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Aims: To assess the relationship of longitudinal changes in fat mass (FM), lean mass (LM) and waist circumference (WC) with incident kidney outcomes in people with overweight/obesity and type 2 diabetes mellitus (T2DM)., Materials and Methods: A total of 3927 participants with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m 2 from the Look AHEAD (Action for Health in Diabetes) trial were included. The primary outcome was kidney outcomes, defined as a decrease in eGFR of at least 40% from baseline at follow-up visit, or end-stage kidney disease., Results: During a median follow-up of 8.0 years, 450 kidney outcomes were documented after the first 1 year. In the intensive lifestyle intervention (ILI) group, reductions in FM (per 10% decrease, adjusted hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.69-0.94) and WC (per 10% decrease, adjusted HR 0.72, 95% CI 0.59-0.88) from baseline to 1-year follow-up were significantly associated with a lower risk of kidney outcomes. The change in LM was not significantly associated with risk of kidney outcomes (per 10% decrease, adjusted HR 0.78, 95% CI 0.58-1.06). In the diabetes support and education group (control group), no significant association was found between changes in body composition and kidney outcomes. Similar results were observed for the 4-year changes in body composition., Conclusions: In this post hoc analysis of the Look AHEAD trial, longitudinal declines in FM and WC were associated with a lower risk of kidney outcomes in the ILI group in participants with overweight/obesity and T2DM., (© 2024 John Wiley & Sons Ltd.)

Levitated diamond particles in high vacuum with internal spin qubits have been proposed for exploring macroscopic quantum mechanics, quantum gravity, and precision measurements. The coupling between spins and particle rotation can be utilized to study quantum geometric phase, create gyroscopes and rotational matter-wave interferometers. However, previous efforts in levitated diamonds struggled with vacuum level or spin state readouts. To address these gaps, we fabricate an integrated surface ion trap with multiple stabilization electrodes. This facilitates on-chip levitation and, for the first time, optically detected magnetic resonance measurements of a nanodiamond levitated in high vacuum. The internal temperature of our levitated nanodiamond remains moderate at pressures below 10 -5 Torr. We have driven a nanodiamond to rotate up to 20 MHz (1.2 × 10 9 rpm), surpassing typical nitrogen-vacancy (NV) center electron spin dephasing rates. Using these NV spins, we observe the effect of the Berry phase arising from particle rotation. In addition, we demonstrate quantum control of spins in a rotating nanodiamond. These results mark an important development in interfacing mechanical rotation with spin qubits, expanding our capacity to study quantum phenomena., (© 2024. The Author(s).)

Straw and biochar, two commonly used soil amendments, have been shown to enhance soil fertility and the composition of microbial communities. To compare the effects of straw and biochar on soil fertility, particularly focusing on soil dissolved organic matter (DOM) components, and the physiochemical properties of soil and microbial communities, a combination of high-throughput sequencing and three-dimensional fluorescence mapping technology was employed. In our study, we set up four treatments, i.e., without biochar and straw (B0S0); biochar only (B1S0); straw returning only (B0S1); and biochar and straw (B1S1). Our results demonstrate that soil organic matter (SOM), available nitrogen (AN), and available potassium (AK) were increased by 34.71%, 22.96%, and 61.68%, respectively, under the B1S1 treatment compared to the B0S0 treatment. In addition, microbial carbon (MBC), dissolved organic carbon (DOC), and particulate organic carbon (POC) were significantly increased with the B1S1 treatment, by 55.13%, 15.59%, and 125.46%, respectively. The results also show an enhancement in microbial diversity, the composition of microbial communities, and the degree of soil humification with the application of biochar and straw. Moreover, by comparing the differences in soil fertility, DOM components, and other indicators under different treatments, the combined treatments of biochar and straw had a more significant positive impact on paddy soil fertility compared to biochar. In conclusion, our study revealed the combination of straw incorporation and biochar application has significant impacts and is considered an effective approach to improving soil fertility.

Background: The association between the TDRD6 variants and human infertility remains unclear, as only one homozygous missense variant of TDRD6 was found to be associated with oligoasthenoteratozoospermia (OAT)., Methods: Whole-exome sequencing and Sanger sequencing were employed to identify potential pathogenic variants of TDRD6 in infertile men. Histology, immunofluorescence, immunoblotting and ultrastructural analyses were conducted to clarify the structural and functional abnormalities of sperm in mutated patients. Tdrd6 -knockout mice were generated using the CRISPR-Cas9 system. Total RNA-seq and single-cell RNA-seq (scRNA-seq) analyses were used to elucidate the underlying molecular mechanisms, followed by validation through quantitative RT-PCR and immunostaining. Intracytoplasmic sperm injection (ICSI) was also used to assess the efficacy of clinical treatment., Results: Bi-allelic TDRD6 variants were identified in five unrelated Chinese individuals with OAT, including homozygous loss-of-function variants in two consanguineous families. Notably, besides reduced concentrations and impaired motility, a significant occurrence of acrosomal hypoplasia was detected in multiple spermatozoa among five patients. Using the Tdrd6 -deficient mice, we further elucidate the pivotal role of TDRD6 in spermiogenesis and acrosome identified. In addition, the mislocalisation of crucial chromatoid body components DDX4 (MVH) and UPF1 was also observed in round spermatids from patients harbouring TDRD6 variants. ScRNA-seq analysis of germ cells from a patient with TDRD6 variants revealed that TDRD6 regulates mRNA metabolism processes involved in spermatid differentiation and cytoplasmic translation., Conclusion: Our findings strongly suggest that TDRD6 plays a conserved role in spermiogenesis and confirms the causal relationship between TDRD6 variants and human OAT. Additionally, this study highlights the unfavourable ICSI outcomes in individuals with bi-allelic TDRD6 variants, providing insights for potential clinical treatment strategies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This study aimed to explore the knowledge and attitude (KA) toward postoperative antithrombotic management and prevention among coronary artery disease (CAD) patients who underwent coronary revascularization., Methods: This cross-sectional study enrolled CAD outpatients and inpatients between May and December 2023 at Kailuan Medical Group at Tangshan. Basic demographic characteristics and KA scores were collected through a self-made questionnaire., Results: This study included 523 valid questionnaires. The mean knowledge and attitude scores were 13.20 ± 6.20 (range: 0-26) and 43.68 ± 6.01 (range: 21-50), respectively, indicating poor knowledge and favorable attitude. Multivariable logistic regression analysis showed that junior high school education (OR = 2.160, P  = 0.035), high school or technical school education (OR = 2.356, P  = 0.039), and monthly average income >5,000 RMB (OR = 3.407, P  = 0.002) were independently associated with knowledge. Knowledge (OR = 1.095, P  = 0.002), BMI ≥ 24.0 kg/m 2 (OR = 0.372, P  = 0.011), junior high school (OR = 3.699, P  = 0.002), high school or technical school (OR = 2.903, P  = 0.028), high associate degree or above education (OR = 6.068, P  = 0.014), monthly average income 3,000-5,000 RMB (OR = 0.296, P  = 0.005), monthly average income > 5,000 RMB (OR = 0.225, P  = 0.021), with hypertension (OR = 0.333, P  = 0.003), blood tests every 2-3 weeks (OR = 10.811, P  = 0.011), blood tests every month (OR = 4.221, P  = 0.024), and blood tests every 2-3 months (OR = 3.342, P  = 0.033) were independently associated with attitude., Conclusion: CAD patients who underwent coronary revascularization had poor knowledge but favorable attitudes toward postoperative antithrombotic management and prevention. The study underscores the need for targeted education, especially for individuals with lower education and income levels, ultimately improving patient compliance and cardiovascular outcomes., 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., (© 2024 Liu, Zhang, Yang, Chen, Zu, Wang, Dai and Zhao.)

The human population will be approximately 9.7 billion by 2050, and food security has been identified as one of the key issues facing the global population. Agrochemicals are an important tool available to farmers that enable high crop yields and continued access to healthy foods, but the average new agrochemical active ingredient takes more than ten years, 350 million dollars, and 20,000 animals to develop and register. The time, monetary, and animal costs incentivize the use of New Approach Methodologies (NAMs) in early-stage screening to prioritize chemical candidates. This review outlines NAMs that are currently available or can be adapted for use in early-stage screening agrochemical programs. It covers new in vitro screens that are on the horizon in key areas of regulatory concern. Overall, early-stage screening with NAMs enables the prioritization of development for agrochemicals without human and environmental health concerns through a more directed, agile, and iterative development program before animal-based regulatory testing is even considered.

