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When a severe medial wall defect is present in revision total hip arthroplasty (THA), simple bone grafting (BG) may not be sufficient, and trabecular metal (TM) augmentation is often necessary. We aimed to evaluate whether there were differences in outcomes of revision THA with medial wall defects depending on the use of TM augmentation. Between 2009-2021, 130 patients were classified into two groups: 80 patients undergoing bone grafting (BG group) and 50 patients undergoing both bone grafting and TM augmentation (BG/TM group). We evaluated the postoperative center of rotation (COR) position and changes in vertical and horizontal COR at last follow-up. Additionally, we categorized the fate of the transplanted bone graft into four groups: unchanged, initially changed, resorption-no further intervention, and resorption-revision. The mean horizontal COR changes were -3.50 mm in the BG group and -1.07 mm in the BG/TM group (p = 0.005). In the BG/TM group, a higher proportion of the patients showed unchanged or only initial changes when compared to the BG group (88.0% and 65.0%, respectively). The BG/TM group showed more favorable results regarding horizontal changes in the COR and fate of the bone graft. Therefore, for revision THA in patients with severe medial wall defects, the combined use of bone graft and TM augmentation can be a suitable option., (© 2024. The Author(s).)

The aim of this study was to evaluate safety and efficacy of a poly-L-lactic acid (PLLA)-coated magnesium (Mg)-Dysprosium (Dy) membrane in guided bone regeneration (GBR) using a rabbit calvarium model. The microstructure of the Mg-Dy membrane surface and thickness of the PLLA coating were examined. In vitro degradation and cytotoxicity test was conducted. The in vivo study used 24 white male rabbits with two 8 mm-diameter defects created on the calvaria; 12 defects were randomly assigned per group: (1) Negative control, (2) positive control, (3) uncoated Mg, and (4) PLLA-coated Mg group. Specimens were harvested at 4, 8, and 12 weeks postoperatively for radiological, histological, and histomorphometric analyses. The PLLA-coated Mg-Dy membrane showed a low degree of degradation, indicating that the coating exerted a protective effect. In the cytotoxicity test, no deformed or degenerated cells were observed. In the in vivo study, radiographic and histomorphometric analyses indicated favorable new bone formation and maintenance of the graft material for PLLA-coated Mg group. PLLA-coated Mg group, compared to the uncoated counterpart, restored the bony contour more completely, without inducing significant inflammatory response. Our results support the safety and efficacy of PLLA-coated Mg-Dy membranes for GBR both in vitro and in vivo., (© 2024. The Author(s).)

The rapid response system (RRS) is associated with a reduction in in-hospital mortality. This study aimed to determine the characteristics and outcomes of patients transferred to the intensive care unit (ICU) by a rapid response team (RRT). This retrospective, multicenter cohort study included patients from nine hospitals in South Korea. Adult patients who were admitted to the general ward (GW) and required RRS activation were included. Patients with do-not-resuscitate orders and without lactate level or Sequential Organ Failure Assessment score were excluded. A total of 8228 patients were enrolled, 3379 were transferred to the ICU. The most common reasons for RRT activation were respiratory distress, sepsis and septic shock. The number of patients who underwent interventions, the length of hospital stays, 28-day mortality, and in-hospital mortality were higher in the ICU group than in the GW group. Factors that could affect both 28-day and in-hospital mortality included the severity score, low PaO 2 /FiO 2 ratio, higher lactate and C-reactive protein levels, and hospitalization time prior to RRT activation. Patients admitted to the ICU after RRT activation generally face more challenging clinical situations, which may affect their survival outcomes., (© 2024. The Author(s).)

The White Blood Cell (WBC) differential test ranks as the second most frequently performed diagnostic assay. It requires manual confirmation of the peripheral blood smear by experts to identify signs of abnormalities. Automated digital microscopy has emerged as a solution to reduce this labor-intensive process and improve efficiency. Several publicly available datasets provide various WBC subtypes of differing quality and resolution. These datasets have contributed to advancing WBC classification using machine learning techniques. However, digital microscopy of blood cells with high magnification often requires a wider depth of field, posing challenges for automatic digital microscopy that necessitates capturing multiple stacks of focal planes to obtain complete images of specific blood cells. Our dataset provides 25,773 image stacks from 72 patients. The image labels consist of 18 classes encompassing normal and abnormal cells, with two experts reviewing each label. Each image includes 10 z-stacks of cropped 200 by 200 pixel images, captured using a 50X microscope with 400 nm intervals. This study presents a comprehensive multi-focus dataset for WBC classification., (© 2024. The Author(s).)

Neuromorphic computing research is being actively pursued to address the challenges posed by the need for energy-efficient processing of big data. One of the promising approaches to tackle the challenges is the hardware implementation of spiking neural networks (SNNs) with bio-plausible learning rules. Numerous research works have been done to implement the SNN hardware with different synaptic plasticity rules to emulate human brain operations. While a standard spike-timing-dependent-plasticity (STDP) rule is emulated in many SNN hardware, the various STDP rules found in the biological brain have rarely been implemented in hardware. This study proposes a CMOS-memristor hybrid synapse circuit for the hardware implementation of a Ca ion-based plasticity model to emulate the various STDP curves. The memristor was adopted as a memory device in the CMOS synapse circuit because memristors have been identified as promising candidates for analog non-volatile memory devices in terms of energy efficiency and scalability. The circuit design was divided into four sub-blocks based on biological behavior, exploiting the non-volatile and analog state properties of memristors. The circuit was designed to vary weights using an H-bridge circuit structure and PWM modulation. The various STDP curves have been emulated in one CMOS-memristor hybrid circuit, and furthermore a simple neural network operation was demonstrated for associative learning such as Pavlovian conditioning. The proposed circuit is expected to facilitate large-scale operations for neuromorphic computing through its scale-up., (© 2024. The Author(s).)

There is limited evidence regarding the causal inference of emphysema and functional small airway disease in the subsequent progression of chronic obstructive pulmonary disease (COPD). Patients consisting of two independent cohorts diagnosed with COPD and underwent two serial chest CT scans were included. Total percent emphysema (PRM Emph ) and fSAD (PRM fSAD ) was quantified via PRM. To investigate the progression of emphysema, we divided COPD patients with PRM Emph  < 10% into low and high PRM fSAD group, matched with similar baseline characteristics, and conducted nonparametric hypothesis tests based on randomization inference using Wilcoxon signed rank test and Huber's M statistics. In patients with baseline PRMEmph < 10%, there were 26 and 16 patients in the low PRM fSA group and 52 and 64 patients in the high PRM fSA in the derivation and validation cohorts, respectively. In the both low and high PRM fSAD  groups, there were 0.11 and 1.43 percentage point increases (Huber's M statistic p = 0.016) and 0.58 and 2.09 percentage point increases (p = 0.038) in the proportion of emphysema in the derivation and validation cohorts, respectively. On the contrary, among patients with baseline PRM fSAD  < 20%, there was no significant differences in the interval changes of PRM fSAD between the low and high PRM Emph groups in both cohorts. In COPD patients with low emphysema, group with baseline high PRM fSAD showed greater change of PRM Emph than those with low PRM fSAD in both the derivation and validation cohorts. Imaging-based longitudinal quantitative analysis may provide important evidence that small airway disease precedes emphysema in CT-based early COPD patients., (© 2024. The Author(s).)

