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Background: This study aimed to assess the safety and feasibility of a 3-month flushing interval for totally implantable venous access ports (TIVAPs), particularly regarding intraluminal clot formation., Methods: Between May 2017 and September 2018, we established a single-center cohort of 151 patients who were referred for TIVAP removal and categorized them into three flushing-interval groups: A (⩽1 month), B (1-2 months), and C (2-3 months). Odds ratios (OR) with 95% confidence intervals (CI) were computed using logistic regression to determine the risk of intraluminal clot occurrence. To compare clot lengths among the groups, we employed linear regression. Restricted cubic splines were used to model the flushing interval as a continuous variable., Results: Compared to Group A, Groups B and C had adjusted ORs of 0.82 (0.35-1.92) and 0.78 (0.29-2.11) for intraluminal clot risk. Occlusion was rare (1/151; 0.7%) and successfully treated with mechanical recanalization. Adjusted differences in clot length compared to Group A were 0.01 (-0.85 to 0.87) for Group B and -0.23 (-1.21 to 0.76) for Group C. Spline regression analysis showed no significant association between the flushing interval and clot length ( p for trend = 0.84)., Conclusion: The incidence and burden of intraluminal clots did not increase significantly within the first 3 months. Occlusion was rare, even in the presence of clots, and was successfully treated. Therefore, a 3-month flushing interval appears to be a safe and practical option, aligning with the common recommendation for surveillance intervals in patients with cancer., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Pressures generated by external forces or by internal body processes represent parameters of critical importance in diagnosing physiological health and in anticipating injuries. Examples span intracranial hypertension from traumatic brain injuries, high blood pressure from poor diet, pressure-induced skin ulcers from immobility, and edema from congestive heart failure. Pressures measured on the soft surfaces of vital organs or within internal cavities of the body can provide essential insights into patient status and progression. Challenges lie in the development of high-performance pressure sensors that can softly interface with biological tissues to enable safe monitoring for extended periods of time. This review focuses on recent advances in mechanically active materials and structural designs for classes of soft pressure sensors that have proven uses in these contexts. The discussions include applications of such sensors as implantable and wearable systems, with various unique capabilities in wireless continuous monitoring, minimally invasive deployment, natural degradation in biofluids, and/or multiplexed spatiotemporal mapping. A concluding section summarizes challenges and future opportunities for this growing field of materials and biomedical research., (© 2023 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)

The level of tumor and circulating CXCR1/2-expressing neutrophils and CXCR1/2 ligands correlate with poor patient outcomes, inversely correlate with tumoral lymphocyte content, and predict immune checkpoint inhibitor (ICI) treatment failure. Accordingly, CXCR2-selective and CXCR1/2 dual inhibitors exhibit activity both as single agents and in combination with ICI treatment in mouse tumor models. Based on such reports, clinical trials combining CXCR1/2 axis antagonists with ICI treatment for cancer patients are underway. It has been assumed that CXCR1/2 blockade impacts tumors by blocking neutrophil chemotaxis and reducing neutrophil content in tumors. Here, we show that while CXCR2 antagonism does slow tumor growth, it does not preclude neutrophil recruitment into tumor. Instead, CXCR1/2 inhibition alters neutrophil function by blocking the polarization of transcriptional programs toward immune suppressive phenotypes and rendering neutrophils incapable of suppressing lymphocyte proliferation. This is associated with decreased release of reactive oxygen species and Arginase-1 into the extracellular milieu. Remarkably, these therapeutics do not impact the ability of neutrophils to phagocytose and kill ingested bacteria. Taken together, these results mechanistically explain why CXCR1/2 inhibition has been active in cancer but without infectious complications., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Partial cystectomy procedures for urinary bladder-related dysfunction involve long recovery periods, during which urodynamic studies (UDS) intermittently assess lower urinary tract function. However, UDS are not patient-friendly, they exhibit user-to-user variability, and they amount to snapshots in time, limiting the ability to collect continuous, longitudinal data. These procedures also pose the risk of catheter-associated urinary tract infections, which can progress to ascending pyelonephritis due to prolonged lower tract manipulation in high-risk patients. Here, we introduce a fully bladder-implantable platform that allows for continuous, real-time measurements of changes in mechanical strain associated with bladder filling and emptying via wireless telemetry, including a wireless bioresorbable strain gauge validated in a benchtop partial cystectomy model. We demonstrate that this system can reproducibly measure real-time changes in a rodent model up to 30 d postimplantation with minimal foreign body response. Studies in a nonhuman primate partial cystectomy model demonstrate concordance of pressure measurements up to 8 wk compared with traditional UDS. These results suggest that our system can be used as a suitable alternative to UDS for long-term postoperative bladder recovery monitoring., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Femoral neck fractures need to be treated in their early stages with accurate reduction and stable fixation to reduce complications. The authors compared the early radiologic outcomes of femoral neck fractures treated with the recently introduced Femoral Neck System (FNS, Depuy-Synthes) with conventional cannulated screws (CS) in a multicenter design. Furthermore, the factors associated with early failure after FNS were analyzed., Methods: The FNS group included 40 patients treated between June 2019 and January 2020, and the CS group included 65 patients treated between January 2015 and May 2019. The operation was performed in 3 university hospitals. Patient demographics, fracture classification, postoperative reduction quality, sliding distance of FNS or CS, union and time to union, and complication rates were examined. Logistic regression analysis was performed on candidate factors for early failure of the FNS group., Results: The FNS group had a 90% union rate and a mean time to union of 4.4 months, while the CS group had similar results with an 83.1% union rate and a mean time to union of 5.1 months. In the subgroup analysis of Pauwels type III fractures, the union rates were 75.0% and 58.8% in the FNS and CS groups, respectively, and the time to union was significantly shorter in the FNS group with 4.8 months compared to 6.8 months in the CS group. Early failure rate within 6 months of FNS fixation was observed to be 10%, which included 3 reduction failures and 1 excessive sliding with a broken implant. Risk factors for early failure after FNS were identified as displaced fractures (Garden classification type III or IV), poor reduction quality, longer tip-apex distance, greater sliding distance, and 1-hole implants, of which sliding distance was the only significant risk factor in multivariate analysis., Conclusions: In femoral neck fractures, FNS and CS did not show significant differences for short-term radiologic results. FNS resulted in shorter operative time than cannulated screw fixation and favorable outcomes in Pauwels type III femoral neck fractures. The FNS could be considered a reliable and safe alternative to CS when treating femoral neck fractures., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported., (Copyright © 2024 by The Korean Orthopaedic Association.)

Objectives: The aim of this study was to compare the outcomes of the transjugular approach with those of the conventional approach for endovascular treatment of arteriovenous fistulas (AVFs)., Methods: Between May 2015 and July 2019, 112 patients with endovascular treatment of dysfunctional or immature AVFs were included and divided into the transjugular (n = 46) and conventional (n = 66) groups. Electronic medical records and angiography of the patients were retrospectively reviewed to assess technical and clinical success rates, time to first fistulography, total procedure time, primary and secondary patency, and complications in both groups., Results: There were no significant differences in technical success rate (87.0% vs 97.0%; P = .062), clinical success rate (80.4% vs 90.9%; P = .109), or total procedure time (60.2 vs 57.9 min; P = .670) between the groups. Cox proportional hazards models showed that the cumulative primary patency was significantly higher in the transjugular group than in the conventional group (P = .041; 6-month patency rates, 93.8% vs 91.5%). Also, a statistically significant difference was found between the cumulative secondary patency of the groups (P = .014; 6-month patency rates, 91.4% vs 86.5%). No major complications were observed., Conclusions: Transjugular endovascular treatment of AVFs was successful and effective. Longer patency periods were observed when treated via transjugular access., Advances in Knowledge: This article compared the outcomes of transjugular approaches with those of conventional approaches in the endovascular treatment of native AVFs and showed higher patency periods/rates in the transjugular group than in the conventional group., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Institute of Radiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Synthetic data generation addresses the challenges of obtaining extensive empirical datasets, offering benefits such as cost-effectiveness, time efficiency, and robust model development. Nonetheless, synthetic data-generation methodologies still encounter significant difficulties, including a lack of standardized metrics for modeling different data types and comparing generated results. This study introduces PVS-GEN, an automated, general-purpose process for synthetic data generation and verification. The PVS-GEN method parameterizes time-series data with minimal human intervention and verifies model construction using a specific metric derived from extracted parameters. For complex data, the process iteratively segments the empirical dataset until an extracted parameter can reproduce synthetic data that reflects the empirical characteristics, irrespective of the sensor data type. Moreover, we introduce the PoR metric to quantify the quality of the generated data by evaluating its time-series characteristics. Consequently, the proposed method can automatically generate diverse time-series data that covers a wide range of sensor types. We compared PVS-GEN with existing synthetic data-generation methodologies, and PVS-GEN demonstrated a superior performance. It generated data with a similarity of up to 37.1% across multiple data types and by 19.6% on average using the proposed metric, irrespective of the data type.