Soil amendment is an important strategy for improving soil quality and crop yield. From 2014 to 2019, we conducted a study to investigate the effects of tobacco straw return with lime on soil nutrients, soil microbial community structure, tobacco leaf yield, and quality in southern Anhui, China. A field experiment was conducted with four treatments: straw removed (CK), straw return (St), straw return with dolomite (St + D), and straw return with lime (St + L). Results showed that after 5 years of application, the St + L significantly increased the soil pH by 16.9%, and the contents of soil alkaline nitrogen (N) and available potassium (K) by 17.2% and 23.0%, respectively, compared with the CK. Moreover, the St + L significantly increased tobacco leaf yield (24.0%) and the appearance (9.1%) and sensory (5.9%) quality of flue-cured tobacco leaves. The addition of soil conditioners (straw, dolomite, and lime) increased both the total reads and effective sequences of soil microorganisms. Bacterial diversity was more sensitive to changes in the external environment compared to soil fungi. The application of soil amendments (lime and straw) promoted the growth of beneficial microorganisms in the soil. Additionally, bacterial species had greater competition and limited availability of resources for survival compared to fungi. The results showed that soil microorganisms were significantly influenced by the presence of AK, AN, and pH contents. These findings can provide an effective method for improving the quality of flue-cured tobacco leaves and guiding the amelioration of acidic soil in regions where tobacco-rice rotation is practiced., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Patients with relapsed or refractory hematologic cancers have a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy as a bridge to allogeneic hematopoietic stem-cell transplantation (HSCT) has the potential for long-term tumor elimination. However, pre-HSCT myeloablation and graft-versus-host disease (GVHD) prophylaxis agents have toxic effects and could eradicate residual CAR T cells and compromise antitumor effects. Whether the integration of CAR T-cell therapy and allogeneic HSCT can preserve CAR T-cell function and improve tumor control is unclear., Methods: We tested a novel "all-in-one" strategy consisting of sequential CD7 CAR T-cell therapy and haploidentical HSCT in 10 patients with relapsed or refractory CD7-positive leukemia or lymphoma. After CAR T-cell therapy led to complete remission with incomplete hematologic recovery, patients received haploidentical HSCT without pharmacologic myeloablation or GVHD prophylaxis drugs. Toxic effects and efficacy were closely monitored., Results: After CAR T-cell therapy, all 10 patients had complete remission with incomplete hematologic recovery and grade 4 pancytopenia. After haploidentical HSCT, 1 patient died on day 13 of septic shock and encephalitis, 8 patients had full donor chimerism, and 1 patient had autologous hematopoiesis. Three patients had grade 2 HSCT-associated acute GVHD. The median follow-up was 15.1 months (range, 3.1 to 24.0) after CAR T-cell therapy. Six patients remained in minimal residual disease-negative complete remission, 2 had a relapse of CD7-negative leukemia, and 1 died of septic shock at 3.7 months. The estimated 1-year overall survival was 68% (95% confidence interval [CI], 43 to 100), and the estimated 1-year disease-free survival was 54% (95% CI, 29 to 100)., Conclusions: Our findings suggest that sequential CD7 CAR T-cell therapy and haploidentical HSCT is safe and effective, with remission and serious but reversible adverse events. This strategy offers a feasible approach for patients with CD7-positive tumors who are ineligible for conventional allogeneic HSCT. (Funded by the National Natural Science Foundation of China and the Key Project of Science and Technology Department of Zhejiang Province; ClinicalTrials.gov numbers, NCT04599556 and NCT04538599.)., (Copyright © 2024 Massachusetts Medical Society.)

Vaccines play essential roles in the fight against the COVID-19 pandemic. The development and assessment of COVID-19 vaccines have generally focused on the induction and boosting of neutralizing antibodies targeting the SARS-CoV-2 spike (S) protein. Due to rapid and continuous variation in the S protein, such vaccines need to be regularly updated to match newly emerged dominant variants. T-cell vaccines that target MHC I- or II-restricted epitopes in both structural and non-structural viral proteins have the potential to induce broadly cross-protective and long-lasting responses. In this work, the entire proteome encoded by SARS-CoV-2 (Wuhan-hu-1) is subjected to immunoinformatics-based prediction of HLA-A*02:01-restricted epitopes. The immunogenicity of the predicted epitopes is evaluated using peripheral blood mononuclear cells from convalescent Wuhan-hu-1-infected patients. Furthermore, predicted epitopes that are conserved across major SARS-CoV-2 lineages and variants are used to construct DNA vaccines expressing multi-epitope polypeptides. Most importantly, two DNA vaccine constructs induce epitope-specific CD8 + T-cell responses in a mouse model of HLA-A*02:01 restriction and protect immunized mice from challenge with Wuhan-hu-1 virus after hACE2 transduction. These data provide candidate T-cell epitopes useful for the development of T-cell vaccines against SARS-CoV-2 and demonstrate a strategy for quick T-cell vaccine candidate development applicable to other emerging pathogens.

Introduction: Porcine viral diarrhea is a common clinical disease, which results in high mortality and economic losses in the pig industry. Porcine epidemic diarrhea virus (PEDV), porcine rotavirus (PoRV), and porcine deltacoronavirus (PDCoV) are important diarrhea viruses in pig herds. The similarities of their clinical symptoms and pathological changes make it difficult to distinguish these three viruses clinically. Therefore, there is a need for a highly sensitive and specific method to simultaneously detect and differentiate these viruses., Methods: A multiplex real-time PCR assay using TaqMan probes was developed to simultaneously detect PEDV, PoRV, and PDCoV. To assess the efficacy of the established assay, 30 clinical samples with diarrhea symptoms were used to compare the results obtained from the multiplex real-time PCR assay with those obtained from commercial singleplex real-time PCR kit. Importantly, a total of 4,800 diarrhea samples were tested and analyzed to validate the utility of the assay., Results: This multiplex real-time PCR assay showed high sensitivity, specificity, and excellent repeatability with a detection limit of 1 × 10 2 copies/μL. Comparing the results of the commercial singleplex real-time PCR kit and the multiplex real-time PCR method for detecting PEDV, PoRV, and PDCoV, there was complete agreement between the two approaches. Clinical data revealed single infection rates of 6.56% for PEDV, 21.69% for PoRV, and 6.65% for PDCoV. The co-infection rates were 11.83% for PEDV + PoRV, 0.29% for PEDV + PDCoV, 5.71% for PoRV + PDCoV, and 1.29% for PEDV + PDCoV + PoRV, respectively., Discussion: The multiplex real-time PCR method established in this study is a valuable diagnostic tool for simultaneously differentiating PEDV, PoRV, and PDCoV. This method is expected to significantly contribute to prevent and control the spread of infectious diseases, as well as aid in conducting epidemiological investigations., Competing Interests: CZ, YL, and XL were employed by Shandong New Hope Liuhe Agriculture and Animal Husbandry Technology Co., Ltd. (NHLH Academy of Swine Research). The remaining 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 © 2024 Ren, Zu, Li, Li, Gu, Chen and Li.)

Objective: We assessed the relationship of body weight time in target range (TTR) with composite kidney outcome in people with overweight/obesity and type 2 diabetes mellitus (T2DM)., Research Design and Methods: Included in this study were 3,601 participants with baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 from the Look AHEAD (Action for Health in Diabetes) trial. Body weight TTR was defined as the proportion of time during the first 4 years that body weight was within the weight loss target (a weight loss of ≥7% from baseline). The primary outcome was composite kidney outcome, defined as eGFR decline ≥30% from baseline and to a level <60 mL/min/1.73 m2 at follow-up visit, or end-stage kidney disease., Results: During a median follow-up of 8.0 years, 435 cases of composite kidney outcome were documented. Body weight TTR during the first 4 years was inversely associated with the subsequent risk of composite kidney outcome (per SD increment; adjusted hazard ratio [HR] 0.81; 95% CI 0.70-0.93). Accordingly, the adjusted HRs (95% CI) of composite kidney outcome were 1.00 (reference), 0.73 (0.54-1.00), 0.71 (0.52-0.99), and 0.54 (0.36-0.80) for participants with body weight TTR of 0%, >0% to <29.9%, 29.9% to <69.7%, and 69.7% to <100%, respectively. Similar results were found for a doubling of the urine albumin to creatinine ratio (secondary outcome)., Conclusions: A higher body weight TTR, with a weight loss target of losing ≥7% of initial weight, was associated with a lower risk of kidney outcomes in participants with overweight/obesity and T2DM., (© 2024 by the American Diabetes Association.)

