectively (p < 0.0001). Among PE rats, 33.3% exhibited focal severe lung injury, which closely resembled the pathological damage of community‐acquired pneumonia. The wet/dry ratio was significantly higher in the PE group than in the PE‐control group (4.98 ± 0.08 vs. 4.39 ± 0.06, p < 0.0001). Among PE plasma‐injected rats, individuals with focal proven lung injury were found at all experimental points, with an incidence of 27.6%. The lung wet/dry ratio was significantly higher in the PE plasma group than in the PE‐control plasma group at 1 and 2 h postinjection (5.02 ± 0.12 vs. 4.61 ± 0.06 and 4.76 ± 0.16 vs. 4.34 ± 0.09, respectively; p < 0.05). In conclusion, the manifestation of pneumonia lesions in chest CT images was higher among PE patients than among DVT patients. Plasma of PE rats could induce focal pneumonia‐like lung injury in healthy rats

Ultrastructural Study of Alveolar Epithelial Type II Cells by High-Frequency Oscillatory Ventilation

Alveolar epithelial type II cells (AECIIs) containing lamellar bodies (LBs) are alveolar epithelial stem cells that have important functions in the repair of lung structure and function after lung injury. The ultrastructural changes in AECIIs after high-frequency oscillatory ventilation (HFOV) with a high lung volume strategy or conventional ventilation were evaluated in a newborn piglet model with acute lung injury (ALI). After ALI with saline lavage, newborn piglets were randomly assigned into five study groups (three piglets in each group), namely, control (no mechanical ventilation), conventional ventilation for 24 h, conventional ventilation for 48 h, HFOV for 24 h, and HFOV for 48 h. The lower tissues of the right lung were obtained to observe the AECII ultrastructure. AECIIs with reduced numbers of microvilli, decreased LBs electron density, and vacuole-like LBs deformity were commonly observed in all five groups. Compared with conventional ventilation groups, the decrease in numbers of microvilli and LBs electron density, as well as LBs with vacuole-like appearance and polymorphic deformity, was less severe in HFOV with high lung volume strategy groups. AECIIs were injured during mechanical ventilation. HFOV with a high lung volume strategy resulted in less AECII damage than conventional ventilation