TMEM2 inhibits the development of Graves' orbitopathy through the JAK-STAT signaling pathway.

A mouse model was used to investigate the role of the hyaluronidase, transmembrane protein 2 (TMEM2), on the progression of Graves' orbital (GO) disease. We established a GO mouse model through immunization with a plasmid expressing the thyroid stimulating hormone receptor. Orbital fibroblasts (OFs) were subsequently isolated from both GO and non-GO mice for comprehensive in vitro analyses. The expression of TMEM2 was assessed using qRT-PCR, Western blot and immunohistochemistry in vivo. Disease pathology was evaluated by H&E staining and Masson's trichrome staining in GO mouse tissues. Our investigation revealed a notable reduction in TMEM2 expression in GO mouse orbital tissues. Through overexpression and knockdown assays, we demonstrated that TMEM2 suppresses inflammatory cytokines and reactive oxygen species production. TMEM2 also inhibits the formation of lipid droplets in OFs and the expression of adipogenic factors. Further incorporating Gene Set Enrichment Analysis of relevant GEO datasets and subsequent in vitro cell experiments, robustly confirmed that TMEM2 overexpression was associated with a pronounced upregulation of the JAK/STAT signaling pathway. In vivo, TMEM2 overexpression reduced inflammatory cell infiltration, adipogenesis, and fibrosis in orbital tissues. These findings highlight the varied regulatory role of TMEM2 in GO pathogenesis. Our study reveals that TMEM2 plays a crucial role in mitigating inflammation, suppressing adipogenesis, and reducing fibrosis in GO. TMEM2 has potential as a therapeutic target and biomarker for treating or alleviating GO. These findings advance our understanding of GO pathophysiology and provide opportunities for targeted interventions to modulate TMEM2 for therapeutic purposes.

Association of peritumoral region features assessed on breast MRI and prognosis of breast cancer: a systematic review and meta-analysis.

BACKGROUND: Increasing attention has been given to the peritumoral region. However, conflicting findings have been reported regarding the relationship between peritumoral region features on MRI and the prognosis of breast cancer. PURPOSE: To evaluate the relationship between peritumoral region features on MRI and prognosis of breast cancer. MATERIALS AND METHODS: A retrospective meta-analysis of observational studies comparing either qualitative or quantitative assessments of peritumoral MRI features on breast cancer with poor prognosis and control subjects was performed for studies published till October 2022. Pooled odds ratios (ORs) or standardized mean differences and 95% confidence intervals (CIs) were estimated by using random-effects models. The heterogeneity across the studies was measured using the statistic I2. Sensitivity analyses were conducted to test this association according to different study characteristics. RESULTS: Twenty-four studies comprising 1853 breast cancers of poor prognosis and 2590 control participants were included in the analysis. Peritumoral edema was associated with non-luminal breast cancers (OR=3.56; 95%CI: 2.17, 5.83; p=.000), high expression of the Ki-67 index (OR=3.70; 95%CI: 2.41, 5.70; p =.000), high histological grade (OR=5.85; 95%CI: 3.89, 8.80; p=.000), lymph node metastasis (OR=2.83; 95%CI: 1.71, 4.67; p=.000), negative expression of HR (OR=3.15; 95%CI: 2.03, 4.88; p=.000), and lymphovascular invasion (OR=1.72; 95%CI: 1.28, 2.30; p=.000). The adjacent vessel sign was associated with greater odds of breast cancer with poor prognosis (OR=2.02; 95%CI: 1.68, 2.44; p=.000). Additionally, breast cancers with poor prognosis had higher peritumor-tumor ADC ratio (SMD=0.67; 95%CI: 0.54, 0.79; p=.000) and peritumoral ADCmean (SMD=0.29; 95%CI: 0.15, 0.42; p=.000). A peritumoral region of 2-20 mm away from the margin of the tumor is recommended. CONCLUSION: The presence of peritumoral edema and adjacent vessel signs, higher peritumor-tumor ADC ratio, and peritumoral ADCmean were significantly correlated with poor prognosis of breast cancer. CLINICAL RELEVANCE STATEMENT: MRI features of the peritumoral region can be used as a non-invasive index for the prognostic evaluation of invasive breast cancer. KEY POINTS: • Peritumoral edema was positively associated with non-luminal breast cancer, high expression of the Ki-67 index, high histological grade, lymph node metastasis, negative expression of HR, and lymphovascular invasion. • The adjacent vessel sign was associated with greater odds of breast cancers with poor prognosis. • Breast cancers with poor prognosis had higher peritumor-tumor ADC ratio and peritumoral ADCmean.

Diagnostic efficiency of [68 Ga]Ga-DOTA-FAPI-04 in differentiating periprosthetic hip joint infection and aseptic failure.