By directly altering microscopic interactions, pressure provides a powerful tuning knob for the exploration of condensed phases and geophysical phenomena 1 . The megabar regime represents an interesting frontier, in which recent discoveries include high-temperature superconductors, as well as structural and valence phase transitions 2-6 . However, at such high pressures, many conventional measurement techniques fail. Here we demonstrate the ability to perform local magnetometry inside a diamond anvil cell with sub-micron spatial resolution at megabar pressures. Our approach uses a shallow layer of nitrogen-vacancy colour centres implanted directly within the anvil 7-9 ; crucially, we choose a crystal cut compatible with the intrinsic symmetries of the nitrogen-vacancy centre to enable functionality at megabar pressures. We apply our technique to characterize a recently discovered hydride superconductor, CeH 9 (ref.  10 ). By performing simultaneous magnetometry and electrical transport measurements, we observe the dual signatures of superconductivity: diamagnetism characteristic of the Meissner effect and a sharp drop of the resistance to near zero. By locally mapping both the diamagnetic response and flux trapping, we directly image the geometry of superconducting regions, showing marked inhomogeneities at the micron scale. Our work brings quantum sensing to the megabar frontier and enables the closed-loop optimization of superhydride materials synthesis., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Objective: The prospective association between dietary zinc (Zn) intake and cognitive decline remains uncertain. We aimed to assess the relationship of dietary Zn intake with the risk of cognitive decline in the Chinese older people, and examine the possible effect modifiers on this association., Methods: A total of 3,106 older Chinese adults aged 55 years or older from China Health and Nutrition Survey were included. Dietary nutrients intake information was collected by combined 24-h dietary recalls with weighing food inventory. The cognitive decline was defined as the 5-year decline rate in global and composite cognitive scores, based on a subset of items from the Telephone Interview for Cognitive Status-modified., Results: The median follow-up duration was 5.9 years. There was an L-shaped association between dietary Zn intake and the 5-year decline rates in global and composite cognitive scores, with an inflection point at 8.8 mg/day of dietary Zn. For the composite cognitive scores, compared with the first quantile (<7.9 mg/day) of dietary Zn intake, quantiles 2-6 (≥7.9 mg/day) had a significantly slower cognitive decline rate (β: -0.24; 95% confidence interval: -0.40 to -0.07). Similar results were found for the global cognitive scores. Moreover, the inverse association between dietary Zn intake and cognitive decline in composite cognitive scores was significantly stronger in those with lower levels of physical activity (P-interactions = 0.041)., Conclusion: Dietary Zn intake was negatively associated with cognitive decline in the older people. Maintaining appropriate dietary Zn levels may prevent cognitive decline., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Spin defects in van der Waals materials offer a promising platform for advancing quantum technologies. Here, we propose and demonstrate a powerful technique based on isotope engineering of host materials to significantly enhance the coherence properties of embedded spin defects. Focusing on the recently-discovered negatively charged boron vacancy center ([Formula: see text]) in hexagonal boron nitride (hBN), we grow isotopically purified h 10 B 15 N crystals. Compared to [Formula: see text] in hBN with the natural distribution of isotopes, we observe substantially narrower and less crowded [Formula: see text] spin transitions as well as extended coherence time T 2 and relaxation time T 1 . For quantum sensing, [Formula: see text] centers in our h 10 B 15 N samples exhibit a factor of 4 (2) enhancement in DC (AC) magnetic field sensitivity. For additional quantum resources, the individual addressability of the [Formula: see text] hyperfine levels enables the dynamical polarization and coherent control of the three nearest-neighbor 15 N nuclear spins. Our results demonstrate the power of isotope engineering for enhancing the properties of quantum spin defects in hBN, and can be readily extended to improving spin qubits in a broad family of van der Waals materials., (© 2024. The Author(s).)

Positron emission tomography (PET) scans can reveal abnormal metabolic activities of cells and provide favorable information for clinical patient diagnosis. Generally, standard-dose PET (SPET) images contain more diagnostic information than low-dose PET (LPET) images but higher-dose scans can also bring higher potential radiation risks. To reduce the radiation risk while acquiring high-quality PET images, in this paper, we propose a 3D multi-modality edge-aware Transformer-GAN for high-quality SPET reconstruction using the corresponding LPET images and T1 acquisitions from magnetic resonance imaging (T1-MRI). Specifically, to fully excavate the metabolic distributions in LPET and anatomical structural information in T1-MRI, we first use two separate CNN-based encoders to extract local spatial features from the two modalities, respectively, and design a multimodal feature integration module to effectively integrate the two kinds of features given the diverse contributions of features at different locations. Then, as CNNs can describe local spatial information well but have difficulty in modeling long-range dependencies in images, we further apply a Transformer-based encoder to extract global semantic information in the input images and use a CNN decoder to transform the encoded features into SPET images. Finally, a patch-based discriminator is applied to ensure the similarity of patch-wise data distribution between the reconstructed and real images. Considering the importance of edge information in anatomical structures for clinical disease diagnosis, besides voxel-level estimation error and adversarial loss, we also introduce an edge-aware loss to retain more edge detail information in the reconstructed SPET images. Experiments on the phantom dataset and clinical dataset validate that our proposed method can effectively reconstruct high-quality SPET images and outperform current state-of-the-art methods in terms of qualitative and quantitative metrics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background & Aims: This study aims to assess the nutritional status of patients during the different phases of the Chimeric Antigen Receptor (CAR)-T cell therapy and to identify prominent risk factors of hypoalbuminemia in patients after CAR-T treatment. The clinical consequences of malnutrition in cancer patients have been highlighted by growing evidence from previous clinical studies. Given CAR-T cell therapy's treatment intensity and possible side effects, it is important to provide patients with sufficient medical attention and support for their nutritional well-being., Methods: This study was conducted from May 2021 to December 2021 among patients undergoing CAR-T cell therapy at the Bone Marrow Transplantation Center in The First Affiliated Hospital of Zhejiang University School of Medicine. Logistic regression analysis was performed to investigate the risk factors associated with hypoalbuminemia. Participants were divided into the cytokine release syndrome (CRS) group (n = 60) and the non-CRS group (n = 11) to further analyze the relationship between hypoalbuminemia and CRS., Results: CRS (OR = 13.618; 95% CI = 1.499-123.709; P = 0.013) and baseline albumin (ALB) (OR = 0.854; 95% CI = 0.754-0.967; P = 0.020) were identified as the independent clinical factors associated with post-CAR-T hypoalbuminemia. According to the nadir of serum albumin, hypoalbuminemia occurred most frequently in patients with severe CRS (78.57%). The nadir of serum albumin (r =  - 0.587, P < 0.001) and serum albumin at discharge (r =  - 0.315, P = 0.01) were negatively correlated for the duration of CRS. Furthermore, patients with hypoalbuminemia deserved longer hospitalization (P = 0.04)., Conclusions: CRS was identified as a significant risk factor associated with post-CAR-T hypoalbuminemia. An obvious decline in serum albumin was observed as the grade and duration of CRS increase. However, further research is still needed to elucidate the mechanisms of CRS-associated hypoalbuminemia., (© 2023. The Author(s).)

Background Aims: With the increasing application of chimeric antigen receptor (CAR)-T cell therapy in various malignancies, an extra toxicity profile has been revealed, including a severe complication resembling hemophagocytic lymphohistiocytosis (HLH), which is usually disguised by severe cytokine release syndrome (CRS)., Methods: In a clinical trial in whom 99 patients received B-cell maturation antigen CAR-T cells, we identified 20 (20.20%) cases of CAR-T cell-associated HLH (carHLH), most of whom possessed a background of severe CRS (grade ≥3). The overlapping features of carHLH and severe CRS attracted us to further explore the differences between them., Results: We showed that carHLH can be distinguished by extreme elevation of interferon-γ, granzyme B, interleukin-1RA and interleukin-10, which can be informative in developing prevention and management strategies of this toxicity. Moreover, we developed a predictive model of carHLH with a mean area under the curve of 0.81 ± 0.07, incorporating serum lactate dehydrogenase at day 6 post-CRS and serum fibrinogen at day 3 post-CRS., Conclusions: The incidence of carHLH in CAR-T recipients might be relatively higher than we previously thought. relatively higher than we previously. A cytokine network distinguished from CRS is responsible for carHLH. And corresponding cytokine-directed therapies, especially targeting IL-10, are worth trying., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: The association between dietary copper (Cu) intake and cognitive decline remains uncertain. We aim to investigate the longitudinal association of dietary Cu with cognitive decline in Chinese elderly., Methods: A total of 3,106 Chinese adults aged older than or equal to 55 years from China Health and Nutrition Survey (CHNS) were included. Dietary nutrients information was collected by 24-hours dietary recalls in combination with a food-weighted method. The 5-year change rates in global or composite cognitive scores based on a subset of items from the Telephone Interview for Cognitive Status-modified (TICS-m) was calculated as the last-survey score minus the baseline score, then divided by the follow-up time (unit, years) and multiplied by five., Results: The median follow-up duration was 5.9 years. There was a nonlinear association of dietary Cu intake with the 5-year change rates in global or composite cognitive scores, with the inflection point at approximately 1.3 mg/day of dietary Cu intake. Accordingly, for the composite cognitive score, compared to the first quantile (<1.28 mg/day), those with dietary Cu in quantiles 2-8 (≥1.28 mg/day) had a significantly slower cognitive decline rate (B, 0.30; 95% CI, 0.13, 0.47). Similar results were found for the global cognitive score. Moreover, the inverse association between dietary Cu and cognitive decline was stronger in those with lower dietary fat intake and lower levels of physical activity (All p-interactions <0.05)., Conclusion: There was a nonlinear inverse association of dietary Cu intake with cognitive decline in the elderly, with an inflection point at approximately 1.3 mg/day of dietary Cu intake., (Copyright © 2023 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Floquet (periodic) driving has recently emerged as a powerful technique for engineering quantum systems and realizing nonequilibrium phases of matter. A central challenge to stabilizing quantum phenomena in such systems is the need to prevent energy absorption from the driving field. Fortunately, when the frequency of the drive is significantly larger than the local energy scales of the many-body system, energy absorption is suppressed. The existence of this so-called prethermal regime depends sensitively on the range of interactions and the presence of multiple driving frequencies. Here, we report the observation of Floquet prethermalization in a strongly interacting dipolar spin ensemble in diamond, where the angular dependence of the dipolar coupling helps to mitigate the long-ranged nature of the interaction. Moreover, we extend our experimental observation to quasi-Floquet drives with multiple incommensurate frequencies. In contrast to a single-frequency drive, we find that the existence of prethermalization is extremely sensitive to the smoothness of the applied field. Our results open the door to stabilizing and characterizing nonequilibrium phenomena in quasiperiodically driven systems.