In this paper, we propose a bit depth compression (BDC) technique, which performs bit packing by dynamically determining the pack size based on the pattern of the bit depth level of the sensor data, thereby maximally reducing the space wastage that may occur during the bit packing process. The proposed technique can dynamically perform bit packing according to the data's characteristics, which may have many outliers or several multidimensional variations, and therefore has a high compression ratio. Furthermore, the proposed method is a lossless compression technique, which is especially useful as training data in the field of artificial intelligence or in the predictive analysis of data science. The proposed method effectively addresses the spatial inefficiency caused by unpredictable outliers during time-series data compression. Additionally, it offers high compression efficiency, allowing for storage space savings and optimizing network bandwidth utilization while transmitting large volumes of data. In the experiment, the BDC method demonstrated an improvement in the compression ratio of up to 247%, with 30% on average, compared with other compression algorithms. In terms of energy consumption, the proposed BDC also improves data transmission using Bluetooth up to 34%, with 18% on average, compared with other compression algorithms.

Background: Carcinoembryonic antigen (CEA) is a commonly used tumor marker in cancer screening. However, it has also been associated with metabolic alterations. Hepatic steatosis, the accumulation of fat in liver cells, is associated with various cardiovascular risk factors. This study investigated the risk of ischemic heart disease (IHD) in individuals with elevated CEA levels, hepatic steatosis, and their co-occurrence., Methods: The study cohort comprised 5,580 Korean adults who underwent health examinations between November 2006 and June 2010. Data regarding baseline CEA levels, hepatic steatosis status, and development of IHD were collected. Hepatic steatosis was defined as more than two findings: deep attenuation, vascular blurring, and increased liver echogenicity on abdominal ultrasound. Participants were divided into four groups based on their CEA and hepatic steatosis status: no hepatic steatosis and low CEA (group 1), no hepatic steatosis and elevated CEA (group 2), low CEA and hepatic steatosis (group 3), and elevated CEA and hepatic steatosis (group 4)., Results: A total of 226 (4.1%) participants developed IHD during the follow-up period. Participants with elevated CEA levels and hepatic steatosis (group 4) had the highest cumulative incidence of IHD in comparison to other groups ( p  < 0.001). The combined effect of elevated CEA levels and hepatic steatosis showed significantly greater area under the receiver operating characteristic curve than hepatic steatosis alone ( p  < 0.001). Furthermore, participants with elevated CEA and hepatic steatosis (group 4) had higher risk of developing IHD compared to those with low CEA and no hepatic steatosis (group 1) (hazard ratio: 1.63, 95% confidence interval: 1.04-2.55, p  = 0.034)., Conclusion: Co-occurrence of elevated CEA levels and hepatic steatosis increases the risk of IHD. Comprehensive risk assessment is crucial to guide interventions and improve cardiovascular health in individuals with both the conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kwak, Lee, Park and Jung.)

Importance: The antiandrogenic effect of the 5α-reductase inhibitor (5-ARI) has been investigated for its role in preventing male-predominant cancers. Although 5-ARI has been widely associated with prostate cancer, its association with urothelial bladder cancer (BC), another cancer experienced predominantly by males, has been less explored., Objective: To assess the association between 5-ARI prescription prior to BC diagnosis and reduced risk of BC progression., Design, Setting, and Participants: This cohort study analyzed patient claims data from the Korean National Health Insurance Service database. The nationwide cohort included all male patients with BC diagnosis in this database from January 1, 2008, to December 31, 2019. Propensity score matching was conducted to balance the covariates between 2 treatment groups: α-blocker only group and 5-ARI plus α-blocker group. Data were analyzed from April 2021 to March 2023., Exposure: Newly dispensed prescriptions of 5-ARIs at least 12 months prior to cohort entry (BC diagnosis), with a minimum of 2 prescriptions filled., Main Outcomes and Measures: The primary outcomes were the risks of bladder instillation and radical cystectomy, and the secondary outcome was all-cause mortality. To compare the risk of outcomes, the hazard ratio (HR) was estimated using a Cox proportional hazards regression model and difference in restricted mean survival time analysis., Results: The study cohort initially included 22 845 males with BC. After propensity score matching, 5300 patients each were assigned to the α-blocker only group (mean [SD] age, 68.3 [8.8] years) and 5-ARI plus α-blocker group (mean [SD] age, 67.8 [8.6] years). Compared with the α-blocker only group, the 5-ARI plus α-blocker group had a lower risk of mortality (adjusted HR [AHR], 0.83; 95% CI, 0.75-0.91), bladder instillation (crude HR, 0.84; 95% CI, 0.77-0.92), and radical cystectomy (AHR, 0.74; 95% CI, 0.62-0.88). The differences in restricted mean survival time were 92.6 (95% CI, 25.7-159.4) days for all-cause mortality, 88.1 (95% CI, 25.2-150.9) days for bladder instillation, and 68.0 (95% CI, 31.6-104.3) days for radical cystectomy. The incidence rates per 1000 person-years were 85.59 (95% CI, 80.53-90.88) for bladder instillation and 19.57 (95% CI, 17.41-21.91) for radical cystectomy in the α-blocker only group and 66.43 (95% CI, 62.22-70.84) for bladder instillation and 13.56 (95% CI, 11.86-15.45) for radical cystectomy in the 5-ARI plus α-blocker group., Conclusions and Relevance: Results of this study suggest an association between prediagnostic prescription of 5-ARI and reduced risk of BC progression.