This article presents the design and implementation of a dipole array antenna based on a radial waveguide power divider for millimeter-wave IoT sensing applications. The dipole array and radial waveguide power divider techniques are used in tandem to achieve high gain with omnidirectional radiation properties. The proposed antenna is comprised of eight non-uniform array dipole structures, a circular radiating loop, and shorting vias. The one-to-eight power divider is created with the shorting vias to feed the circularly arranged eight non-uniform dipole arrays simultaneously. The proposed antenna is simulated and manufactured on Rogers-RO3003C substrate with a thickness of 8 mils. Both simulated and tested results confirm that the proposed method enables the antenna to offer a quasi-omnidirectional pattern with a high peak gain of 5.42 dBi. The antenna offers an impedance bandwidth (S 11  < ‒ 10 dB) of more than 1 GHz ranging from 27.93 to 29.13 GHz. Moreover, by optimizing the parameters of the power divider network the proposed antenna can be tuned between a wide bandwidth range of 14.53 GHz as the designed dipole array offering the operating bandwidth from 25.56 to 40.09 GHz. Due to its comprehensive set of performance attributes, particularly for the quasi-omnidirectional radiation characteristics, the presented antenna is a viable candidate for the 5G millimeter wave wireless IoT sensing applications. Additionally, this work will accommodate other researchers to explore the proposed method for developing high-gain omnidirectional antennas for millimeter-wave applications., (© 2024. The Author(s).)

Nucleic acid amplification testing has great potential for point-of-need diagnostic testing with high detection sensitivity and specificity. Current sample preparation is limited by a tedious workflow requiring multiple steps, reagents and instrumentation, hampering nucleic acid testing at point of need. In this study, we present the use of mixed cellulose ester (MCE) paper for DNA binding by ionic interaction under molecular crowding conditions and fluid transport by wicking. The poly(ethylene) glycol-based (PEG) reagent simultaneously provides the high pH for alkaline lysis and crowding effects for ionic binding of the DNA under high salt conditions. In this study, we introduce Paper-based Abridged Solid-Phase Extraction with Alkaline Poly(ethylene) Glycol Lysis (PASAP). The anionic mixed cellulose ester (MCE) paper is used as solid phase and allows for fluid transport by wicking, eliminating the need for pipetting skills and the use of a magnet to retain beads. Following the release of DNA from the cells due to the lytic activity of the PASAP solution, the DNA binds to the anionic surface of the MCE paper, concentrating at the bottom while the sample matrix is transported towards the top by wicking. The paper was washed by dipping it in 40% isopropanol for 10 s. After air-drying for 30 s, the bottom section of the paper (3 mm × 4 mm) was snapped off using the cap of a PCR tube and immersed in the colourimetric loop-mediated isothermal amplification (cLAMP) solution for direct amplification and colourimetric detection. The total sample processing was completed in 15 min and ready for amplification. cLAMP enabled the detection of 10 2 CFU/mL of Escherichia coli (E. coli) from culture media and the detection of E. coli in milk < 10 3  CFU/mL (10 CFU) after incubation at 68 °C for 60 min, demonstrating applicability of the method to complex biological samples., (© 2024. The Author(s).)

HER2 amplification-associated molecular alterations and clinicopathologic features in colorectal cancers (CRCs) have not been well established. In this study, we assessed the prevalence of HER2 amplification and microsatellite instability (MSI) status of 992 patients with primary CRC. In addition, molecular alterations of HER2 amplified and unamplified CRCs were examined and compared by next-generation sequencing. HER2 amplifications were found in 41 (4.1%) of 992 primary CRCs. HER2 amplification was identified in 1.0% of the right colonic tumors, 5.1% of the left colonic tumors, and 4.8% of the rectal tumors. Approximately 95% of HER2 amplification was observed in the left colon and rectum. Seven (87.5%) of eight metastatic tumors showed HER2 amplification. Most clinicopathologic features were unrelated to HER2 amplification except tumor size and MSI status. All 41 HER2 amplified CRCs were microsatellite stable. In a molecular analysis of frequently identified somatic mutations in CRCs, HER2 amplified CRCs showed a lower rate of KRAS mutations (24.4%) but a higher rate of TP53 mutations (83%) than unamplified CRCs. No BRAF and NRAS mutations were identified in HER2 amplified CRCs. Our study suggests that HER2 amplified CRCs are mutually exclusive of MSI and harbor less frequent KRAS/NRAS/BRAF mutations but frequent T53 mutations., (© 2024. The Author(s).)

Skeletal muscle aging results in the gradual suppression of myogenesis, leading to muscle mass loss. However, the specific role of cardiolipin in myogenesis has not been determined. This study investigated the crucial role of mitochondrial cardiolipin and cardiolipin synthase 1 (Crls1) in age-related muscle deterioration and myogenesis. Our findings demonstrated that cardiolipin and Crls1 are downregulated in aged skeletal muscle. Moreover, the knockdown of Crls1 in myoblasts reduced mitochondrial mass, activity, and OXPHOS complex IV expression and disrupted the structure of the mitochondrial cristae. AAV9-shCrls1-mediated downregulation of Crls1 impaired muscle regeneration in a mouse model of cardiotoxin (CTX)-induced muscle damage, whereas AAV9-mCrls1-mediated Crls1 overexpression improved regeneration. Overall, our results highlight that the age-dependent decrease in CRLS1 expression contributes to muscle loss by diminishing mitochondrial quality in skeletal muscle myoblasts. Hence, modulating CRLS1 expression is a promising therapeutic strategy for mitigating muscle deterioration associated with aging, suggesting potential avenues for developing interventions to improve overall muscle health and quality of life in elderly individuals., (© 2024. The Author(s).)