Low response rate of immune checkpoint blockade (ICB) has limited its clinical application. A promising strategy to overcome this limitation is the use of therapeutic cancer vaccines, which aim to induce robust immune responses that synergize with ICB through immune enhancement and immune normalization strategies. Herein, we developed a combination immunotherapy by combining nano-vaccines consisting of whole tumor cell lysates/CpG liposomes (LCLs) with an anti-PD-L1 loaded lipid gel (aPD-L1@LG). The LCLs were fabricated using cationic liposomes, while the lipid gels (LGs) were prepared by using soybean phosphatidylcholine (SPC) and glycerol dioleate (GDO). Subcutaneous administration of LCLs successfully activated dendritic cells (DCs), and intratumoral administration of anti-PD-L1@LG ensured sustained ICB activity. These results demonstrated that this combination immunotherapy enhanced anti-tumor efficacy and prolonged the survival time in melanoma by activating systemic anti-tumor immune responses. These findings highlight the potential of this rational design as a promising strategy for tumor treatment., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2023. Published by Elsevier Inc.)

Background & Aims: The association of dietary intake of carbohydrate (CHO), especially high- and low-quality CHO, with the decline of cognitive function remains uncertain. We aimed to investigate the prospective association of dietary total, low- and high-quality CHO intake with cognitive decline, and further examine the effect of isocaloric substitution with protein or fat, in the elderly population., Methods: A total of 3106 Chinese participants aged ≥55 years from China Health and Nutrition Survey (CHNS) were included in this study. Dietary nutrient intake information was collected by 24-h dietary recalls on 3 consecutive days. The cognitive decline was defined as the 5-year decline rates in global or composite cognitive scores based on a subset of items from the Telephone Interview for Cognitive Status-modified (TICS-m)., Results: The median follow-up duration was 5.9 years. There was a significantly positive association of dietary low-quality CHO (per 10 percentage energy [%E] increment, β, 0.06; 95%CI, 0.01-0.11) and a no significant association of dietary high-quality CHO (per 10%E increment, β, 0.04; 95%CI, -0.07-0.14) with the 5-year decline rate in the composite cognitive scores. Similar results were found for the global cognitive scores. In model simulations, substituting dietary low-quality CHO with isocaloric animal protein or fat, instead of isocaloric plant protein or fat, was significantly and inversely associated with cognitive decline (All P values < 0.05)., Conclusions: The dietary intake of low-quality CHO, rather than high-quality CHO, was significantly associated with a faster cognitive decline in the elderly. In model simulations, isocaloric substitution of dietary low-quality CHO with animal protein or fat, rather than plant protein or fat, was inversely associated with cognitive decline., (Copyright © 2023. Published by Elsevier Ltd.)

Objective: This cohort study investigated the association between cardiovascular health index scores and pregnancy-induced hypertension (PIH)., Methods: A total of 1466 first-time pregnant women who delivered a single child between 2006 and 2016 were included in the study. All participants underwent a physical examination before delivery, and seven cardiovascular health indexes were collected and scored. Three groups were created based on the tri-sectional quantiles of the total score to observe whether PIH occurred among the groups. A dichotomous logistic regression analysis was carried out to investigate the relationship between cardiovascular health index scores and the occurrence of PIH., Results: During the observation of 1150 subjects, 103 cases of PIH were identified, resulting in an incidence rate of 8.96%. The study found that the incidence of PIH in the three groups was 17.5% in the first group, 6.7% in the second, and 5.8% in the third group. These rates showed a sequential decrease with statistically significant differences (P < .001). The multifactorial regression analysis revealed that after adjusting for various factors, there was a significant inverse relationship between cardiovascular health index scores and the risk of PIH. Specifically, for every one-point increase in the seven cardiovascular health index scores, the risk of PIH decreased by 29% (OR = 0.71, 95% CI 0.59-0.86)., Conclusions: The study found an inverse correlation between cardiovascular health index scores and PIH, with higher scores associated with lower incidences of PIH. Each cardiovascular health indicator helps to lower the risk of PIH, and optimum cardiovascular health behaviors and variables are protective factors against PIH.

The association between dietary Cu intake and mortality risk remains uncertain. We aimed to investigate the relationship of dietary Cu intake with all-cause mortality among Chinese adults. A total of 17 310 participants from the China Health and Nutrition Survey, a national ongoing open cohort of Chinese participants, were included in the analysis. Dietary intake was measured by three consecutive 24-h dietary recalls in combination with a weighing inventory over the same 3 d. The average intakes of the 3-d dietary macronutrients and micronutrients were calculated. The study outcome was all-cause mortality. During a median follow-up of 9·0 years, 1324 (7·6 %) participants died. After adjusting for sex, age, BMI, ever alcohol drinking, ever smoking, education levels, occupations, urban or rural residents, systolic blood pressure, diastolic blood pressure and the intakes of fat, protein and carbohydrate, the association between dietary Cu intake and all-cause mortality followed a J-shape ( P for nonlinearity = 0·047). When dietary Cu intake was assessed as quartiles, compared with those in the first quartile (<1·60 mg/d), the adjusted hazard ratios for all-cause mortality were 0·87 (95 % CI (0·71, 1·07)), 0·98 (95 % CI (0·79, 1·21)) and 1·49 (95 % CI (1·19, 1·86)), respectively, in participants in the second (1·60-<1·83 mg/d), third (1·83-<2·09 mg/d) and fourth (≥2·09 mg/d) quartiles. A series of subgroup analyses and sensitivity analyses showed similar results. Overall, our findings emphasised the importance of maintaining optimal dietary Cu intake levels for prevention of premature death.

Optically active spin defects in van der Waals materials are promising platforms for modern quantum technologies. Here we investigate the coherent dynamics of strongly interacting ensembles of negatively charged boron-vacancy ([Formula: see text]) centers in hexagonal boron nitride (hBN) with varying defect density. By employing advanced dynamical decoupling sequences to selectively isolate different dephasing sources, we observe more than 5-fold improvement in the measured coherence times across all hBN samples. Crucially, we identify that the many-body interaction within the [Formula: see text] ensemble plays a substantial role in the coherent dynamics, which is then used to directly estimate the concentration of [Formula: see text]. We find that at high ion implantation dosage, only a small portion of the created boron vacancy defects are in the desired negatively charged state. Finally, we investigate the spin response of [Formula: see text] to the local charged defects induced electric field signals, and estimate its ground state transverse electric field susceptibility. Our results provide new insights on the spin and charge properties of [Formula: see text], which are important for future use of defects in hBN as quantum sensors and simulators., (© 2023. The Author(s).)