Background: Although many superior capsule reconstruction (SCR) techniques are currently practiced in clinical settings, guidelines for choosing the appropriate graft material are lacking. Therefore, at most times, the surgeon's personal preference becomes the deciding factor. This study compared 2 fairly recent SCR techniques-SCR with biceps tendon (BT) autograft and SCR with human dermis (HD) allograft-by evaluating clinical and radiologic outcomes to aid the surgeon's decision in choosing the appropriate graft., Methods: Thirty-one patients underwent SCR using BT autograft (SCR BT), and 22 underwent SCR using HD allograft (SCR HD). SCR BT was selected for patients with a partial BT tear <20%, no severe inflammation signs, and favorable anchor conditions. SCR HD was performed in patients with a BT tear >20%, a superior labrum anterior-posterior (SLAP) lesion, severe inflammation, or subluxation. Range of motion (ROM), strength and shoulder function scoring, plain radiography, and magnetic resonance imaging were evaluated before and after surgery at regular intervals., Results: In the SCR BT group, forward flexion ROM increased from 122° ± 43° to 149° ± 18° at 2 years postoperatively, whereas in the SCR HD group, forward flexion ROM improved from 129° ± 28° to 149° ± 18°. In the SCR BT group, internal rotation (IR) ROM increased from 5 ± 3 to 6 ± 2 at 2 years postoperatively, whereas in the SCR HD group, IR ROM improved from 5 ± 3 to 6 ± 1. Although ROM, strength, visual analog scale score, American Shoulder and Elbow Surgeons score, and Constant score all improved 2 years after surgery, no statistically significant differences were found. Six months after surgery, graft thickness was 3.58 ± 0.384 mm in the SCR BT group and 2.49 ± 0.326 mm in the SCR HD group (P < .001). At 2 years postoperatively, graft thickness was 3.54 ± 0.399 mm in the SCR BT group and 2.49 ± 0.306 mm in the SCR HD group (P < .001). The SCR HD group showed a negative correlation of -0.475 between graft thickness and IR ROM (P = .026). In the SCR BT group, a negative correlation of -0.466 was found between graft thickness and IR ROM (P = .008). A positive correlation of 0.363 was found between IR ROM and the acromiohumeral distance when the results were compared before and 2 years after surgery (P = .045)., Conclusion: Both SCR using BT autograft and SCR using HD allograft tissue showed favorable results, and no significant difference was noted between the 2 techniques. Given that the 2 techniques show equally favorable results, the surgeon's personal preference in choosing the SCR technique appears to be acceptable. Understanding the costs and patient's characteristics may aid the surgeon in deciding on the graft material., (Copyright © 2022 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Purpose: We evaluated the effectiveness of transarterial embolization (TAE) for intractable postpartum hemorrhage in patients with disseminated intravascular coagulation (DIC) despite emergency hysterectomy., Materials and Methods: We retrospectively assessed TAE performed after emergency hysterectomy in 15 patients between July 2008 and January 2022. Underlying condition, technical success, clinical success, angiographic findings, laboratory findings, pregnancy-modified DIC score (The International Society on Thrombosis and Haemostasis), blood transfusion, ICU (Intensive care unit) admission day, hospital day, in-hospital mortality, and long-term sequelae were evaluated., Results: All patients were diagnosed with DIC before embolization, with a 43.9 mean DIC score. All patients showed positive angiographic findings for active bleeding. Thirty-eight bleeding arteries were confirmed. The remnant uterine artery (n=25) was the most common focus of persistent bleeding, followed by the cervicovaginal artery (n=6), pudendal artery (n=3), obturator artery (n=2), vesical artery (n=1), and unspecified artery from the internal iliac artery (n=1). Technical and clinical success rates were 100% (15/15) and 93.3% (14/15), respectively. Mean nadir hemoglobin (Hb) level before embolization was 4.9 g/dL. All patients underwent massive transfusion before embolization (mean 33.2 packs of RBC). Postoperatively, a smaller amount of blood was transfused than before the procedure (mean 10.6 packs of RBC). Mean nadir Hb level after embolization was 8.2 g/dL. There was one instance each of in-hospital death, hypoxic brain damage, and ischemic acute kidney injury., Conclusion: Despite hysterectomy for postpartum bleeding, there could be multiple residual or uncontrolled bleeding foci, especially in case of DIC, for which TAE could be an effective treatment., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Myeloid lineage cells suppress T cell viability through arginine depletion via arginase 1 (ARG1). Despite numerous studies exploring the mechanisms by which ARG1 perturbs lymphocyte function, the cellular populations responsible for its generation and release remain poorly understood. Here, we showed that neutrophil lineage cells and not monocytes or macrophages expressed ARG1 in human non-small cell lung cancer (NSCLC). Importantly, we showed that approximately 40% of tumor-associated neutrophils (TANs) actively transcribed ARG1 mRNA. To determine the mechanism by which ARG1 mRNA is induced in TANs, we utilized FPLC followed by MS/MS to screen tumor-derived factors capable of inducing ARG1 mRNA expression in neutrophils. These studies identified ANXA2 as the major driver of ARG1 mRNA expression in TANs. Mechanistically, ANXA2 signaled through the TLR2/MYD88 axis in neutrophils to induce ARG1 mRNA expression. The current study describes what we believe to be a novel mechanism by which ARG1 mRNA expression is regulated in neutrophils in cancer and highlights the central role that neutrophil lineage cells play in the suppression of tumor-infiltrating lymphocytes.

The intradermal (ID) space has been actively explored as a means for drug delivery and diagnostics that is minimally invasive. Microneedles or microneedle patches or microarray patches (MAPs) are comprised of a series of micrometer-sized projections that can painlessly puncture the skin and access the epidermal/dermal layer. MAPs have failed to reach their full potential because many of these platforms rely on dated lithographic manufacturing processes or molding processes that are not easily scalable and hinder innovative designs of MAP geometries that can be achieved. The DeSimone Laboratory has recently developed a high-resolution continuous liquid interface production (CLIP) 3D printing technology. This 3D printer uses light and oxygen to enable a continuous, noncontact polymerization dead zone at the build surface, allowing for rapid production of MAPs with precise and tunable geometries. Using this tool, we are now able to produce new classes of lattice MAPs (L-MAPs) and dynamic MAPs (D-MAPs) that can deliver both solid state and liquid cargos and are also capable of sampling interstitial fluid. Herein, we will explore how additive manufacturing can revolutionize MAP development and open new doors for minimally invasive drug delivery and diagnostic platforms., Competing Interests: The authors declare the following competing financial interest(s): The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Joseph M DeSimone reports financial support to our research group was provided by Wellcome Leap Fund and startup funds provided by Stanford University School of Medicine and the School of Engineering. Netra U. Rajesh reports financial support was provided by the Knight-Hennessy Scholarship. Joseph M DeSimone reports a relationship with Carbon that includes board membership and cofounder equity. Provisional patents have also been filed by Stanford for both the L-MAP and D-MAP technologies disclosed in this paper., (© 2022 The Authors. Published by American Chemical Society.)

We diagnosed 66 peripheral nerve injuries in 34 patients who survived severe coronavirus disease 2019 (COVID-19). We combine this new data with published case series re-analyzed here (117 nerve injuries; 58 patients) to provide a comprehensive accounting of lesion sites. The most common are ulnar (25.1%), common fibular (15.8%), sciatic (13.1%), median (9.8%), brachial plexus (8.7%) and radial (8.2%) nerves at sites known to be vulnerable to mechanical loading. Protection of peripheral nerves should be prioritized in the care of COVID-19 patients. To this end, we report proof of concept data of the feasibility for a wearable, wireless pressure sensor to provide real time monitoring in the intensive care unit setting., (© 2022. The Author(s).)

Low modulus materials that can shape-morph into different three-dimensional (3D) configurations in response to external stimuli have wide-ranging applications in flexible/stretchable electronics, surgical instruments, soft machines and soft robotics. This paper reports a shape-programmable system that exploits liquid metal microfluidic networks embedded in an elastomer matrix, with electromagnetic forms of actuation, to achieve a unique set of properties. Specifically, this materials structure is capable of fast, continuous morphing into a diverse set of continuous, complex 3D surfaces starting from a two-dimensional (2D) planar configuration, with fully reversible operation. Computational, multi-physics modeling methods and advanced 3D imaging techniques enable rapid, real-time transformations between target shapes. The liquid-solid phase transition of the liquid metal allows for shape fixation and reprogramming on demand. An unusual vibration insensitive, dynamic 3D display screen serves as an application example of this type of morphable surface., (© 2022. The Author(s).)

Purpose: The ideal surgical treatment of extra-articular distal-third diaphyseal humeral fractures is controversial in terms of the surgical approach and plate position. The aim of this study was to compare the clinical and radiological outcomes between anterior and posterior plating methods for extra-articular distal-third diaphyseal humeral fractures., Methods: Twenty-four patients were treated with anterior plating with modified placement of the proximal humeral internal locking system (PHILOS) plate, and 22 patients were treated with posterior plating of the extra-articular distal humerus plate (EADHP). Patient demographics, the fracture configuration, the number of screws in the distal fragment, the operation time, and the time to union were analyzed. The range of elbow motion, Mayo elbow performance score (MEPS), plate-related symptoms, and complications were evaluated at the final follow-up., Results: There were no statistically significant differences in the demographic data between the two groups. The mean operation time for anterior plating (108.2 ± 24.5 min) was significantly shorter than that for posterior plating (144.2 ± 29.5 minutes, p < 0.001). The average number of screws used in the distal humeral fragment was significantly higher with anterior plating (5.7 ± 0.7) than with posterior plating (4.8 ± 0.5, p < 0.001). No patients in the anterior plating group had plate-related symptoms, while 17 patients in the posterior plating group (77%) had discomfort or cosmetic problems related to the plate (p < 0.001). Plate removal was performed upon patient request in nine patients of the posterior plating (52.9%) and four (17%) in anterior plating (p = 0.040). Nonunion occurred in one patient who underwent anterior plating, and one patient who underwent posterior plating had post-operative radial nerve palsy. There were no significant differences in the MEPS or elbow range of motion between the two surgical methods., Conclusion: Both anterior and posterior plating provide satisfactory clinical and radiologic outcomes for extra-articular distal-third diaphyseal humeral fractures. Despite the satisfactory outcomes, however, posterior plating is highly associated with plate-related complaints, which might be one of the considerations when the surgical method is selected for extra-articular distal-third diaphyseal humeral fractures., (© 2022. The Author(s) under exclusive licence to SICOT aisbl.)