Recent studies reported the long-term cardiovascular risk of preeclampsia. However, only a few studies have investigated the association between preeclampsia and long-term cardiovascular disease in Asian populations, although there could be racial/ethnic differences in the risk of cardiovascular diseases. Therefore, we aimed to evaluate the long-term effects of preeclampsia on cardiovascular disease in an Asian population. This study included 68,658 parous women in the Health Examinees Study (HEXA) cohort of South Korea and compared the risk of long-term cardiovascular disease, including ischemic heart disease and stroke, according to the history of preeclampsia. We also performed a meta-analysis combining current study data with data from existing literature in the Asian population. Among the study population, 3413 (5.23%) women had a history of preeclampsia, and 767 (1.12%) and 404 (0.59%) women developed ischemic heart disease and stroke for 22 years. Women with a history of preeclampsia were at a higher risk for both ischemic heart disease (adjusted hazard ratio 1.66 [1.19-2.04]) and stroke (adjusted hazard ratio 1.48 [1.02-2.16]) than those without. In the meta-analysis, the pooled hazard ratio of ischemic heart disease and stroke were also increased in women with a history of preeclampsia (ischemic heart disease 1.65 [1.51-1.82]; stroke 1.78 [1.52-2.10])., (© 2024. The Author(s).)

The aim of our study was to assess the performance of content-based image retrieval (CBIR) for similar chest computed tomography (CT) in obstructive lung disease. This retrospective study included patients with obstructive lung disease who underwent volumetric chest CT scans. The CBIR database included 600 chest CT scans from 541 patients. To assess the system performance, follow-up chest CT scans of 50 patients were evaluated as query cases, which showed the stability of the CT findings between baseline and follow-up chest CT, as confirmed by thoracic radiologists. The CBIR system retrieved the top five similar CT scans for each query case from the database by quantifying and comparing emphysema extent and size, airway wall thickness, and peripheral pulmonary vasculatures in descending order from the database. The rates of retrieval of the same pairs of query CT scans in the top 1-5 retrievals were assessed. Two expert chest radiologists evaluated the visual similarities between the query and retrieved CT scans using a five-point scale grading system. The rates of retrieving the same pairs of query CTs were 60.0% (30/50) and 68.0% (34/50) for top-three and top-five retrievals. Radiologists rated 64.8% (95% confidence interval 58.8-70.4) of the retrieved CT scans with a visual similarity score of four or five and at least one case scored five points in 74% (74/100) of all query cases. The proposed CBIR system for obstructive lung disease integrating quantitative CT measures demonstrated potential for retrieving chest CT scans with similar imaging phenotypes. Further refinement and validation in this field would be valuable., (© 2024. The Author(s).)

Despite advances in obstetric care, hypoxic ischemic encephalopathy (HIE) remains a significant disease burden. We determined the national trends of HIE prevalence, therapeutic hypothermia (TH) use, mortality, and outcomes from 2012 to 2019. This study included term infants diagnosed with HIE between 2012 and 2019 from the National Health Insurance Service database. The prevalence of HIE was 2.4 per 1000 births without significant change during the period. TH was performed in approximately 6.7% of infants with HIE, and the annual variation ranged from 2.4 to 12.5%. The mortality among all term infants with HIE was 4.6%. The mortality rate among infants with HIE and TH significantly declined from 40 to 16.9% during the eight years. Infants with TH had higher mortality, increased use of inhaled nitric oxide, and more invasive ventilator use, indicating greater disease severity in the TH group. Infants with TH also showed significantly poorer outcomes, including delayed development, cerebral palsy, sensorineural hearing loss, and seizure, compared to infants without TH (p < 0.0001). With the increasing application of TH, mortality and developmental outcomes among infants with HIE have been improving in the past eight years in Korea. Further efforts to improve outcomes should be needed., (© 2024. The Author(s).)

The use of a large femoral head in total hip arthroplasty (THA) to stabilize and reduce the incidence of dislocation is on the increase, but concerns arise when combining them with small acetabular components due to potential mechanical failures in thin polyethylene (PE) liners. A single-institution, retrospective cohort study was conducted on 116 patients with minimum 2-year follow-up who received 36-mm femoral heads and acetabular components ≤ 52 mm, using either remelted highly cross-linked polyethylene (remelted HXLPE) or vitamin E-infused HXLPE (VEPE). Osteolysis and implant loosening were not observed in either group. Although a fracture of the PE liner was observed in each group (1.7%), the clinical outcomes were excellent, as the mean modified Harris Hip Score (mHHS) at the last follow-up was 93.5. Moreover, the mean linear wear rates measured by digital imaging software in both groups were low, with 0.035 mm/y in remelted HXLPE and 0.030 mm/y in VEPE. In conclusion, The use of a large femoral head on a thin PE liner can be a viable treatment option in patients who need to prioritize stability; however, careful attention should be paid to mechanical fractures of the PE liner., (© 2023. The Author(s).)

Coats' disease is an idiopathic retinal vascular disorder, known to usually occur unilaterally; however, recent studies have highlighted vascular abnormalities in the fellow unaffected eyes. This retrospective study investigated the peripheral vascular features and macular vascular structure of unaffected fellow eyes in patients with unilateral Coats' disease using multimodal imaging tools. We analysed images of patients, including bilateral ultra-widefield imaging, fluorescein angiography (FA), ultra-widefield FA, or standard fundus photography. Available bilateral optical coherence tomography angiography (OCT-A) images were used for macular vascular structure analysis. OCT-A parameters, including foveal avascular zone (FAZ), perfusion index, and vessel density (VD) in the superficial and deep capillary plexuses (SCP, DCP), were calculated using Image J software. The mean age at diagnosis was 34.5 ± 17.9 years. The mean final best-corrected visual acuity of the affected eyes was logMAR 0.78 ± 0.79, while that of the fellow eyes was logMAR 0.04 ± 0.12. Ten fellow eyes had microaneurysms (47.6%), two had tortuous vessel abnormalities (9.5%), and 11(52.4%) had abnormal vascular findings on FA. Although there was a trend towards larger DCP FAZ (1.201 ± 0.086 vs. 1.072 ± 0.226), and lower DCP VD (8.593 ± 1.583 vs. 10.827 ± 3.392) in the affected eyes as measured by the Cirrus machine, the difference was not statistically significant between affected and fellow eyes when measured using the Zeiss Cirrus machine (P = 0.686, P = 0.343, respectively). However, when measured with the Spectralis machine, DCP FAZ was larger in affected eyes (0.828 ± 0.426 vs. 0.254 ± 0.092, P = 0.002) and DCP VD was lower in affected eyes (6.901 ± 2.634 vs. 17.451 ± 7.207, P = 0.002) compared to the fellow eyes, while other parameters showed no significant variations. These findings indicate that there may be subtle vascular abnormalities primarily located in the peripheral regions of the unaffected fellow eyes in patients with unilateral Coats' disease, while the macular microvasculature remains unaffected., (© 2023. The Author(s).)