B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). Concern of the safety and efficacy of CAR-T cell therapy in patients with chronic or resolved HBV infection is raised. In this study, we retrospectively reviewed 99 patients with r/r MM treated with BCMA-targeted CAR-T cell therapy, of which 7 (7.1%) patients had chronic HBV infection, 43 (43.4%) with resolved HBV infection, and the remaining 49 (49.49%) HBV-uninfected. Patients' characteristics before CAR-T cell administration were comparable in different status of HBV infection. Patients' liver function, cytokine levels, CAR-T cell expansion and cytokine release syndrome (CRS) grade after CAR-T cell therapy did not differ in different HBV serologic status. Furthermore, chronic HBV infection or resolved HBV infection did not affect clinical response, progress-free survival (PFS), or overall survival (OS). Four (4.04%) patients experienced HBV reactivation, 3 (6.98%) with resolved HBV infection, and 1 (14.29%) chronic HBV infection. Of 4 patients with HBV reactivation, 2 cases (50%) of severe hepatitis were noted and reported. Drops of serum IgG and elevation of alanine aminotransferase (ALT), alanine aminotransferase (AST), total bilirubin (TB) were observed in all four patients around the date of HBV reactivation., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Thus far, all approved chimeric antigen receptor (CAR)-T products are manufactured using modified viruses, which increases the risk of tumorigenesis, costs and production time. We aimed to evaluate the safety and efficacy of a kind of virus-free CAR-T cells (PD1-19bbz), in which an anti-CD19 CAR sequence is specifically integrated at the PD1 locus using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, in adults with relapsed/refractory (r/r) B cell non-Hodgkin's lymphoma (B-NHL)., Methods: This single-arm phase I dose-escalation clinical trial evaluated PD1-19bbz in adult patients with r/r B-NHL from May 3rd 2020 to August 10th 2021. The patients were recruited and treated at the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Patients underwent leukapheresis and lymphodepleting chemotherapy before PD1-19bbz infusion. After the dose-escalation phase including three cohorts: 2 × 10 6 /kg, 4 × 10 6 /kg, 6 × 10 6 /kg with three patients at each dose level, the optimal biological dose was determined to be 2 × 10 6 /kg, which was then applied to an extended cohort of nine patients. The primary endpoint was the incidence of dose-limiting toxicities (DLT). The secondary endpoint was the response and survival. This trial was registered at www.clinicaltrials.gov as #NCT04213469., Findings: Twenty-one patients received PD1-19bbz infusion. Among all treated patients, 19 (90%) patients were diagnosed with stage III or IV disease. Meanwhile, 19 (90%) were stratified as intermediate risk or worse. Of note, four participants had >50% programmed death ligand-1 (PD-L1) expression in pre-treatment tumour sample, including two with extremely high levels (∼80%). There was no DLT identified. Fourteen patients had low-grade (1-2) cytokine release syndrome and two patients received tocilizumab. Four patients experienced immune effector cell-associated neurotoxicity syndrome of grade 1-2. The most common adverse events were hematologic toxicities, including anaemia (n = 6), lymphocyte count decreased (n = 19), neutrophil count decreased (n = 17), white blood cell count decreased (n = 10), and platelet count decreased (n = 2). All patients had objective response and 18 patients reached complete response. At a median follow-up of 19.2 months, nine patients remained in remission, and the estimated median progression-free survival duration was 19.5 months (95% confidence interval: 9.9-infinity), with the median overall survival not reached., Interpretation: In this first-in-human study of non-viral specifically integrated CAR-T products, PD1-19bbz exhibited promising efficacy with a manageable toxicity profile. A phase I/II trial of PD1-19bbz in a larger patient cohort is underway., Funding: National Key R&D Program of China, National Natural Science Foundation of China, Key Project of Science and Technology Department of Zhejiang Province, Shanghai Zhangjiang National Independent Innovation Demonstration Area, Key Projects of Special Development Funds., Competing Interests: This study was partially supported by BRL Medicine, Inc. Patent applications related to this manuscript have been submitted (J.Z., B.D., M.L. ‘sgRNA guiding PD1 gene for cleavage to achieve efficient integration of exogenous sequences’; J.Z., B.D., M.L. ‘Method for performing gene editing on target site in cell’). All of the authors declare that the research was conducted in the absence of any other commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 The Author(s).)

Background Aims: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor-T cell (CAR-T) therapy is used for refractory or relapsed multiple myeloma (r/r MM). However, CAR-T-related tumor lysis syndrome (TLS) has been observed. We aimed to elucidate the incidence, clinical and laboratory characteristics, and prognosis of CAR-T cell-related TLS., Methods: Patients (n=105) with r/r MM treated with BCMA-targeted CAR-T cell therapy were included. Patient characteristics, laboratory parameters, and clinical outcomes were assessed., Results: Eighteen (17.1%) patients developed TLS after BCMA-targeted CAR-T cell therapy. The median time till TLS onset was 8 days. Patients with TLS had steep rise in uric acid (UA), creatinine, and lactate dehydrogenase (LDH) within 6 days following CAR-T cell infusion and presented earlier and persistent escalation of cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-γ [IFN-γ], and ferritin levels). All 18 patients had cytokine release syndrome (CRS), of which 13 (72.2%) developed grade 3-4 CRS. Three of 18 patients (16.7%) developed immune effector cell-associated neurotoxicity syndrome (ICANS): two patients with grade 1 ICANS and one with grade 2 ICANS. TLS development had a negative effect on the objective response rate (77.8% in the TLS group vs. 95.4% in the non-TLS group, p<0.01). During the median follow-up of 15.1 months, the median PFS was poorer of patients with TLS (median: 3.4 months in the TLS group vs. 14.7 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.5 [95% confidence interval [CI] 1.5-8.5]). Also, TLS development exhibited significant effects on OS (median: 5.0 months in the TLS group vs. 39.8 months in the non-TLS group, p<0.001, hazard ratio [HR]=3.7 [95% CI 1.3-10.3]). TLS was associated with a higher tumor burden, elevated baseline creatinine and UA levels, severe CRS, pronounced CAR-T cell expansion, and corticosteroid use., Conclusion: TLS is a frequently observed CAR-T therapy complication and negatively influences clinical response and prognosis. Close monitoring for TLS should be implemented during CAR-T cell therapy, especially for those at high TLS risk., Competing Interests: Authors YZ and AC are employed by Shanghai YaKe Biotechnology Ltd. The remaining 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 Zhang, Zu, Jing, Feng, Zhang, Zhang, Lv, Cui, Zhou, Meng, Wang, Cen, Chang, Hu and Huang.)

Facial expression recognition (FER) plays a vital role in the field of human-computer interaction. To achieve automatic FER, various approaches based on deep learning (DL) have been presented. However, most of them lack for the extraction of discriminative expression semantic information and suffer from the problem of annotation ambiguity. In this paper, we propose an elaborately designed end-to-end recognition network with contrastive learning and uncertainty-guided relabeling, to recognize facial expressions efficiently and accurately, as well as to alleviate the impact of annotation ambiguity. Specifically, a supervised contrastive loss (SCL) is introduced to promote inter-class separability and intra-class compactness, thus helping the network extract fine-grained discriminative expression features. As for the annotation ambiguity problem, we present an uncertainty estimation-based relabeling module (UERM) to estimate the uncertainty of each sample and relabel the unreliable ones. In addition, to deal with the padding erosion problem, we embed an amending representation module (ARM) into the recognition network. Experimental results on three public benchmarks demonstrate that our proposed method facilitates the recognition performance remarkably with 90.91% on RAF-DB, 88.59% on FERPlus and 61.00% on AffectNet, outperforming current state-of-the-art (SOTA) FER methods. Code will be available at http//github.com/xiaohu-run/fer&#95;supCon.

Gastric cancer is a tumor type characterized by lymph node metastasis and the invasion of local tissues. There is thus a critical need to clarify the molecular mechanisms governing gastric cancer onset and progression to guide the treatment of this disease. Long non-coding RNAs and mRNA expression profiles associated with early and local advanced gastric cancer were examined through microarray analyses, with GO and KEGG analyses being employed as a means of exploring the functional roles of those long non-coding RNAs and mRNAs that were differentially expressed in gastric cancer. In total, 1005 and 1831 lncRNAs and mRNAs, respectively, were found to be differentially expressed between early and local advanced gastric cancer. GO and KEGG analyses revealed several pathways and processes that were dysregulated, including the RNA transport, ECM-receptor interaction, and mRNA splicing pathways. In co-expression networks, E2F1, E2F4, and STAT2 were identified as key transcriptional regulators of these processes. Moreover, thrombospondin-2 was confirmed as being expressed at high levels in more advanced gastric cancer by both the GEO and TCGA databases. RNA-sequencing analyses of SGC-790 cells transfected to express thrombospondin-2 further revealed this gene to enhance NF-kB and TNF pathway signaling activity. These results offer insight into gastric cancer-related regulatory networks and suggest thrombospondin-2 to be an important oncogene that drives the progression of this deadly cancer type., 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. The reviewer YJ declared a shared parent affiliation with the author K-KS to the handling editor at the time of review., (Copyright © 2023 Sun, Zu, Wu, Wang, Hua, Zhang, Shen and Wu.)