Background: Ultrasound (US)-guided techniques reported for the treatment of calcific tendinitis have mostly demonstrated good results. This study investigates the effect of US-guided barbotage using a spinal needle in patients with calcific tendinitis of the shoulder., Methods: Thirty-six patients with calcific tendinitis of the shoulder treated by US-guided barbotage with a spinal needle and subacromial steroid injection were included in the study. We evaluated clinical outcomes based on American Shoulder and Elbow Surgeons (ASES) score, Constant score, and visual analog scale (VAS) for pain score. Radiological outcomes were assessed by X-ray imaging at each visit., Results: Our results showed that US-guided barbotage and subacromial steroid injection produced good clinical and radiological outcomes in patients with calcific tendinitis of the shoulder. Of the 36 patients, only one required surgical treatment, while the others showed improvement without any complications. Compared to values before the procedure, calcific deposit size and VAS, ASES, and Constant scores showed significant improvement 6 weeks after the procedure. No significant correlation was found between the initial calcific deposit size and clinical outcomes at each time point., Conclusions: In patients with calcific tendinitis of the shoulder, US-guided barbotage using a spinal needle and subacromial steroid injection can yield satisfactory clinical and radiological results.

Robots with submillimeter dimensions are of interest for applications that range from tools for minimally invasive surgical procedures in clinical medicine to vehicles for manipulating cells/tissues in biology research. The limited classes of structures and materials that can be used in such robots, however, create challenges in achieving desired performance parameters and modes of operation. Here, we introduce approaches in manufacturing and actuation that address these constraints to enable untethered, terrestrial robots with complex, three-dimensional (3D) geometries and heterogeneous material construction. The manufacturing procedure exploits controlled mechanical buckling to create 3D multimaterial structures in layouts that range from arrays of filaments and origami constructs to biomimetic configurations and others. A balance of forces associated with a one-way shape memory alloy and the elastic resilience of an encapsulating shell provides the basis for reversible deformations of these structures. Modes of locomotion and manipulation span from bending, twisting, and expansion upon global heating to linear/curvilinear crawling, walking, turning, and jumping upon laser-induced local thermal actuation. Photonic structures such as retroreflectors and colorimetric sensing materials support simple forms of wireless monitoring and localization. These collective advances in materials, manufacturing, actuation, and sensing add to a growing body of capabilities in this emerging field of technology.

Background: Various graft materials have been used to repair nasoseptal perforation, but there is no standardized treatment method. The anterior maxillary sinus wall is flattened in appearance and can be easily obtained in a sufficient amount for a large-sized nasoseptal perforation., Objectives: The aim of this study is to determine whether the anterior maxillary sinus wall is suitable as an interpositional graft in the surgical repair of septal or nasoseptal perforation., Methods: This is a retrospective review of 21 patients who underwent repair of nasoseptal perforation using anterior maxillary sinus wall as an interpositional graft. The etiology , pre- and post-operative NOSE and GBI score, and perforation size were reviewed. The surgical outcome was considered successful if total closure was achieved after postoperative follow-up., Results: 19 of the 21 perforations were successfully repaired with anterior maxillary sinus wall. Failure of the repair was found in 2 patients. Causal etiology of perforation was previous septoplasty in 10 patients, and electrocautery in 1 case, but not identified in 10 cases. The largest size was 2.7 × 2.2 cm. The most common symptoms were epistaxis, crusting, and nasal obstruction. Closure of septal perforation resulted in improved subjective symptoms and quality of life which were evaluated with NOSE and GBI score., Conclusion: Anterior maxillary sinus wall as interpositional graft between mucoperichondrial flaps can be used to reliably repair nasoseptal perforations.

The pathogenesis of allergic rhinitis is associated with genetic, environmental, and epigenetic factors. Genotyping of single nucleotide polymorphisms (SNPs) is an advanced technique in the field of molecular genetics that is closely correlated with genome-wide association studies (GWASs) in large population groups with allergic diseases. Many recent studies have paid attention to the role of epigenetics, including alteration of DNA methylation, histone acetylation, and miRNA levels in the pathogenesis of allergic rhinitis. In this review article, genetics and epigenetics of allergic rhinitis, including information regarding functions and significance of previously known and newly-discovered genes, are summarized. Directions for future genetic and epigenetic studies of allergic rhinitis are also proposed.

EphA2 receptor and its ephrin ligands are involved in virus infection, epithelial permeability, and chemokine secretion. We hypothesized that ephrinA1/ephA2 signaling participates in rhinovirus (RV)-induced antiviral immune response in sinonasal mucosa of patients with chronic rhinosinusitis (CRS). Therefore, we investigated the expression of ephrinA1/ephA2 in normal and inflamed sinonasal mucosa and evaluated whether they regulate chemokine secretion and the production of antiviral immune mediators including interferons (IFNs) in RV-infected human primary sinonasal epithelial cells. For this purpose, the expression and distribution of ephrinA1/ephA2 in sinonasal mucosa were evaluated with RT-qPCR, immunofluorescence, and western blot. Their roles in chemokine secretion and the production of antiviral immune mediators such as type I and III IFNs, and interferon stimulated genes were evaluated by stimulating ephA2 with ephrinA1 and inactivating ephA2 with ephA2 siRNA or inhibitor in cells exposed to RV and poly(I:C). We found that ephrinA1/ephA2 were expressed in normal mucosa and their levels increased in inflamed sinonasal mucosa of CRS patients. RV infection or poly(I:C) treatment induced chemokine secretion which were attenuated by blocking the action of ephA2 with ephA2 siRNA or inhibitor. The production of antiviral immune mediators enhanced by rhinovirus or poly (I:C) is increased by blocking ephA2 compared with that of cells stimulated by either rhinovirus or poly(I:C) alone. In addition, blocking ephA2 attenuated RV replication in cultured cells. Taken together, these results describe a novel role of ephrinA1/ephA2 signaling in antiviral innate immune response in sinonasal epithelium, suggesting their participation in RV-induced development and exacerbations of CRS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lee, Kang, Han, Kwak, Kim, Lee, Lee and Kim.)

Microfluidic technologies have wide-ranging applications in chemical analysis systems, drug delivery platforms, and artificial vascular networks. This latter area is particularly relevant to 3D cell cultures, engineered tissues, and artificial organs, where volumetric capabilities in fluid distribution are essential. Existing schemes for fabricating 3D microfluidic structures are constrained in realizing desired layout designs, producing physiologically relevant microvascular structures, and/or integrating active electronic/optoelectronic/microelectromechanical components for sensing and actuation. This paper presents a guided assembly approach that bypasses these limitations to yield complex 3D microvascular structures from 2D precursors that exploit the full sophistication of 2D fabrication methods. The capabilities extend to feature sizes <5 μm, in extended arrays and with various embedded sensors and actuators, across wide ranges of overall dimensions, in a parallel, high-throughput process. Examples include 3D microvascular networks with sophisticated layouts, deterministically designed and constructed to expand the geometries and operating features of artificial vascular networks.

Indwelling arterial lines, the clinical gold standard for continuous blood pressure (BP) monitoring in the pediatric intensive care unit (PICU), have significant drawbacks due to their invasive nature, ischemic risk, and impediment to natural body movement. A noninvasive, wireless, and accurate alternative would greatly improve the quality of patient care. Recently introduced classes of wireless, skin-interfaced devices offer capabilities in continuous, precise monitoring of physiologic waveforms and vital signs in pediatric and neonatal patients, but have not yet been employed for continuous tracking of systolic and diastolic BP-critical for guiding clinical decision-making in the PICU. The results presented here focus on materials and mechanics that optimize the system-level properties of these devices to enhance their reliable use in this context, achieving full compatibility with the range of body sizes, skin types, and sterilization schemes typically encountered in the PICU. Systematic analysis of the data from these devices on 23 pediatric patients, yields derived, noninvasive BP values that can be quantitatively validated against direct recordings from arterial lines. The results from this diverse cohort, including those under pharmacological protocols, suggest that wireless, skin-interfaced devices can, in certain circumstances of practical utility, accurately and continuously monitor BP in the PICU patient population., (© 2021 Wiley-VCH GmbH.)