Complement-dependent cytotoxicity (CDC), which eliminates aberrant target cells through the assembly and complex formation of serum complement molecules, is one of the major effector functions of anticancer therapeutic antibodies. In this study, we discovered that breaking the symmetry of natural immunoglobulin G (IgG) antibodies significantly increased the CDC activity of anti-CD20 antibodies. In addition, the expression of CD55 (a checkpoint inhibitor in the CDC cascade) was significantly increased in a rituximab-resistant cell line generated in-house, suggesting that CD55 overexpression might be a mechanism by which cancer cells acquire rituximab resistance. Based on these findings, we developed an asymmetric bispecific antibody (SBU-CD55 × CD20) that simultaneously targets both CD55 and CD20 to effectively eliminate rituximab-resistant cancer cells. In various cancer cell lines, including rituximab-resistant lymphoma cells, the SBU-CD55 × CD20 antibody showed significantly higher CDC activity than either anti-CD20 IgG antibody alone or a combination of anti-CD20 IgG antibody and anti-CD55 IgG antibody. Furthermore, the asymmetric bispecific antibody (SBU-CD55 × CD20) exhibited significantly higher CDC activity against rituximab-resistant cancer cells compared to other bispecific antibodies with symmetric features. These results demonstrate that enhancing CDC with an asymmetric CD55-binding bispecific antibody could be a new strategy for developing therapeutics to treat patients with relapsed or refractory cancers., (© 2023. Springer Nature Limited.)

Despite recent progress in medical and endovascular therapy, the prognosis for patients with critical limb ischemia (CLI) remains poor. In response, various stem cells and growth factors have been assessed for use in therapeutic neovascularization and limb salvage in CLI patients. However, the clinical outcomes of cell-based therapeutic angiogenesis have not provided the promised benefits, reinforcing the need for novel cell-based therapeutic angiogenic strategies to cure untreatable CLI. In the present study, we investigated genetically engineered mesenchymal stem cells (MSCs) derived from human bone marrow that continuously secrete stromal-derived factor-1α (SDF1α-eMSCs) and demonstrated that intramuscular injection of SDF1α-eMSCs can provide long-term paracrine effects in limb ischemia and effectively contribute to vascular regeneration as well as skeletal muscle repair through increased phosphorylation of ERK and Akt within the SDF1α/CXCR4 axis. These results provide compelling evidence that genetically engineered MSCs with SDF-1α can be an effective strategy for successful limb salvage in limb ischemia., (© 2023. The Author(s).)

In this study, the potential of Chlorella sorokiniana JD1-1 for biodiesel production was evaluated using domestic wastewater (DWW) as a diluent for locally-generated livestock wastewater (LWW). This strategy aimed to provide sustainable wastewater treatment, reduce environmental impacts, enhance cost-effectiveness, and promote biodiesel production. LWW was diluted with tap water and DWW at ratios of 75%, 50%, and 25% (v/v), and the effects on microalgal growth, nutrient removal efficiency, and lipid yield were evaluated. Although the maximum biomass concentration was observed in the artificial growth medium (BG-11) (1170 mg L -1 ), 75% dilution using tap water (610 mg L -1 ) and DWW (780 mg L -1 ) yielded results comparable to the exclusive use of DWW (820 mg L -1 ), suggesting a potential for substitution. Total nitrogen (TN) removal rates were consistently high under all conditions, particularly in samples with higher concentrations of LWW. Conversely, total phosphorus (TP) concentrations decreased under most conditions, although some displayed large increases. Further studies are necessary to optimize the nutrient balance while maintaining economic feasibility and maximizing biodiesel production., (© 2023. Springer Nature Limited.)

The number of non-accidental deaths and heat-related illnesses due to the co-occurrence of heatwaves and COVID-19 has been identified to estimate compound health impacts between two risks. We have analyzed data from historical years (2013-2019) to calculate the baseline values of the number of non-accidental deaths and heat-related illness patients from May to September using a quasi-Poisson generalized linear model and compared them to data from 2020 in Korea. We also assessed the relative risk and absolute cumulative number of non-accidental deaths and heat-related illnesses in the summer of 2020 in Seoul, Daegu, and Gyeongnam region of Korea. In the Summer of 2020, Korea experienced 0.8% of non-accidental excess deaths, with the highest in August, and 46% of reduction was observed in heat-related throughout the study period, except in Daegu, where excess of heat-related illness occurred in August. The relative risk (RR) of non-accidental deaths at 33.1 °C, was 1.00 (CI 0.99-1.01) and 1.04 (CI 1.02-1.07) in 2013-2019 and 2020, respectively. The RR of heat-related illness at 33.1 °C, was 1.44 (CI 1.42-1.45) and 1.59 (CI 1.54-1.64) in 2013-2019 and 2020, respectively. The absolute cumulative trends of non-accidental deaths and heat-related illnesses were similar in the three regions, indicating increased non-accidental deaths and decreased heat-related illnesses at similar temperatures in 2020. During the COVID-19 pandemic, the fear of infection by the virus and the limited access to healthcare services led to changes in health-seeking behaviors. These results indicate social distancing could have had adverse impacts on other health conditions. A comprehensive health risk assessment is important when facing simultaneous risks, such as heatwaves and pandemics, in the implementation of effective countermeasures., (© 2023. Springer Nature Limited.)

Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising modality for anti-cancer treatment. Its efficacy is quite remarkable in hematological tumors. Owing to their excellent clinical results, gene- modified cell therapies, including T cells, natural killer (NK) cells, and macrophages, are being actively studied in both academia and industry. However, the protocol to make CAR immune cells is too complicated, so it is still unclear how to efficiently produce the potent CAR immune cells. To manufacture effective CAR immune cells, we need to be aware of not only how to obtain highly infective viral particles, but also how to transduce CAR genes into immune cells. In this paper, we provide detailed information on spinoculation, which is one of the best known protocols to transduce genes into immune cells, in a methodological view. Our data indicate that gene transduction is significantly dependent on speed and duration of centrifugation, concentration and number of viral particles, the concentration of polybrene, and number of infected immune cells. In addition, we investigated on the optimal polyethylene glycol (PEG) solution to concentrate the viral supernatant and the optimized DNA ratios transfected into 293T cells to produce high titer of viral particles. This study provides useful information for practical production of the gene-modified immune cells using viral vectors., (© 2023. The Author(s).)