Background Understanding the natural history of elevated blood pressure (BP) is important to determine the window for primary prevention of hypertension. The authors aimed to investigate the natural history of elevated BP and examine whether there were inflection points in BP trajectories preceding hypertension onset in Chinese adults. Methods and Results A total of 8688 participants with an average of 5 BP measurements were included from the CHNS (China Health and Nutrition Survey). In each wave, triplicate measurements on the same arm were taken, and the mean systolic BP (SBP) and diastolic BP (DBP) were used in the analysis. Hypertension onset was defined as SBP ≥140 mm Hg or DBP ≥90 mm Hg or diagnosed by physician or currently under antihypertensive treatment. The median follow-up time was 13.0 years. Overall, BP elevation with age prior to the onset of hypertension showed a nonlinear trajectory. The increased rates in both SBP and DBP were obviously faster after the inflection point than before. According to hypertension onset at age 30 to 39, 40 to 49, 50 to 59, 60 to 69, and 70 to 79 years, at the inflection point, patients were ≈29, 38, 48, 57, and 67 years, SBP levels were 112.6, 114.8, 116.8, 117.4, and 118.0 mm Hg, and DBP levels were 73.4, 75.7, 76.9, 76.2, and 73.8 mm Hg, respectively. Conclusions There was a nonlinear trajectory of BP elevation preceding hypertension onset. The inflection points for SBP and DBP were in the range of 112 to 118 mm Hg and 73 to 77 mm Hg, respectively. Once BP levels exceeded the changing points, the level of SBP and DBP increased more rapidly.

The most direct approach for characterizing the quantum dynamics of a strongly interacting system is to measure the time evolution of its full many-body state. Despite the conceptual simplicity of this approach, it quickly becomes intractable as the system size grows. An alternate approach is to think of the many-body dynamics as generating noise, which can be measured by the decoherence of a probe qubit. Here we investigate what the decoherence dynamics of such a probe tells us about the many-body system. In particular, we utilize optically addressable probe spins to experimentally characterize both static and dynamical properties of strongly interacting magnetic dipoles. Our experimental platform consists of two types of spin defects in nitrogen delta-doped diamond: nitrogen-vacancy colour centres, which we use as probe spins, and a many-body ensemble of substitutional nitrogen impurities. We demonstrate that the many-body system's dimensionality, dynamics and disorder are naturally encoded in the probe spins' decoherence profile. Furthermore, we obtain direct control over the spectral properties of the many-body system, with potential applications in quantum sensing and simulation., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2023.)

While chimeric antigen receptor (CAR)-T-cell therapy has demonstrated remarkable effectiveness in the treatment of B-cell lymphomas and leukemias, research on T-cell malignancies is still limited. Here, we reported a patient with hepatosplenic γδ T-cell lymphoma refractory to multiple lines of chemotherapy, who eventually achieved first complete remission with flow cytometry-confirmed minimal residual disease negativity after human leukocyte antigen (HLA) fully-mismatched sibling-derived CD7 CAR-T therapy. However, given the allogeneic nature, CAR-T cells dropped rapidly after a peak of 83.4% of circulating T-cells. Cytokine release syndrome, cytopenia, and infections occurred but were manageable after treatments. After the consolidative haploidentical hematopoietic stem cell transplantation (HSCT), the patient remained in remission at the end of the follow-up (13 months post-CAR-T infusion). This is the first case of relapsed/refractory hepatosplenic γδ T-cell lymphoma who achieved lasting CR after HLA fully-mismatched sibling-derived CD7 CAR-T therapy bridging to haploidentical HSCT.

Background: The association between dietary thiamine intake and the risk of diabetes remains unknown., Aim: We aimed to evaluate the relation of dietary thiamine intake with new-onset diabetes and examine possible effect modifiers., Design: Prospective cohort study., Methods: A total of 16 272 participants who were free of diabetes at baseline were enrolled from China Health and Nutrition Survey (CHNS). Dietary nutrients intake information was collected by 3-day dietary recalls in addition to using a 3-day food-weighed method to assess cooking oil and condiment consumption. New-onset diabetes was defined as a fasting blood glucose ≥7.0 mmol/l or a glycated haemoglobin (HbA1c) ≥6.5% (48 mmol/mol) or diagnosed by a physician during the follow-up., Results: During a median follow-up duration of 9.0 years, new-onset diabetes occurred in 1101 participants. Overall, the association between dietary thiamine intake and new-onset diabetes followed a U-shape (P for non-linearity <0.001). Consistently, when thiamine intake was assessed as quartiles, compared with those in the 2-3 quartiles (0.75 to 1.10 mg/day), the significantly higher risks of new-onset diabetes were found in participants in the first quartile [adjusted hazard ratio (HR), 1.33; 95% confidence interval (CI): 1.10, 1.61] and the fourth quartile (adjusted HR, 1.39; 95% CI: 1.17, 1.67). Similar results were found when further adjusting for the intake of other major nutrients or food groups; or using the propensity score weighting to control the imbalance of covariates., Conclusion: Our results suggested that there was a U-shape association between dietary thiamine intake and new-onset diabetes in general Chinese adults, with a minimal risk at 0.75-1.10 mg/day., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Chimeric antigen receptor (CAR)-T cell therapy against T cell malignancies faces major challenges including fratricide between CAR-T cells and product contamination from the blasts. Allogeneic CAR-T cells, generated from healthy donor T cells, can provide ready-to-use, blast-free therapeutic products, but their application could be complicated by graft-versus-host disease (GvHD) and host rejection. Here we developed healthy donor-derived, CD7-targeting CAR-T cells (RD13-01) with genetic modifications to resist fratricide, GvHD and allogeneic rejection, as well as to potentiate antitumor function. A phase I clinical trial (NCT04538599) was conducted with twelve patients recruited (eleven with T cell leukemia/lymphoma, and one with CD7-expressing acute myeloid leukemia). All patients achieved pre-set end points and eleven proceeded to efficacy evaluation. No dose-limiting toxicity, GvHD, immune effector cell-associated neurotoxicity or severe cytokine release syndrome (grade ≥ 3) were observed. 28 days post infusion, 81.8% of patients (9/11) showed objective responses and the complete response rate was 63.6% (7/11, including the patient with AML). 3 of the responding patients were bridged to allogeneic hematopoietic stem cell transplantation. With a median follow-up of 10.5 months, 4 patients remained in complete remission. Cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV) reactivation was observed in several patients, and one died from EBV-associated diffuse large B-cell lymphoma (DLBCL). Expansion of CD7-negative normal T cells was detected post infusion. In summary, we present the first report of a Phase I clinical trial using healthy donor-derived CD7-targeting allogeneic CAR-T cells to treat CD7 + hematological malignancies. Our results demonstrated the encouraging safety and efficacy profiles of the RD13-01 allogeneic CAR-T cells for CD7 + tumors., (© 2022. The Author(s) under exclusive licence to Center for Excellence in Molecular Cell Science, CAS.)

Background: Epoxyeicosatrienoic acids (EETs), the metabolite of arachidonic acid by cytochrome P450 (CYP), reportedly serve as a vital endogenous protective factor in several chronic diseases. EETs are metabolized by soluble epoxide hydrolase (sEH). We have observed that prophylactic blocking sEH alleviates bleomycin- (BLM-) induced pulmonary fibrosis (PF) in mice. However, the underlying mechanism and therapeutic effects of EETs on PF remain elusive., Objective: In this study, we investigated the effect of CYP2J2/EETs on the activation of murine fibroblasts and their mechanisms., Results: we found that administration of the sEH inhibitor (TPPU) 7 days after the BLM injection also reversed the morphology changes and collagen deposition in the lungs of BLM-treated mice, attenuating PF. Fibroblast activation is regarded as a critical role of PF. Therefore, we investigated the effects of EETs on the proliferation and differentiation of murine fibroblasts. Results showed that the overexpression of CYP2J2 reduced the cell proliferation and the expressions of α -SMA and PCNA induced by transforming growth factor- (TGF-) β 1 in murine fibroblasts. Then, we found that EETs inhibited the proliferation and differentiation of TGF- β 1-treated-NIH3T3 cells and primary murine fibroblasts. Mechanistically, we found that 14,15-EET disrupted the phosphorylation of Smad2/3 murine fibroblasts by activating PPAR γ , which was completely abolished by a PPAR γ inhibitor GW9662., Conclusion: our study shows that EETs inhibit the activation of murine fibroblasts by blocking the TGF- β 1-Smad2/3 signaling in a PPAR γ -dependent manner. Regulating CYP2J2-EET-sEH metabolic pathway may be a potential therapeutic option in PF., Competing Interests: The authors declared no conflict of interest., (Copyright © 2022 Jia-Hao Tao et al.)