An association between fiber intake and allergic diseases in children has been reported; however, many studies have not been conducted to assess this association in adults. We aimed to evaluate the association between dietary fiber intake and allergic diseases (asthma, allergic rhinitis, and atopic dermatitis) among 10,479 adults using data from the Korean National Health and Nutrition Examination Survey (2010-2011). As dietary fiber intake increased, the prevalence of asthma (Q4 adjusted odds ratio (OR): 0.656; 95% confidence interval (CI): 0.48-0.91, p for trend < 0.0001) and atopic dermatitis (Q3 crude OR: 0.746; 95% CI: 0.57-0.98; Q4 adjusted OR: 0.712; 95% CI: 0.50-1.01, p for trend < 0.0001) decreased. The prevalence of allergic rhinitis (Q2 adjusted OR: 0.840; 95% CI: 0.70-1.00, p for trend < 0.0001) tended to decrease, especially in males. Subgroup analysis revealed that fiber intake reduced allergic rhinitis symptoms, including watery rhinorrhea (Q3 adjusted OR: 0.734; 95% CI: 0.55-0.97; Q4 adjusted OR: 0.722; 95% CI: 0.54-0.97) and dog allergen sensitization (Q3 adjusted OR: 0.319; 95% CI: 0.13-0.82; Q4 adjusted OR: 0.338; 95% CI: 0.13-0.86), exclusively in males. Thus, dietary fiber intake influences allergic diseases in adults, especially males.

Precise, quantitative measurements of the hydration status of skin can yield important insights into dermatological health and skin structure and function, with additional relevance to essential processes of thermoregulation and other features of basic physiology. Existing tools for determining skin water content exploit surrogate electrical assessments performed with bulky, rigid, and expensive instruments that are difficult to use in a repeatable manner. Recent alternatives exploit thermal measurements using soft wireless devices that adhere gently and noninvasively to the surface of the skin, but with limited operating range (∼1 cm) and high sensitivity to subtle environmental fluctuations. This paper introduces a set of ideas and technologies that overcome these drawbacks to enable high-speed, robust, long-range automated measurements of thermal transport properties via a miniaturized, multisensor module controlled by a long-range (∼10 m) Bluetooth Low Energy system on a chip, with a graphical user interface to standard smartphones. Soft contact to the surface of the skin, with almost zero user burden, yields recordings that can be quantitatively connected to hydration levels of both the epidermis and dermis, using computational modeling techniques, with high levels of repeatability and insensitivity to ambient fluctuations in temperature. Systematic studies of polymers in layered configurations similar to those of human skin, of porcine skin with known levels of hydration, and of human subjects with benchmarks against clinical devices validate the measurement approach and associated sensor hardware. The results support capabilities in characterizing skin barrier function, assessing severity of skin diseases, and evaluating cosmetic and medication efficacy, for use in the clinic or in the home., Competing Interests: Competing interest statement: We have some potential commercial interest in the technology introduced in this paper. A.B. and J.A.R. are co-founders and J.-K.C. is an employee of a company, Wearifi Inc., that may wish to pursue commercialization of this technology in the future., (Copyright © 2021 the Author(s). Published by PNAS.)

Precise form-fitting of prosthetic sockets is important for the comfort and well-being of persons with limb amputations. Capabilities for continuous monitoring of pressure and temperature at the skin-prosthesis interface can be valuable in the fitting process and in monitoring for the development of dangerous regions of increased pressure and temperature as limb volume changes during daily activities. Conventional pressure transducers and temperature sensors cannot provide comfortable, irritation-free measurements because of their relatively rigid construction and requirements for wired interfaces to external data acquisition hardware. Here, we introduce a millimeter-scale pressure sensor that adopts a soft, three-dimensional design that integrates into a thin, flexible battery-free, wireless platform with a built-in temperature sensor to allow operation in a noninvasive, imperceptible fashion directly at the skin-prosthesis interface. The sensor system mounts on the surface of the skin of the residual limb, in single or multiple locations of interest. A wireless reader module attached to the outside of the prosthetic socket wirelessly provides power to the sensor and wirelessly receives data from it, for continuous long-range transmission to a standard consumer electronic device such as a smartphone or tablet computer. Characterization of both the sensor and the system, together with theoretical analysis of the key responses, illustrates linear, accurate responses and the ability to address the entire range of relevant pressures and to capture skin temperature accurately, both in a continuous mode. Clinical application in two prosthesis users demonstrates the functionality and feasibility of this soft, wireless system., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Therapeutic compression garments (TCGs) are key tools for the management of a wide range of vascular lower extremity conditions. Proper use of TCGs involves application of a minimum and consistent pressure across the lower extremities for extended periods of time. Slight changes in the characteristics of the fabric and the mechanical properties of the tissues lead to requirements for frequent measurements and corresponding adjustments of the applied pressure. Existing sensors are not sufficiently small, thin, or flexible for practical use in this context, and they also demand cumbersome, hard-wired interfaces for data acquisition. Here, we introduce a flexible, wireless monitoring system for tracking both temperature and pressure at the interface between the skin and the TCGs. Detailed studies of the materials and engineering aspects of these devices, together with clinical pilot trials on a range of patients with different pathologies, establish the technical foundations and measurement capabilities., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Background and Objectives: Hearing loss (HL) and its repercussions are major problems in today's society. There are limited data on the relationship between degree of HL and otologic disorders. The aim of this study is to estimate mortality rates, rates of sudden idiopathic HL and related otologic surgical procedures in hearing disability patients in South Korea., Subjects and Methods: Retrospective medical data for 160,205 patients with hearing disability was extracted. Mortality rates, rates of sudden idiopathic HL and related otologic surgical procedures were compared with a normal control group consisting of 865,475 people; approximately 5 times the number of hearing disability patients., Results: According to the Korean National Disability Registry (NDR), 0.458% of the population in South Korea suffered from hearing disability in 2015. Higher rates of mortality and sudden idiopathic HL were reported in hearing disability patients, increasing up to a maximum of 1.594 times and 1,039.695 times, respectively, compared to the normal control group. Mastoidectomy surgery was 2.5 times more frequently performed and pressure equalizing (PE) tube insertion was about 15 times more frequently performed in hearing disability patients., Conclusions: Hearing disability is related to higher risks of mortality, sudden idiopathic HL and otologic surgical procedures, including mastoidectomy and PE tubing.