Patients with cancer are at increased risk of hospitalisation and mortality following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the SARS-CoV-2 phenotype evolution in patients with cancer since 2020 has not previously been described. We therefore evaluated SARS-CoV-2 on a UK populationscale from 01/11/2020-31/08/2022, assessing case-outcome rates of hospital assessment(s), intensive care admission and mortality. We observed that the SARS-CoV-2 disease phenotype has become less severe in patients with cancer and the non-cancer population. Case-hospitalisation rates for patients with cancer dropped from 30.58% in early 2021 to 7.45% in 2022 while case-mortality rates decreased from 20.53% to 3.25%. However, the risk of hospitalisation and mortality remains 2.10x and 2.54x higher in patients with cancer, respectively. Overall, the SARS-CoV-2 disease phenotype is less severe in 2022 compared to 2020 but patients with cancer remain at higher risk than the non-cancer population. Patients with cancer must therefore be empowered to live more normal lives, to see loved ones and families, while also being safeguarded with expanded measures to reduce the risk of transmission., (© 2023. The Author(s).)

Several programs are widely used for clinical and research purposes to automatically quantify the degree of amyloid deposition in the brain using positron emission tomography (PET) images. Given that very few studies have investigated the use of Heuron, a PET image quantification software approved for clinical use, this study aimed to compare amyloid deposition values quantified from 18 F-flutemetamol PET images using PMOD and Heuron. Amyloid PET data obtained from 408 patients were analysed using each quantitative program; moreover, the standardized uptake value ratios (SUVRs) of target areas were obtained by dividing the standardized uptake value (SUV) of the target region by the SUV of cerebellar grey matter as a reference. Compared with PMOD, Heuron yielded significantly higher SUVRs for all target areas (paired sample t-test, p < 0.001), except for the PC/PCC (p = 0.986). However, the Bland-Altman plot analysis indicated that the two quantitative methods may be used interchangeably. Moreover, receiver operating characteristic curve analysis revealed no significant between-method difference in the performance of the SUVRs in evaluating the visual positivity of amyloid deposits (p = 0.948). In conclusion, Heuron and PMOD have comparable performance in quantifying the degree of amyloid deposits in PET images., (© 2023. The Author(s).)

Peptides exhibit lower affinity and a shorter half-life in the body than antibodies. Conversely, peptides demonstrate higher efficiency in tissue penetration and cell internalization than antibodies. Regardless of the pros and cons of peptides, they have been used as tumor-homing ligands for delivering carriers (such as nanoparticles, extracellular vesicles, and cells) and cargoes (such as cytotoxic peptides and radioisotopes) to tumors. Additionally, tumor-homing peptides have been conjugated with cargoes such as small-molecule or chemotherapeutic drugs via linkers to synthesize peptide-drug conjugates. In addition, peptides selectively bind to cell surface receptors and proteins, such as immune checkpoints, receptor kinases, and hormone receptors, subsequently blocking their biological activity or serving as hormone analogs. Furthermore, peptides internalized into cells bind to intracellular proteins and interfere with protein-protein interactions. Thus, peptides demonstrate great application potential as multifunctional players in cancer therapy., (© 2023. The Author(s).)

Severe fever with thrombocytopenia syndrome virus was first discovered in 2009 as the causative agent of severe fever with thrombocytopenia syndrome. Despite its potential threat to public health, no prophylactic vaccine is yet available. This study developed a heterologous prime-boost strategy comprising priming with recombinant replication-deficient human adenovirus type 5 (rAd5) expressing the surface glycoprotein, Gn, and boosting with Gn protein. This vaccination regimen induced balanced Th1/Th2 immune responses and resulted in potent humoral and T cell-mediated responses in mice. It elicited high neutralizing antibody titers in both mice and non-human primates. Transcriptome analysis revealed that rAd5 and Gn proteins induced adaptive and innate immune pathways, respectively. This study provides immunological and mechanistic insight into this heterologous regimen and paves the way for future strategies against emerging infectious diseases., (© 2023. The Author(s).)

In patients with sepsis, outcome prediction plays an important role in influencing therapeutic decision making. In this nationwide, prospective, observational cohort study of sepsis patients conducted between September 2019 and December 2020, we evaluated a novel scoring system using serial Sequential Organ Failure Assessment (SOFA) scores and serum lactate to accurately predict mortality in sepsis. Based on the serum lactate score (Lac-score), patients were assigned to 5 categories: lactate < 2, ≥ 2 to < 4, ≥ 4 to < 8, ≥ 8 to < 12, and ≥ 12 mmol/L. Lac-SOFA score was defined as the sum of Lac-score and SOFA score. After screening 7113 patients, 379 were excluded and 6734 were included in analysis. In-hospital mortality AUROC for serial Lac-SOFA score from initial to ICU day 3 was significantly higher than that for serial SOFA score (initial, 0.679 vs. 0.656, day 1, 0.723 vs. 0.709, day 2, 0.760 vs. 0.747, and day 3, 0.797 vs. 0.781; DeLong's test, p < 0.001). The initial Lac-SOFA score significantly correlated with in-hospital mortality when the patients were divided into five classes based on 5-point intervals (p < 0.05). Serial evaluation of lactate levels with the SOFA score may improve the predictive accuracy of the SOFA score for determining mortality risk in sepsis patients., (© 2023. The Author(s).)

Transcranial focused ultrasound stimulation is a promising therapeutic modality for human brain disorders because of its noninvasiveness, long penetration depth, and versatile spatial control capability through beamforming and beam steering. However, the skull presents a major hurdle for successful applications of ultrasound stimulation. Specifically, skull-induced focal aberration limits the capability for accurate and versatile targeting of brain subregions. In addition, there lacks a fully functional preclinical neuromodulation system suitable to conduct behavioral studies. Here, we report a miniature ultrasound system for neuromodulation applications that is capable of highly accurate multiregion targeting based on acoustic holography. Our work includes the design and implementation of an acoustic lens for targeting brain regions with compensation for skull aberration through time-reversal recording and a phase conjugation mirror. Moreover, we utilize MEMS and 3D-printing technology to implement a 0.75-g lightweight neuromodulation system and present in vivo characterization of the packaged system in freely moving mice. This preclinical system is capable of accurately targeting the desired individual or multitude of brain regions, which will enable versatile and explorative behavior studies using ultrasound neuromodulation to facilitate widespread clinical adoption., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2023.)

Metastatic disease is responsible for the majority of cancer-related deaths 1 . We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse., (© 2023. The Author(s).)

Lung cancer is the leading cause of cancer-associated mortality worldwide 1 . Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource., (© 2023. The Author(s).)