The association between transportation physical activity (PA) and the risk of hypertension remains uncertain. We aimed to evaluated the prospective relation of transportation PA and new-onset hypertension among Chinese adults. A total of 9350 adults who were free of hypertension at baseline were enrolled from the China Health and Nutrition Survey (CHNS). Data on transportation PA were obtained by using self-reported questionnaires, and calculated as metabolic equivalent task (MET)-minutes/week. MET-minutes/week may account for both intensity and time spent on activities. The study outcome was new-onset hypertension, defined as systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg or diagnosed by physician or under antihypertensive treatment during the follow-up. During a median of 8.0 years (82,410 person-years) of follow-up, a total of 2949 participants developed hypertension. Overall, there was a U-shaped association between transportation PA and new-onset hypertension (P values for nonlinearity <0.001). Accordingly, compared with those with moderate transportation PA (213-<394 MET-minutes/week, the second quartile), significantly higher risks of new-onset hypertension were observed not only in participants with transportation PA < 213 MET-minutes/week (the first quartile) (HR, 1.29; 95%CI: 1.15-1.44), but in those with transportation PA ≥ 394 MET-minutes/ week (the 3-4 quartiles) (HR, 1.15; 95%CI: 1.04-1.27). Similar U-shaped correlations were found for various types of transportation PA (walking, bicycling, and motorized PA) and new-onset hypertension. In summary, moderate transportation PA is associated with a lower risk of new-onset hypertension among Chinese adults., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

A practical problem in supervised deep learning for medical image segmentation is the lack of labeled data which is expensive and time-consuming to acquire. In contrast, there is a considerable amount of unlabeled data available in the clinic. To make better use of the unlabeled data and improve the generalization on limited labeled data, in this paper, a novel semi-supervised segmentation method via multi-task curriculum learning is presented. Here, curriculum learning means that when training the network, simpler knowledge is preferentially learned to assist the learning of more difficult knowledge. Concretely, our framework consists of a main segmentation task and two auxiliary tasks, i.e. the feature regression task and target detection task. The two auxiliary tasks predict some relatively simpler image-level attributes and bounding boxes as the pseudo labels for the main segmentation task, enforcing the pixel-level segmentation result to match the distribution of these pseudo labels. In addition, to solve the problem of class imbalance in the images, a bounding-box-based attention (BBA) module is embedded, enabling the segmentation network to concern more about the target region rather than the background. Furthermore, to alleviate the adverse effects caused by the possible deviation of pseudo labels, error tolerance mechanisms are also adopted in the auxiliary tasks, including inequality constraint and bounding-box amplification. Our method is validated on ACDC2017 and PROMISE12 datasets. Experimental results demonstrate that compared with the full supervision method and state-of-the-art semi-supervised methods, our method yields a much better segmentation performance on a small labeled dataset. Code is available at https://github.com/DeepMedLab/MTCL.

Due to the difficulty in accessing a large amount of labeled data, semi-supervised learning is becoming an attractive solution in medical image segmentation. To make use of unlabeled data, current popular semi-supervised methods (e.g., temporal ensembling, mean teacher) mainly impose data-level and model-level consistency on unlabeled data. In this paper, we argue that in addition to these strategies, we could further utilize auxiliary tasks and consider task-level consistency to better excavate effective representations from unlabeled data for segmentation. Specifically, we introduce two auxiliary tasks, i.e., a foreground and background reconstruction task for capturing semantic information and a signed distance field (SDF) prediction task for imposing shape constraint, and explore the mutual promotion effect between the two auxiliary and the segmentation tasks based on mean teacher architecture. Moreover, to handle the potential bias of the teacher model caused by annotation scarcity, we develop a tripled-uncertainty guided framework to encourage the three tasks in the student model to learn more reliable knowledge from the teacher. When calculating uncertainty, we propose an uncertainty weighted integration (UWI) strategy for yielding the segmentation predictions of the teacher. In addition, following the advance of unsupervised learning in leveraging the unlabeled data, we also incorporate a contrastive learning based constraint to help the encoders extract more distinct representations to promote the medical image segmentation performance. Extensive experiments on the public 2017 ACDC dataset and the PROMISE12 dataset have demonstrated the effectiveness of our method., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

RNAs are closely associated with human diseases; however, immune-related genes (IRGs) and their potential regulatory networks in relation to spinal cord injury (SCI) are still poorly understood. Here, we investigated the key IRGs as well as the competing endogenous RNA (ceRNA) mechanisms that are associated with SCI pathogenesis based on microarray datasets and the use of a rat SCI model. Specifically, four independent SCI microarray datasets from Gene Expression Omnibus (GEO) database were analyzed and, thereafter, differentially expressed IRGs were annotated via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Furthermore, based on the GEO datasets, differentially expressed RNAs (DERNAs), including DEcircRNAs, DEmiRNAs, and DEmRNAs were identified and interactions between them were also predicted using online databases, and to construct a circular RNA (circRNA) mediated ceRNA network, candidate RNAs were also identified. Furthermore, the support vector machine (SVM) and least absolute shrinkage and selection operator (LASSO) methods were used for the identification of critical DERNAs, while differential gene expression was validated using the GSE20907 dataset. Our results were as follows. In the SCI microarray datasets, 32, 58, and 74 DEIRGs, DEcircRNAs, and DEmiRNAs were identified, respectively. In addition, GO and KEGG analyses showed that the DEIRGs were primarily enriched in neutrophil-mediated immunity and nuclear factor-kappa B (NF-κB) and hypoxia-inducible factor-1 (HIF-1) signaling pathways, and based on LASSO and SVM screening, PLXNB2 was identified as a DEIRG, while hsa&#95;circ&#95;0026646 was identified as the key circRNA, showing a higher SCI expression. Furthermore, our results proved that PLXNB2 and hsa&#95;circ&#95;0026646 were upregulated in SCI, whereas miR-331-3p was downregulated, and, interestingly, similar expression profiles were confirmed using the rat SCI model. Furthermore, fluorescent reporter assay indicated that both hsa&#95;circ&#95;0026646 and PLXNB2 have miR-331-3p target sites, and the ceRNA hypothesis suggested the dysregulation of hsa&#95;circ&#95;0026646, miR-331-3p, and PLXNB2 in SCI. Thus, our results suggested that in SCI pathogenesis, hsa&#95;circ&#95;0026646 correlates with PLXNB2 by targeting miR-331-3p.

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.

Objective: To investigate the risk factors of tumor lysis syndrome (TLS) in relapsed/refractory multiple myeloma (MM) patients undergoing B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy., Method: The clinical data of 99 relapsed/refractory MM patients receiving BCMA CAR-T cell therapy in the First Affiliated Hospital, Zhejiang University School of Medicine from July 2018 to December 2021 were collected in this study. Univariate analysis and multivariate logistic regression were performed to evaluate the risk factors of TLS following BCMA CAR-T cell therapy., Results: Among the 99 patients, TLS occurred in 17 cases (17.2%) with an onset time of (8.9±3.0) d after BCMA CAR-T cell therapy. All TLS patients developed TLS-related clinical manifestations, including 17 cases with renal dysfunction, 8 cases with arrhythmia. All TLS patients developed cytokine release syndrome (CRS) with an onset of 1.0 (1.0, 6.5) d after CAR-T cell therapy, and 13 cases developed grade 3-4 CRS. The levels of serum uric acid, serum creatinine and the ratio of cases with grade 3-4 CRS were significantly higher in TLS patients than in non-TLS patients (all P <0.05). Multivariate logistic regression revealed that serum creatinine ( OR =1.015, P <0.01) and severe CRS ( OR =9.371, P <0.01) were independent risk factors of TLS., Conclusions: Relapsed/refractory MM patients undergoing BCMA CAR-T therapy shows high incidence of TLS, which are related to elevated levels of serum creatinine and severe CRS. TLS can be prevented clinically by reducing serum creatinine and controlling CRS severity.