MHC class II (MHCII) expression is usually restricted to APC but can be expressed by cancer cells. We examined the effect of cancer cell-specific MHCII (csMHCII) expression in lung adenocarcinoma on T cell recruitment to tumors and response to anti-PD-1 therapy using two orthotopic immunocompetent murine models of non-small cell lung cancer: CMT167 (CMT) and Lewis lung carcinoma (LLC). We previously showed that CMT167 tumors are eradicated by anti-PD1 therapy, whereas LLC tumors are resistant. RNA sequencing analysis of cancer cells recovered from tumors revealed that csMHCII correlated with response to anti-PD1 therapy, with immunotherapy-sensitive CMT167 cells being csMHCII positive, whereas resistant LLC cells were csMHCII negative. To test the functional effects of csMHCII, MHCII expression was altered on the cancer cells through loss- and gain-of-function of CIITA, a master regulator of the MHCII pathway. Loss of CIITA in CMT167 decreased csMHCII and converted tumors from anti-PD-1 sensitive to anti-PD-1 resistant. This was associated with lower levels of Th1 cytokines, decreased T cell infiltration, increased B cell numbers, and decreased macrophage recruitment. Conversely, overexpression of CIITA in LLC cells resulted in csMHCII in vitro and in vivo. Enforced expression of CIITA increased T cell infiltration and sensitized tumors to anti-PD-1 therapy. csMHCII expression was also examined in a subset of surgically resected human lung adenocarcinomas by multispectral imaging, which provided a survival benefit and positively correlated with T cell infiltration. These studies demonstrate a functional role for csMHCII in regulating T cell infiltration and sensitivity to anti-PD-1., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Background: Programmed death 1/programmed death ligand 1 (PD-1/PD-L1) targeted immunotherapy affords clinical benefit in ~20% of unselected patients with lung cancer. The factor(s) that determine whether a tumor responds or fails to respond to immunotherapy remains an active area of investigation. We have previously defined divergent responsiveness of two KRAS-mutant cell lines to PD-1/PD-L1 blockade using an orthotopic, immunocompetent mouse model. Responsiveness to PD-1/PD-L1 checkpoint blockade correlates with an interferon gamma (IFNγ)-inducible gene signature and major histocompatibility complex class II (MHC II) expression by cancer cells. In the current study, we aim to identify therapeutic targets that can be manipulated in order to enhance cancer-cell-specific MHC II expression., Methods: Responsiveness to IFNγ and induction of MHC II expression was assessed after various treatment conditions in mouse and human non-small cell lung cancer (NSCLC) cell lines using mass cytometric and flow cytometric analysis., Results: Single-cell analysis using mass and flow cytometry demonstrated that IFNγ consistently induced PD-L1 and MHC class I (MHC I) across multiple murine and human NSCLC cell lines. In contrast, MHC II showed highly variable induction following IFNγ treatment both between lines and within lines. In mouse models of NSCLC, MHC II induction was inversely correlated with basal levels of phosphorylated extracellular signal-regulated kinase (ERK) 1/2, suggesting potential mitogen-activated protein (MAP) kinase-dependent antagonism of MHC II expression. To test this, cell lines were subjected to varying levels of stimulation with IFNγ, and assessed for MHC II expression in the presence or absence of mitogen-activated protein kinase kinase (MEK) inhibitors. IFNγ treatment in the presence of MEK inhibitors significantly enhanced MHC II induction across multiple lung cancer lines, with minimal impact on expression of either PD-L1 or MHC I. Inhibition of histone deacetylases (HDACs) also enhanced MHC II expression to a more modest extent. Combined MEK and HDAC inhibition led to greater MHC II expression than either treatment alone., Conclusions: These studies emphasize the active inhibitory role that epigenetic and ERK signaling cascades have in restricting cancer cell-intrinsic MHC II expression in NSCLC, and suggest that combinatorial blockade of these pathways may engender new responsiveness to checkpoint therapies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Standard clinical care in neonatal and pediatric intensive-care units (NICUs and PICUs, respectively) involves continuous monitoring of vital signs with hard-wired devices that adhere to the skin and, in certain instances, can involve catheter-based pressure sensors inserted into the arteries. These systems entail risks of causing iatrogenic skin injuries, complicating clinical care and impeding skin-to-skin contact between parent and child. Here we present a wireless, non-invasive technology that not only offers measurement equivalency to existing clinical standards for heart rate, respiration rate, temperature and blood oxygenation, but also provides a range of important additional features, as supported by data from pilot clinical studies in both the NICU and PICU. These new modalities include tracking movements and body orientation, quantifying the physiological benefits of skin-to-skin care, capturing acoustic signatures of cardiac activity, recording vocal biomarkers associated with tonality and temporal characteristics of crying and monitoring a reliable surrogate for systolic blood pressure. These platforms have the potential to substantially enhance the quality of neonatal and pediatric critical care.

Lung cancer is a heterogeneous disease in which patient-specific treatments are desirable and the development of targeted therapies has been effective. Although mutations in KRAS are frequent in lung adenocarcinoma, there are currently no targeted agents against KRAS. Using a mouse lung adenocarcinoma cell line with a Kras mutation (CMT167), we previously showed that PPARγ activation in lung cancer cells inhibits cell growth in vitro yet promotes tumor progression when activated in myeloid cells of the tumor microenvironment. Here, we report that PPARγ activation in myeloid cells promotes the production of TGFβ1, which, in turn, acts on CMT167 cancer cells to increase migration and induce an epithelial-mesenchymal transition (EMT). Targeting TGFβ1 signaling in CMT167 cells prevented their growth and metastasis in vivo . Similarly, another mouse lung adenocarcinoma cell line with a Kras mutation, LLC, induced TGFβ1 in myeloid cells through PPARγ activation. However, LLC cells are more mesenchymal and did not undergo EMT in response to TGFβ1, nor did LLC require TGFβ1 signaling for metastasis in vivo . Converting CMT167 cells to a mesenchymal phenotype through overexpression of ZEB1 made them unresponsive to TGFβ1 receptor inhibition. The ability of TGFβ1 to induce EMT in lung tumors may represent a critical process in cancer progression. We propose that TGFβ receptor inhibition could provide an additional treatment option for KRAS -mutant epithelial lung tumors. Implications: This study suggests that TGFβ receptor inhibitors may be an effective therapy in a subset of KRAS -mutant patients with non-small cell lung cancer, which show an epithelial phenotype., (©2019 American Association for Cancer Research.)

Plants have recently received a great deal of attention as a means of producing recombinant proteins. Despite this, a limited number of recombinant proteins are currently on the market and, if plants are to be more widely used, a cost-effective and efficient purification method is urgently needed. Although affinity tags are convenient tools for protein purification, the presence of a tag on the recombinant protein is undesirable for many applications. A cost-effective method of purification using an affinity tag and the removal of the tag after purification has been developed. The family 3 cellulose-binding domain (CBM3), which binds to microcrystalline cellulose, served as the affinity tag and the small ubiquitin-related modifier (SUMO) and SUMO-specific protease were used to remove it. This method, together with size-exclusion chromatography, enabled purification of human interleukin-6 (hIL6) with a yield of 18.49 mg/kg fresh weight from leaf extracts of Nicotiana benthamiana following Agrobacterium-mediated transient expression. Plant-produced hIL6 (P-hIL6) contained less than 0.2 EU/μg (0.02 ng/mL) endotoxin. P-hIL6 activated the Janus kinase-signal transducer and activator of transcriptional pathways in human LNCaP cells, and induced expression of IL-21 in activated mouse CD4 + T cells. This approach is thus a powerful method for producing recombinant proteins in plants., (© 2018 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

Targeting PD-1/PD-L1 is only effective in ∼20% of lung cancer patients, but determinants of this response are poorly defined. We previously observed differential responses of two murine K-Ras-mutant lung cancer cell lines to anti-PD-1 therapy: CMT167 tumors were eliminated, whereas Lewis Lung Carcinoma (LLC) tumors were resistant. The goal of this study was to define mechanism(s) mediating this difference. RNA sequencing analysis of cancer cells recovered from lung tumors revealed that CMT167 cells induced an IFNγ signature that was blunted in LLC cells. Silencing Ifngr1 in CMT167 resulted in tumors resistant to IFNγ and anti-PD-1 therapy. Conversely, LLC cells had high basal expression of SOCS1, an inhibitor of IFNγ. Silencing Socs1 increased response to IFNγ in vitro and sensitized tumors to anti-PD-1. This was associated with a reshaped tumor microenvironment, characterized by enhanced T cell infiltration and enrichment of PD-L1 hi myeloid cells. These studies demonstrate that targeted enhancement of tumor-intrinsic IFNγ signaling can induce a cascade of changes associated with increased therapeutic vulnerability., (© 2019 Bullock et al.)

Lung cancer is the leading cause of cancer death in men and women. Lung adenocarcinoma (LUAD), represents approximately 40% of all lung cancer cases. Advances in recent years, such as the identification of oncogenes and the use of immunotherapies, have changed the treatment of LUAD. Yet survival rates still remain low. Additionally, there is still a gap in understanding the molecular and cellular interactions between cancer cells and the immune tumor microenvironment (TME). Defining how cancer cells with distinct oncogenic drivers interact with the TME and new strategies for enhancing anti-tumor immunity are greatly needed. The complement cascade, a central part of the innate immune system, plays an important role in regulation of adaptive immunity. Initially it was proposed that complement activation on the surface of cancer cells would inhibit cancer progression via membrane attack complex (MAC)-dependent killing. However, data from several groups have shown that complement activation promotes cancer progression, probably through the actions of anaphylatoxins (C3a and C5a) on the TME and engagement of immunoevasive pathways. While originally shown to be produced in the liver, recent studies show localized complement production in numerous cell types including immune cells and tumor cells. These results suggest that complement inhibitory drugs may represent a powerful new approach for treatment of NSCLC, and numerous new anti-complement drugs are in clinical development. However, the mechanisms by which complement is activated and affects tumor progression are not well understood. Furthermore, the role of local complement production vs. systemic activation has not been carefully examined. This review will focus on our current understanding of complement action in LUAD, and describe gaps in our knowledge critical for advancing complement therapy into the clinic.