The DAMA/LIBRA collaboration has reported the observation of an annual modulation in the event rate that has been attributed to dark matter interactions over the last two decades. However, even though tremendous efforts to detect similar dark matter interactions were pursued, no definitive evidence has been observed to corroborate the DAMA/LIBRA signal. Many studies assuming various dark matter models have attempted to reconcile DAMA/LIBRA's modulation signals and null results from other experiments, however no clear conclusion can be drawn. Apart from the dark matter hypothesis, several studies have examined the possibility that the modulation is induced by variations in detector's environment or their specific analysis methods. In particular, a recent study presents a possible cause of the annual modulation from an analysis method adopted by the DAMA/LIBRA experiment in which the observed annual modulation could be reproduced by a slowly varying time-dependent background. Here, we study the COSINE-100 data using an analysis method similar to the one adopted by the DAMA/LIBRA experiment and observe a significant annual modulation, however the modulation phase is almost opposite to that of the DAMA/LIBRA data. Assuming the same background composition for COSINE-100 and DAMA/LIBRA, simulated experiments for the DAMA/LIBRA without dark matter signals also provide significant annual modulation with an amplitude similar to DAMA/LIBRA with opposite phase. Even though this observation does not directly explain the DAMA/LIBRA results directly, this interesting phenomenon motivates more profound studies of the time-dependent DAMA/LIBRA background data., (© 2023. The Author(s).)

Objective: To identify racial/ethnic disparities in postnatal growth by year and gestational age among very low birth weight infants., Study Design: Total 37,122 infants, with birth weight 500-1500 g or gestational age 23-34 weeks in the California Perinatal Quality Care Collaborative in 2008-2016. Postnatal growth failure (PGF) was defined as change in weight Z-score from birth to discharge below -1.28. Multivariable regression analysis with birth hospital as random effect was used to estimate odds ratios (OR)., Results: Infants born to Hispanic mothers had highest risk of PGF at 30%, compared to white (24%, OR 1.33), Black (22%, OR 1.50), or Asian/Pacific Islander mothers (23%, OR 1.38). PGF incidence decreased from 2008 (27.4%) to 2016 (22.8%) with differences in trends by race. Each increasing gestational age week was associated with decreasing risk for PGF (OR 0.73, 95% confidence interval 0.72-0.74)., Conclusion: Targeted interventions addressing PGF are needed to address disparities., (© 2023. The Author(s).)

T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells 1-3 . Here we developed a clinical-grade approach based on CRISPR-Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRβ). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial ( NCT03970382 ). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated., (© 2022. The Author(s).)

An increasing number of chronic renal failure patients are experiencing hip joint disorders. This study aimed to analyze the outcomes of hip arthroplasty in chronic renal failure patients undergoing dialysis. Of 2364 hips that underwent hip arthroplasty during 2003-2017, 37 were retrospectively examined. Radiological and clinical outcomes of hip arthroplasty, and development of local and general complications during follow-up and their associations with dialysis duration were analyzed. The mean patient age, follow-up duration, and bone mineral density T-score were 60.6 years, 36.6 months, and - 2.62, respectively. Osteoporosis was noted in 20 cases. Most patients who underwent total hip arthroplasty with a cementless acetabular cup implant exhibited excellent radiological outcomes. There were no changes in femoral stem alignment, subsidence, osteolysis, and loosening. Thirty-three patients had an excellent or good Harris hip score. Complications developed in 18 patients within 1 year postoperatively. General complications developed in 12 patients at > 1 year postoperatively; no patient experienced local complications. In conclusion, hip arthroplasty for chronic renal failure patients on dialysis yielded excellent radiological and satisfactory clinical outcomes but may be associated with postoperative complications. Careful preoperative treatment planning and overall postoperative management are required to reduce the complication risk., (© 2023. The Author(s).)

Low dose and accessibility have increased the application of cone beam computed tomography (CBCT). Often serial images are captured for patients to diagnose and plan treatment in the craniofacial region. However, CBCT images are highly variable and lack harmonious reproduction, especially in the head's orientation. Though user-defined orientation methods have been suggested, the reproducibility remains controversial. Here, we propose a landmark-free reorientation methodology based on principal component analysis (PCA) for harmonious orientation of serially captured CBCTs. We analyzed three serial CBCT scans collected for 29 individuals who underwent orthognathic surgery. We first defined a region of interest with the proposed protocol by combining 2D rendering and 3D convex hull method, and identified an intermediary arrangement point. PCA identified the y-axis (anterioposterior) followed by the secondary x-axis (transverse). Finally, by defining the perpendicular z-axis, a new global orientation was assigned. The goodness of alignment (Hausdorff distance) showed a marked improvement (> 50%). Furthermore, we clustered cases based on clinical asymmetry and validated that the protocol was unaffected by the severity of the skeletal deformity. Therefore, it could be suggested that integrating the proposed algorithm as the preliminary step in CBCT evaluation will address a fundamental step towards harmonizing the craniofacial imaging records., (© 2023. The Author(s).)

The generative adversarial network (GAN) is a promising deep learning method for generating images. We evaluated the generation of highly realistic and high-resolution chest radiographs (CXRs) using progressive growing GAN (PGGAN). We trained two PGGAN models using normal and abnormal CXRs, solely relying on normal CXRs to demonstrate the quality of synthetic CXRs that were 1000 × 1000 pixels in size. Image Turing tests were evaluated by six radiologists in a binary fashion using two independent validation sets to judge the authenticity of each CXR, with a mean accuracy of 67.42% and 69.92% for the first and second trials, respectively. Inter-reader agreements were poor for the first (κ = 0.10) and second (κ = 0.14) Turing tests. Additionally, a convolutional neural network (CNN) was used to classify normal or abnormal CXR using only real images and/or synthetic images mixed datasets. The accuracy of the CNN model trained using a mixed dataset of synthetic and real data was 93.3%, compared to 91.0% for the model built using only the real data. PGGAN was able to generate CXRs that were identical to real CXRs, and this showed promise to overcome imbalances between classes in CNN training., (© 2023. The Author(s).)

The wild boar (Sus scrofa), a polygynous species, rapidly expanded its geographical range and increased its population size in South Korea following the extinction of large carnivores and changes to rural environments. Understanding wild boar reproductive traits and strategies is essential for their effective management; however, studies in this area are lacking. Using samples collected from hunting bags, the relationships between 1) litter size and female weight and 2) fetal sex ratio and female body condition were examined to understand wild boar life-history strategies. Wild boars showed a seasonal breeding pattern that maximized reproduction. Litter size (mean = 5.7 ± 1.7) was correlated with female weight, whereas fetal sex ratio was not explained by female body condition. However, the heaviest ranked fetuses within the litters were male-biased. Wild boars aged three years or less accounted for 90% of the total population, and sexual dimorphism developed from two years of age. Considering that their reproductive strategy is more effective (i.e., early gestation and large litter size) than that of other polygynous species, the Trivers-Willard model was not supported for the wild boars in this study. Instead, females adjusted the sex of the heaviest fetus in the litter to maximize lifetime reproductive success., (© 2022. The Author(s).)