Objective: To analyze the clinical features of hemophagocytic syndrome (HLH) following B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy in patients with relapsed/refractory multiple myeloma., Methods: Ninety-nine patients with relapsed/refractory multiple myeloma (including 3 cases of plasma cell leukemia) undergoing BCMA CAR-T cell therapy (monocentric phaseⅠclinical trial, ChiCTR1800017404) in the First Affiliated Hospital, Zhejiang University School of Medicine from July 2018 to December 2021 were enrolled in the study. The baseline features, laboratory findings, treatment, and clinical response of these patients were analyzed., Results: CAR-T cell associated HLH (carHLH) occurred in 20 patients (20.20%), and the median onset time was 7(0-19) d after cytokine release syndrome (CRS). Patients with carHLH were maily male patients, and manifested as high percentage of abnormal plasma cells, higher incidence of severe CRS (grade 3-4), and robust expansion of CAR-T cells in the peripheral blood (all P <0.05). The levels of interleukin (IL)-6, IL-10 and interferon (IFN)-γ, the peak value of international normalized ratio and D-dimer were elevated, and the valley value of fibrinogen was decreased in patients with carHLH (all P <0.01). All carHLH patients resolved with proper intervention (including 7 cases with tocilizumab, 5 with steroids, 6 with both). The objective response rate in carHLH patients was slightly higher than that in non-carHLH patients [100.0% (17/17) vs. 94.87% (74/78), P >0.05]., Conclusions: The incidence of carHLH is relatively high in BCMA CAR-T cell treated patients, which is closely related to pretreatment tumor cell percentage in bone marrow, expansion of CAR-T cells and the secretion of cytokines. Medication based on tocilizumab and steroids can achieve considerable therapeutic effects in patient with carHLH.

Radiation therapy (RT) is regarded as the primary treatment for cancer in the clinic, aiming to deliver an accurate dose to the planning target volume (PTV) while protecting the surrounding organs at risk (OARs). To improve the effectiveness of the treatment planning, deep learning methods are widely adopted to predict dose distribution maps for clinical treatment planning. In this paper, we present a novel multi-constraint dose prediction model based on generative adversarial network, named Mc-GAN, to automatically predict the dose distribution map from the computer tomography (CT) images and the masks of PTV and OARs. Specifically, the generator is an embedded UNet-like structure with dilated convolution to capture both the global and local information. During the feature extraction, a dual attention module (DAM) is embedded to force the generator to take more heed of internal semantic relevance. To improve the prediction accuracy, two additional losses, i.e., the locality-constrained loss (LCL) and the self-supervised perceptual loss (SPL), are introduced besides the conventional global pixel-level loss and adversarial loss. Concretely, the LCL tries to focus on the predictions of locally important areas while the SPL aims to prevent the predicted dose maps from the possible distortion at the feature level. Evaluated on two in-house datasets, our proposed Mc-GAN has been demonstrated to outperform other state-of-the-art methods in almost all PTV and OARs criteria., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: A survey was conducted to analyze the epidemiological differences in ideal cardiovascular health (CVH) behaviors and factors after delivery in females with and without gestational hypertension (GH) and evaluate the influence of GH on cardiovascular health behaviors and factors., Methods: The present study adopted a cross-sectional design. A total of 4620 female workers who gave birth between 1976 and 2012 and received the annual health examination (2012 to 2013) at hospitals belonging to the Kailuan Medical Group were recruited. These subjects were divided into the GH group and non-GH (NGH) group, depending on whether they were combined with GH or not at delivery. The epidemiological differences in CVH behaviors and factors were compared between the two groups., Result: In both groups, the percentage of subjects achieving ideal smoking status was the highest, while the percentage of subjects achieving an ideal level of physical activity was the lowest among all behaviors and factors. Compared with the NGH group, the percentages of subjects achieving each of the seven ideal CVH metrics decreased in the GH group. The percentages of subjects achieving ideal body mass index (BMI), blood pressure, blood glucose level, and cholesterol level were significantly lower in the GH group than in the NGH group ( P < 0.05). The percentage of subjects with an ideal level of physical activity was higher in the NGH group than in the GH group. After stratification by age, the percentages of patients achieving ideal BMI, blood pressure, and blood glucose decreased with age regardless of the history of GH ( P < 0.05). In the younger age group, the percentage of subjects with GH achieving ideal body mass index was significantly lower than that of those without GH., Conclusion: Compared with females without GH, those with GH had higher BMI, blood pressure, blood glucose level, and cholesterol level among the seven CVH metrics surveyed., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2022 Haiyan Zhao et al.)

Introduction: This study was aimed to investigate the mechanisms of advanced glycation end products (AGEs) in promoting invasion and metastasis of breast cancer., Research Design and Methods: Patients with 131 breast cancer were enrolled in a cohort and followed up to investigate the association between AGEs and metastasis. Serum AGE concentrations were detected by ELISA. Breast cancer MDA-MB-231 cells were exposed to generated AGE-bovine serum albumin (BSA). CCK-8 assay was used to select the non-cytotoxic concentrations of AGE-BSA. Small interfering RNA was used to knock down Toll-like receptor 4 (TLR4). Migration and invasion were evaluated by wound healing and transwell assays. Real-time PCR and western blotting were used to detect the gene expressions., Results: In the cohort study, metastasis incidence was significantly correlated with serum AGE concentrations in patients with breast cancer (adjusted OR=1.75, 95% CI=1.20 to 2.57, p=0.004). During follow-up, metastasis interval was significantly shorter in diabetic than non-diabetic subjects. In the in vitro study, AGE-BSA incubation significantly promoted migration and invasion of cancer cells in a concentration-dependent manner. AGE-BSA dramatically increased expressions of receptor for AGEs (RAGE), TLR4, myeloid differentiation factor (MyD88), matrix metalloproteinase 9 (MMP9), promoted nuclear translocation of nuclear factor κB (NFκB) p65, but decreased the expression of inhibitor of NFκB (IκBα). TLR4 silencing significantly suppressed migration and invasion of cancer cells exposed to AGE-BSA. TLR4 silencing reduced the expression of MyD88 and MMP9, as well as nuclear translocation of NFκB p65 but increased IκBα expression in AGE-BSA-incubated breast cancer cells., Conclusions: AGEs are correlated with metastasis of breast cancer. AGEs' promoting effects on migration and invasion of breast cancer cells via activating RAGE/TLR4/MyD88 signaling were suggested as the involved mechanism., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cytomegalovirus (CMV) retinitis is a rare end-organ disease of CMV infection and is a marker of severe immunosuppression, especially in human immunodeficiency virus (HIV)-positive patients. In multiple myeloma (MM) patients, CMV retinitis has been reported in the post-transplant setting, with an incidence lower than 0.2%, and in patients receiving lenalidomide. Here, we describe the first case of CMV retinitis in myeloma patients following B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T (BCMA CAR-T) cell therapy. In addition to CMV, the patient developed multiple infections including a mouth ulcer, pneumonia, and fungal enteritis. While the complete remission (CR) status of MM was maintained, he regained a visual acuity of 20/1000 after appropriate ophthalmologic treatment. This single case illustrates the potential of BCMA CAR-T therapy to induce profound humoral immunosuppression, and demonstrates an imperative need for an established standard of monitoring and prophylaxis of post-CAR-T infections.

This review discusses the major concerns and changes emerged during the rapidly extended clinical application of chimeric antigen receptor (CAR) T therapy based on our experience and understanding. In the past decades, the CAR-T cells have been questioned, sequentially, about their capability of inducing initial remission, their safety profile, their ability to sustain long-term persistence and response, and their potential to be industrialized. Significant advances, novel targeting strategies, innovative molecular structure, fine tuning of both CAR-T and host immune system, combination with other therapies, streamlined manufacturing, and etc., have been made to overcome these challenges. Although not perfectly resolved, rational pathways have been proposed to pass through the barriers. Here, we present the recent achievements on these pathways, and look into the possible future directions.

Central nervous system (CNS) involvement is a rare complication of multiple myeloma (MM) that portends an extremely poor prognosis. Although chimeric antigen receptor (CAR)-T cell therapy is considered a promising strategy for patients with MM, the role of CAR-T cell therapy in MM involving the CNS has not been fully elucidated. In this study, we retrospectively analyzed 4 cases of B-cell maturation antigen CAR-T cell therapy for patients with relapsed/refractory MM involving the CNS. Patients received a range of 2-7 lines of prior therapy, including 1 autologous hematopoietic stem cell transplant. The most common adverse event was cytokine release syndrome, which was observed in all 4 patients, including 2 with grade 1 and 2 with grade 2. No patient was complicated with immune effector cell-associated neurotoxicity syndrome. Within the follow-up (median: 257 d, range: 116-392 d), 3 of 4 patients reached complete remission (CR), and 1 patient reached partial response. At the data cutoff, 1 patient continued to remain in CR at day 220, and the patient with partial response died at day 116. The other 2 patients relapsed at 317 and 111 days with CR durations of 287 and 81 days, respectively. Our results show promising effectiveness and acceptable safety of CAR-T cell therapy for heavily pretreated patients with CNS MM., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)