Existing vital sign monitoring systems in the neonatal intensive care unit (NICU) require multiple wires connected to rigid sensors with strongly adherent interfaces to the skin. We introduce a pair of ultrathin, soft, skin-like electronic devices whose coordinated, wireless operation reproduces the functionality of these traditional technologies but bypasses their intrinsic limitations. The enabling advances in engineering science include designs that support wireless, battery-free operation; real-time, in-sensor data analytics; time-synchronized, continuous data streaming; soft mechanics and gentle adhesive interfaces to the skin; and compatibility with visual inspection and with medical imaging techniques used in the NICU. Preliminary studies on neonates admitted to operating NICUs demonstrate performance comparable to the most advanced clinical-standard monitoring systems., (Copyright © 2019, American Association for the Advancement of Science.)

Exposure to electromagnetic radiation can have a profound impact on human health. Ultraviolet (UV) radiation from the sun causes skin cancer. Blue light affects the body's circadian melatonin rhythm. At the same time, electromagnetic radiation in controlled quantities has beneficial use. UV light treats various inflammatory skin conditions, and blue light phototherapy is the standard of care for neonatal jaundice. Although quantitative measurements of exposure in these contexts are important, current systems have limited applicability outside of laboratories because of an unfavorable set of factors in bulk, weight, cost, and accuracy. We present optical metrology approaches, optoelectronic designs, and wireless modes of operation that serve as the basis for miniature, low-cost, and battery-free devices for precise dosimetry at multiple wavelengths. These platforms use a system on a chip with near-field communication functionality, a radio frequency antenna, photodiodes, supercapacitors, and a transistor to exploit a continuous accumulation mechanism for measurement. Experimental and computational studies of the individual components, the collective systems, and the performance parameters highlight the operating principles and design considerations. Evaluations on human participants monitored solar UV exposure during outdoor activities, captured instantaneous and cumulative exposure during blue light phototherapy in neonatal intensive care units, and tracked light illumination for seasonal affective disorder phototherapy. Versatile applications of this dosimetry platform provide means for consumers and medical providers to modulate light exposure across the electromagnetic spectrum in a way that can both reduce risks in the context of excessive exposure and optimize benefits in the context of phototherapy., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objective: We investigated the effect of optimization in dose-limiting shell method on the dosimetric quality of CyberKnife (CK) plans in treating brain metastases (BMs)., Methods: We selected 19 BMs previously treated using CK between 2014 and 2015. The original CK plans (CKoriginal) had been produced using 1 to 3 dose-limiting shells : one at the prescription isodose level (PIDL) for dose conformity and the others at lowisodose levels (10-30% of prescription dose) for dose spillage. In each case, a modified CK plan (CKmodified) was generated using 5 dose-limiting shells : one at the PIDL, another at intermediate isodose level (50% of prescription dose) for steeper dose fall-off, and the others at low-isodose levels, with an optimized shell-dilation size based on our experience. A Gamma Knife (GK) plan was also produced using the original contour set. Thus, three data sets of dosimetric parameters were generated and compared., Results: There were no differences in the conformity indices among the CKoriginal, CKmodified, and GK plans (mean 1.22, 1.18, and 1.24, respectively; p=0.079) and tumor coverage (mean 99.5%, 99.5%, and 99.4%, respectively; p=0.177), whereas the CKmodified plans produced significantly smaller normal tissue volumes receiving 50% of prescription dose than those produced by the CKoriginal plans (p<0.001), with no statistical differences in those volumes compared with GK plans (p=0.345)., Conclusion: These results indicate that significantly steeper dose fall-off is able to be achieved in the CK system by optimizing the shell function while maintaining high conformity of dose to tumor.

The complement cascade is a part of the innate immune system that acts primarily to remove pathogens and injured cells. However, complement activation is also peculiarly associated with tumor progression. Here we report mechanistic insights into this association in multiple immunocompetent orthotopic models of lung cancer. After tumor engraftment, we observed systemic activation of the complement cascade as reflected by elevated levels of the key regulator C3a. Notably, growth of primary tumors and metastases was both strongly inhibited in C3-deficient mice (C3 -/- mice), with tumors undetectable in many subjects. Growth inhibition was associated with increased numbers of IFNγ + /TNFα + /IL10 + CD4 + and CD8 + T cells. Immunodepletion of CD4 + but not CD8 + T cells in tumor-bearing subjects reversed the inhibitory effects of C3 deletion. Similarly, antagonists of the C3a or C5a receptors inhibited tumor growth. Investigations using multiple tumor cell lines in the orthotopic model suggested the involvement of a C3/C3 receptor autocrine signaling loop in regulating tumor growth. Overall, our findings offer functional evidence that complement activation serves as a critical immunomodulator in lung cancer progression, acting to drive immune escape via a C3/C5-dependent pathway. Significance: This provocative study suggests that inhibiting complement activation may heighten immunotherapeutic responses in lung cancer, offering findings with immediate implications, given the existing clinical availability of complement antagonists. Cancer Res; 78(1); 143-56. ©2017 AACR ., (©2017 American Association for Cancer Research.)

This study describes a conductive ink formulation that exploits electrochemical sintering of Zn microparticles in aqueous solutions at room temperature. This material system has relevance to emerging classes of biologically and environmentally degradable electronic devices. The sintering process involves dissolution of a surface passivation layer of zinc oxide in CH 3 COOH/H 2 O and subsequent self-exchange of Zn and Zn 2+ at the Zn/H 2 O interface. The chemical specificity associated with the Zn metal and the CH 3 COOH/H 2 O solution is critically important, as revealed by studies of other material combinations. The resulting electrochemistry establishes the basis for a remarkably simple procedure for printing highly conductive (3 × 10 5 S m -1 ) features in degradable materials at ambient conditions over large areas, with key advantages over strategies based on liquid phase (fusion) sintering that requires both oxide-free metal surfaces and high temperature conditions. Demonstrations include printed magnetic loop antennas for near-field communication devices., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Low modulus, compliant systems of sensors, circuits and radios designed to intimately interface with the soft tissues of the human body are of growing interest, due to their emerging applications in continuous, clinical-quality health monitors and advanced, bioelectronic therapeutics. Although recent research establishes various materials and mechanics concepts for such technologies, all existing approaches involve simple, two-dimensional (2D) layouts in the constituent micro-components and interconnects. Here we introduce concepts in three-dimensional (3D) architectures that bypass important engineering constraints and performance limitations set by traditional, 2D designs. Specifically, open-mesh, 3D interconnect networks of helical microcoils formed by deterministic compressive buckling establish the basis for systems that can offer exceptional low modulus, elastic mechanics, in compact geometries, with active components and sophisticated levels of functionality. Coupled mechanical and electrical design approaches enable layout optimization, assembly processes and encapsulation schemes to yield 3D configurations that satisfy requirements in demanding, complex systems, such as wireless, skin-compatible electronic sensors.

A collection of materials and device architectures are introduced for thin, stretchable arrays of ion sensors that mount on open cellular substrates to facilitate solution exchange for use in biointegrated electronics. The results include integration strategies and studies of fundamental characteristics in chemical sensing and mechanical response. The latter involves experimental measurements and theoretical simulations that establish important considerations in the design of low modulus, stretchable properties in cellular substrates, and in the realization of advanced capabilities in spatiotemporal mapping of chemicals' gradients. As the chemical composition of extracellular fluids contains valuable information related to biological function, the concepts introduced here have potential utility across a range of skin- and internal-organ-integrated electronics where soft mechanics, fluidic permeability, and advanced chemical sensing capabilities are key requirements.