Skeletal muscle communicates with other organs via myokines, which are secreted by muscle during exercise and exert various effects. Despite much investigation of the exercise, the underlying molecular mechanisms are still not fully understood. Here, we applied an in vitro exercise model in which cultured C2C12 myotubes were subjected to electrical pulse stimulation (EPS), which mimics contracting muscle. Based on the significantly up- and down-regulated genes in EPS, we constructed an in silico model to predict exercise responses at the transcriptional level. The in silico model revealed similarities in the transcriptomes of the EPS and exercised animals. Comparative analysis of the EPS data and exercised mouse muscle identified putative biomarkers in exercise signaling pathways and enabled to discover novel exercise-induced myokines. Biochemical analysis of selected exercise signature genes in muscle from exercised mice showed that EPS mimics in vivo exercise, at least in part, at the transcriptional level. Consequently, we provide a novel myokine, Amphiregulin (AREG), up-regulated both in vitro and in vivo, that would be a potential target for exercise mimetics., (© 2022. The Author(s).)

Clinical guidelines recommend several risk factors to identify women in early pregnancy at high risk of developing pregnancy-associated hypertension. However, these variables result in low predictive accuracy. Here, we developed a prediction model for pregnancy-associated hypertension using graph-based semi-supervised learning. This is a secondary analysis of a prospective study of healthy pregnant women. To develop the prediction model, we compared the prediction performances across five machine learning methods (semi-supervised learning with both labeled and unlabeled data, semi-supervised learning with labeled data only, logistic regression, support vector machine, and random forest) using three different variable sets: [a] variables from clinical guidelines, [b] selected important variables from the feature selection, and [c] all routine variables. Additionally, the proposed prediction model was compared with placental growth factor, a predictive biomarker for pregnancy-associated hypertension. The study population consisted of 1404 women, including 1347 women with complete follow-up (labeled data) and 57 women with incomplete follow-up (unlabeled data). Among the 1347 with complete follow-up, 2.4% (33/1347) developed pregnancy-associated HTN. Graph-based semi-supervised learning using top 11 variables achieved the best average prediction performance (mean area under the curve (AUC) of 0.89 in training set and 0.81 in test set), with higher sensitivity (72.7% vs 45.5% in test set) and similar specificity (80.0% vs 80.5% in test set) compared to risk factors from clinical guidelines. In addition, our proposed model with graph-based SSL had a higher performance than that of placental growth factor for total study population (AUC, 0.71 vs. 0.80, p &lt; 0.001). In conclusion, we could accurately predict the development pregnancy-associated hypertension in early pregnancy through the use of routine clinical variables with the help of graph-based SSL., (© 2022. The Author(s).)

Since an impaired coronary blood supply following myocardial infarction (MI) negatively affects heart function, therapeutic neovascularization is considered one of the major therapeutic strategies for cell-based cardiac repair. Here, to more effectively achieve therapeutic neovascularization in ischemic hearts, we developed a dual stem cell approach for effective vascular regeneration by utilizing two distinct types of stem cells, CD31 + -endothelial cells derived from human induced pluripotent stem cells (hiPSC-ECs) and engineered human mesenchymal stem cells that continuously secrete stromal derived factor-1α (SDF-eMSCs), to simultaneously promote natal vasculogenesis and angiogenesis, two core mechanisms of neovascularization. To induce more comprehensive vascular regeneration, we intramyocardially injected hiPSC-ECs to produce de novo vessels, possibly via vasculogenesis, and a 3D cardiac patch encapsulating SDF-eMSCs (SDF-eMSC-PA) to enhance angiogenesis through prolonged secretion of paracrine factors, including SDF-1α, was implanted into the epicardium of ischemic hearts. We verified that hiPSC-ECs directly contribute to de novo vessel formation in ischemic hearts, resulting in enhanced cardiac function. In addition, the concomitant implantation of SDF1α-eMSC-PAs substantially improved the survival, retention, and vasculogenic potential of hiPSC-ECs, ultimately achieving more comprehensive neovascularization in the MI hearts. Of note, the newly formed vessels through the dual stem cell approach were significantly larger and more functional than those formed by hiPSC-ECs alone. In conclusion, these results provide compelling evidence that our strategy for effective vascular regeneration can be an effective means to treat ischemic heart disease., (© 2022. The Author(s).)

High-density carbon blocks have excellent mechanical, thermal, and electrical properties. In particular, these blocks are applied in various fields while maintaining excellent physical properties even in harsh environments. In this study, binderless coke manufactured under certain conditions was used to form green bodies (GBs) under various pressure conditions of 50 to 250 MPa, and the bodies were carbonized to form a high-density carbon block (CB). Then, the effect of the β-resin and oxygen functional groups of binderless coke on the mechanical properties of the high-density carbon block according to molding pressure was considered. When molding at a pressure of under 200 MPa, the ratio of O and C (O/C) has a greater effect, and the larger the O/C, the higher the mechanical properties. On the other hand, when molding at a high pressure of 250 MPa, the β-resin content has a greater effect and steadily increases when the β-resin content is low and when the mechanical properties are sufficiently reduced. In particular, in the case of CB-N7A3-250, which has the highest β-resin content of 3.7 wt%, the density was 1.79 g/cm3, the flexural strength was 106 MPa, and the shore hardness was 99 HSD., (© 2022. The Author(s).)

In hypoxia and hyperglycemia, SET7/9 plays an important role in controlling HIF-1α methylation and regulating the transcription of HIF-1α target genes, which are responsible for angiogenesis and wound healing. Here, we report the Ir(III) complex Set7&#95;1a bearing acetonitrile (ACN) ligands as a SET7/9 methyltransferase inhibitor and HIF-1α stabilizer. Interestingly, Set7&#95;1a could engage SET7/9 and strongly inhibit SET7/9 activity, especially after preincubation with homocysteine (Hcy), which is elevated in diabetes. We hypothesize that Set7&#95;1a exchanges ACN subunits for Hcy to disrupt the interaction between SET7/9 and SAM/SAH, which are structurally related to Hcy. Inhibition of SET7/9 methyltransferase activity by Set7&#95;1a led to reduced HIF-1α methylation at the lysine 32 residue, causing increased HIF-1α level and recruitment of HIF-1α target genes that promote angiogenesis, such as VEGF, GLUT1, and EPO, in hypoxia and hyperglycemia. Significantly, Set7&#95;1a improved wound healing in a type 2 diabetic mouse model by activating HIF-1α signaling and downstream proangiogenic factors. To our knowledge, this is the first Hcy-targeting iridium compound shown to be a SET7/9 antagonist that can accelerate diabetic wound healing. More importantly, this study opens a therapeutic avenue for the treatment of diabetic wounds by the inhibition of SET7/9 lysine methyltransferase activity., (© 2022. The Author(s).)

Bronchopulmonary dysplasia (BPD) can cause respiratory morbidity beyond the neonatal period. We aimed to analyze the association of BPD on childhood lower respiratory illness (LRI) and asthma among patients diagnosed with respiratory distress syndrome (RDS). This case-control study analyzed data between 2002 and 2015 from a nationwide database. We included 55,066 children with RDS. Two-year LRI and asthma at ages 3 and 5 were assessed. Readmission for LRIs within 2 years of birth occurred in 53.9% and 37.9% of the BPD (n = 9470) and non-BPD (n = 45,596) cases, respectively. In the BPD group, the median number of hospitalizations, mechanical ventilation and oxygen use rates were significantly higher, while the hospitalization duration was significantly longer (P < 0.001 for all). The relative risk of BPD was 1.42 (1.39-1.45) on total readmission and 6.53 (5.96-7.15) on intensive care unit readmission. Asthma prevalence was significantly higher in BPD group (57.6% vs. 48.9% at age 3 and 44.3% vs. 38.2% at age 5, P < 0.001). In children with RDS, BPD could affect repetitive and worse LRI as an independent risk factor for respiratory morbidity during the first 2 years of life. BPD may also be a crucial risk factor for asthma in preschoolers., (© 2022. The Author(s).)

Age-related bone loss and disease strongly affect the quality of life of the elderly population. Cellular circadian rhythms have been reported to regulate bone aging, and micro RNAs (miRNAs) play crucial posttranscriptional regulatory roles in the peripheral clock network. Proliferation capability, osteogenic lineage commitment, senescence-associated secreted phenotype (SASP) and circadian oscillation of clock genes under osteogenic condition were assessed in bone marrow mesenchymal stromal cells (BMSCs) from young adult and aged adult mice. miRNAs targeting the core clock gene brain and muscle arntl-like protein 1 (Bmal1) were screened and verified in young and old BMSCs with RT-qPCR and Western Blot analysis. ChIP-seq and RNA-seq datasets were mined to define the downstream mechanism and gain- and loss-of-function genetic experiments were performed to confirm the hypothesis. To compare the therapeutic effect of these clock-engineered BMSCs, SASP and osteogenic capability of Bmal1-overexpressing and miR-142-3p-inhibited BMSCs were investigated in vitro and transplanted into bone defects and femur cavities of aged mice. Aged BMSCs displayed an abolished circadian rhythm, impaired self-renewal capability and decreased osteoblast differentiation. miR-142-3p was elevated with aging, which downregulated Bmal1 and diminished the osteogenic potential of BMSCs. In addition, Bmal1 inhibited YAP expression to promote BMSCs osteogenesis, which was independent from the activation of Hippo signaling pathway. Overexpression of Bmal1 or inhibition of miR-142-3p rescued the molecular temporal rhythm and osteoblast differentiation ex vivo. Cell-based circadian therapy showed improved bone formation and higher turnover levels in vivo. This study demonstrates that transcriptional and post-transcriptional level clock-modified BMSCs rescued circadian oscillation and age-related bone loss via miR-142-3p/Bmal1/YAP signaling axis. These data provide promising clinical prospects of circadian-mediated stromal cell-based therapy and bone tissue regeneration., (© 2022. The Author(s).)

Despite the strong influence of the gut microbiota on atherosclerosis, a causal relationship between atherosclerosis pathophysiology and gut microbiota is still unverified. This study was performed to determine the impact of the gut microbiota on the pathogenesis of atherosclerosis caused by genetic deficiency. To elucidate the influence of the gut microbiota on atherosclerosis pathogenesis, an atherosclerosis-prone mouse model (C1q/TNF-related protein 9-knockout (CTRP9-KO) mice) was generated. The gut microbial compositions of CTRP9-KO and WT control mice were compared. Fecal microbiota transplantation (FMT) was performed to confirm the association between gut microbial composition and the progression of atherosclerosis. FMT largely affected the gut microbiota in both CTRP9-KO and WT mice, and all transplanted mice acquired the gut microbiotas of the donor mice. Atherosclerotic lesions in the carotid arteries were decreased in transplanted CTRP9-KO mice compared to CTRP9-KO mice prior to transplantation. Conversely, WT mice transplanted with the gut microbiotas of CTRP9-KO mice showed the opposite effect as that of CTRP9-KO mice transplanted with the gut microbiotas of WT mice. Here, we show that CTRP9 gene deficiency is related to the distribution of the gut microbiota in subjects with atherosclerosis. Transplantation of WT microbiotas into CTRP9-KO mice protected against the progression of atherosclerosis. Conversely, the transplantation of CTRP9-KO microbiotas into WT mice promoted the progression of atherosclerosis. Treating atherosclerosis by restoring gut microbial homeostasis may be an effective therapeutic strategy., (© 2022. The Author(s).)

This retrospective cohort study aimed to investigate the effects of neonatal oxygen care and retinopathy of prematurity (ROP) treatment on ROP-related ocular and neurological prognoses. We included premature infants treated for ROP at a tertiary referral center between January 2006 and December 2019. Demographic and clinical data were collected from electronic medical records. Odds ratios (ORs) of oxygen care- and ROP treatment-related factors were calculated for ocular and neurological comorbidities 3 years after ROP treatment, after adjusting for potential confounders. ROP requiring treatment was detected in 171 eyes (88 infants). Laser treatment for ROP (OR = 4.73, 95% confidence interval [CI] 1.64-13.63) and duration of invasive ventilation (OR = 1.02, 95% CI 1.00-1.03) were associated with an increase in ocular comorbidities, along with a history of neonatal seizure (OR = 28.29, 95% CI 5.80-137.95) and chorioamnionitis (OR = 32.13, 95% CI 5.47-188.74). No oxygen care- or ROP treatment-related factors showed significant odds for neurological comorbidities. Shorter duration of invasive oxygen supply during neonatal care (less than 49 days) and anti-vascular endothelial growth factor injection as the primary treatment for ROP are less likely to cause ocular comorbidities. No association was identified between ROP treatment modalities and the risk of neurological comorbidities., (© 2022. The Author(s).)