Background: The skin consists of tightly connected keratinocytes, and prevents extensive water loss while simultaneously protecting against the entry of microbial pathogens. Excessive cellular levels of reactive oxygen species can induce cell apoptosis and also damage skin integrity. Propofol (2,6-diisopropylphenol) has antioxidant properties. In this study, we investigated how propofol influences intracellular autophagy and apoptotic cell death induced by oxidative stress in human keratinocytes., Method: The following groups were used for experimentation: control, cells were incubated under normoxia (5% CO 2 , 21% O 2 , and 74% N 2 ) without propofol; hydrogen peroxide (H 2 O 2 ), cells were exposed to H 2 O 2 (300 µM) for 2 h; propofol preconditioning (PPC)/H 2 O 2 , cells pretreated with propofol (100 µM) for 2 h were exposed to H 2 O 2 ; and 3-methyladenine (3-MA)/PPC/H 2 O 2 , cells pretreated with 3-MA (1 mM) for 1 h and propofol were exposed to H 2 O 2 . Cell viability, apoptosis, and migration capability were evaluated. Relation to autophagy was detected by western blot analysis., Results: Cell viability decreased significantly in the H 2 O 2 group compared to that in the control group and was improved by propofol preconditioning. Propofol preconditioning effectively decreased H 2 O 2 -induced cell apoptosis and increased cell migration. However, pretreatment with 3-MA inhibited the protective effect of propofol on cell apoptosis. Autophagy was activated in the PPC/H 2 O 2 group compared to that in the H 2 O 2 group as demonstrated by western blot analysis and autophagosome staining., Conclusion: The results suggest that propofol preconditioning induces an endogenous cellular protective effect in human keratinocytes against oxidative stress through the activation of signaling pathways related to autophagy., Competing Interests: NOTES: Thesis for the degree of Doctor of Philosophy. There are no financial or other issues that might lead to conflict of interest.

This paper introduces a class of ferromagnetic, folded, soft composite material for skin-interfaced electrodes with releasable interfaces to stretchable, wireless electronic measurement systems. These electrodes establish intimate, adhesive contacts to the skin, in dimensionally stable formats compatible with multiple days of continuous operation, with several key advantages over conventional hydrogel based alternatives. The reported studies focus on aspects ranging from ferromagnetic and mechanical behavior of the materials systems, to electrical properties associated with their skin interface, to system-level integration for advanced electrophysiological monitoring applications. The work combines experimental measurement and theoretical modeling to establish the key design considerations. These concepts have potential uses across a diverse set of skin-integrated electronic technologies.

The main mechanism of pathogenesis which causes systemic complications in obstructive sleep apnea (OSA) patients is believed to be intermittent hypoxia-induced intermediary effect and it depends on the burden of oxidative stress during sleep. We aimed to search the predictive markers which reflect the burden of systemic oxidative stress in patients with OSA and whether excessive telomere length shortening is a characteristic feature that can assess oxidative stress levels. We used quantitative PCR to measure telomere length using peripheral blood genomic DNA. Telomere lengths were compared in an age- and body mass index (BMI)-dependent manner in 34 healthy volunteers and 43 OSA subjects. We also performed reactive oxygen species assay to measure the concentration of hydrogen peroxide in the peripheral blood of healthy volunteers and OSA subjects. We found that the serum concentration of hydrogen peroxide was considerably higher in OSA patients, and that this was closely related with the severity of OSA. Significantly shortened telomere length was observed in the circulating leukocytes of the peripheral blood of OSA patients, and telomere length shortening was aggravated more acutely in an age- and BMI-dependent manner. An inverse correlation was observed between the concentration of hydrogen peroxide and the telomere length of OSA patients and excessive telomere length shortening was also linked to severity of OSA. The results provided evidence that telomere length shortening or excessive cellular aging might be distinctive in circulating leukocyte of OSA patients and may be an predictive biomarker for reflect the burden of oxidative stress in the peripheral blood of OSA patients.

Recently developed classes of electronics for biomedical applications exploit substrates that offer low elastic modulus and high stretchability, to allow intimate, mechanically biocompatible integration with soft biological tissues. A challenge is that such substrates do not generally offer protection of the electronics from high peak strains that can occur upon large-scale deformation, thereby creating a potential for device failure. The results presented here establish a simple route to compliant substrates with strain-limiting mechanics based on approaches that complement those of recently described alternatives. Here, a thin film or mesh of a high modulus material transferred onto a prestrained compliant substrate transforms into wrinkled geometry upon release of the prestrain. The structure formed by this process offers a low elastic modulus at small strain due to the small effective stiffness of the wrinkled film or mesh; it has a high tangent modulus (e.g., >1000 times the elastic modulus) at large strain, as the wrinkles disappear and the film/mesh returns to a flat geometry. This bilinear stress-strain behavior has an extremely sharp transition point, defined by the magnitude of the prestrain. A theoretical model yields analytical expressions for the elastic and tangent moduli and the transition strain of the bilinear stress-strain relation, with quantitative correspondence to finite element analysis and experiments.

Foxp3(+) CD25(+)CD4(+) regulatory T (Treg) cells are crucial for the maintenance of immunological self-tolerance and are abundant in tumors. Most of these cells are chemo-attracted to tumor tissues and suppress anti-tumor responses inside the tumor. Currently, several cancer immunotherapies targeting Treg cells are being clinically tested. Cisplatin is one of the most potent chemotherapy drugs widely used for cancer treatment. While cisplatin is a powerful drug for the treatment of multiple cancers, there are obstacles that limit its use, such as renal dysfunction and the development of cisplatin-resistant cancer cells after its use. To minimize these barriers, combinatorial therapies of cisplatin with other drugs have been developed and have proven to be more effective to treat cancer. In the present study, we evaluated the eff ect of the combination therapy using methyl gallate with cisplatin in EL4 murine lymphoma bearing C57BL/6 mice. The combinatorial therapy of methyl gallate and cisplatin showed stronger anti-cancer eff ects than methyl gallate or cisplatin as single treatments. In Treg cell-depleted mice, however, the eff ect of methyl gallate vanished. It was found that methyl gallate treatment inhibited Treg cell migration into the tumor regardless of cisplatin treatment. Additionally, in both the normal and cisplatin-treated tumor-bearing mice, there was no renal toxicity attributed to methyl gallate treatment. These findings suggest that methyl gallate treatment could be useful as an adjuvant method accompanied with cisplatin therapy.

The aim of this study is to develop a new method to align the patient setup lasers in a radiation therapy treatment room and examine its validity and efficiency. The new laser alignment method is realized by a device composed of both a metallic base plate and a few acrylic transparent plates. Except one, every plate has either a crosshair line (CHL) or a single vertical line that is used for alignment. Two holders for radiochromic film insertion are prepared in the device to find a radiation isocenter. The right laser positions can be found optically by matching the shadows of all the CHLs in the gantry head and the device. The reproducibility, accuracy, and efficiency of laser alignment and the dependency on the position error of the light source were evaluated by comparing the means and the standard deviations of the measured laser positions. After the optical alignment of the lasers, the radiation isocenter was found by the gantry and collimator star shots, and then the lasers were translated parallel to the isocenter. In the laser position reproducibility test, the mean and standard deviation on the wall of treatment room were 32.3 ± 0.93 mm for the new method whereas they were 33.4 ± 1.49 mm for the conventional method. The mean alignment accuracy was 1.4 mm for the new method, and 2.1 mm for the conventional method on the walls. In the test of the dependency on the light source position error, the mean laser position was shifted just by a similar amount of the shift of the light source in the new method, but it was greatly magnified in the conventional method. In this study, a new laser alignment method was devised and evaluated successfully. The new method provided more accurate, more reproducible, and faster alignment of the lasers than the conventional method.

Hard and soft structural composites found in biology provide inspiration for the design of advanced synthetic materials. Many examples of bio-inspired hard materials can be found in the literature; far less attention has been devoted to soft systems. Here we introduce deterministic routes to low-modulus thin film materials with stress/strain responses that can be tailored precisely to match the non-linear properties of biological tissues, with application opportunities that range from soft biomedical devices to constructs for tissue engineering. The approach combines a low-modulus matrix with an open, stretchable network as a structural reinforcement that can yield classes of composites with a wide range of desired mechanical responses, including anisotropic, spatially heterogeneous, hierarchical and self-similar designs. Demonstrative application examples in thin, skin-mounted electrophysiological sensors with mechanics precisely matched to the human epidermis and in soft, hydrogel-based vehicles for triggered drug release suggest their broad potential uses in biomedical devices.