PURPOSE: To assess the efficiency of [68 Ga]Ga-DOTA-FAPI-04 in diagnosing periprosthetic hip joint infection and establish a diagnostic standard of clinical significance based on uptake pattern. METHODS: [68 Ga]Ga-DOTA-FAPI-04 PET/CT was performed in patients with symptomatic hip arthroplasty from December 2019 to July 2022. The reference standard was based on the 2018 Evidence-Based and Validation Criteria. Two diagnostic criteria, SUVmax and uptake pattern, were used to diagnose PJI. Meanwhile, original data were imported into IKT-snap to draw the view of interest, A.K. was used to extract features of clinical cases, and unsupervised clustering analysis was applied according to the groups. RESULTS: A total of 103 patients were included, 28 of whom had PJI. The area under the curve of SUVmax was 0.898, which was better than that of all of the serological tests. The cutoff value of SUVmax was 7.53, and the sensitivity and specificity were 100 and 72%, respectively. The sensitivity, specificity and accuracy of the uptake pattern were 100, 93.1 and 95%, respectively. In radiomics analysis, the features of PJI were significantly different from those of aseptic failure. CONCLUSION: The efficiency of [68 Ga]Ga-DOTA-FAPI-04 PET/CT in diagnosing PJI showed promising results, and the diagnostic criteria of the uptake pattern were more clinically instructive. Radiomics also showed certain application prospects in the field of PJI. TRIAL REGISTRATION NUMBER: Trial registration: ChiCTR2000041204. Registered 24 September 2019.

Associations of parental feeding practices with children's eating behaviors and food preferences: a Chinese cross-sectional study.

BACKGROUND: Childhood inadequate eating behaviors contribute to the epidemic of obesity. Previous research suggests that parental feeding practices are partially associated with development of eating behaviors among children, but the results are inconsistent. The present study was to investigate whether parental feeding practices were associated with eating behaviors and food preferences among Chinese children. METHODS: A cross-sectional study was conducted to collect data from 242 children (ages 7-12) in six-primary schools in Shanghai, China. A series of questionnaires including parental feeding practices and children's eating behaviors have been validated, and were completed by one of parent who has responded for child's daily diet and living. In addition, researchers instructed children to complete the questionnaire of food preference. After adjustment for children's age, sex and BMI status, as well as parental education and family income, the linear regression analysis was used to evaluate relationships of parental feeding practices with children's eating behaviors and food preferences. RESULTS: Parents with boys had higher level of control overeating practice than those with girls. Mothers who responded to child's daily diet and living and completed feeding practices questionnaire used a greater level of emotional feeding practices than fathers. Boys had higher levels of food responsiveness, emotional overeating, enjoyment of food and desire to drink than girls. Boys had different preferences for meat, processed meat products, fast foods, dairy foods, eggs, and snacks and starchy staples & beans from girls. In addition, scores of instrumental feeding practice and preference for meat significantly differed among children with different weight status. Furthermore, parental emotional feeding practice was positively associated with children's emotional undereating (ß 0.54, 95% CI 0.16 to 0.92). There were also positive associations of parental encouragement to eat with children's preference for the processed meat (ß 0.43, 95% CI 0.08 to 0.77). Moreover, instrumental feeding practice was negatively associated with children's fish liking (ß -0.47, 95% CI -0.94 to -0.01). CONCLUSION: The current findings support associations of emotional feeding practice with some children's emotional undereating, as well as parental encouragement to eat and instrumental feeding practice related to preference for processed meat and fish, respectively. Further studies should continue to ascertain these associations using longitudinal designs, and to evaluate efficacy of parental feeding practices impacting developments of healthy eating behaviors and preferences for healthy foods among children by interventional studies.

Synthesis, preclinical evaluation, and first-in-human study of Al18F-PSMA-Q for prostate cancer imaging.

PURPOSE: To investigate the potential of a novel Al18F-labeled PSMA-targeted radiotracer for PCa diagnosis through both preclinical and pilot clinical studies. METHODS: Al18F-PSMA-Q was prepared automatically. The binding affinity to PSMA was evaluated in vitro using the 22Rv1 (PSMA +) and PC-3 (PSMA -) cell lines. Pharmacokinetics evaluation, biodistribution study, Micro-PET imaging of Al18F-PSMA-Q in normal mice and tumor-bearing mice, and a comparison with 18F-DCFPyL were performed. PET/CT imaging was performed on 8 healthy volunteers and 20 newly diagnosed PCa patients at 1 h post-injection (p.i.). The biodistribution in human and preliminary diagnostic efficacy of Al18F-PSMA-Q were evaluated, and the radiation dosimetry was estimated using OLINDA/EXM 2.0 software. RESULT: Qualified Al18F-PSMA-Q was efficiently prepared with a non-decay-corrected radiochemical yield (RCY) of 22.0-28.3%, a specific activity (SA) of > 50 GBq/µmol. The hydrophilicity was comparably high with a log P value of - 3.69 ± 0.39. Al18F-PSMA-Q was found to bind to PSMA specifically with a Ki value of 17.05 ± 1.14 nM. The distribution and elimination half-lives of Al18F-PSMA-Q were 3.93 min and 14.22 min, respectively, which were shorter than those of 18F-DCFPyL. Micro-PET imaging of Al18F-PSMA-Q can clearly differentiate 22Rv1 tumors from PC-3 tumors and background with a high SUVmax of 2.17 ± 0.42 and a tumor-to-muscle ratio of 84.37 ± 31.62, which were higher than those of 18F-DCFPyL (1.79 ± 0.39 and 13.25 ± 1.65). The uptake of Al18F-PSMA-Q in 22Rv1 cells and tumors can be substantially blocked by 2-PMPA. High level accumulation of Al18F-PSMA-Q was observed in organs physiologically expressing PSMA. Twenty-six tumor lesions were detected in 20 PCa patients, and the mean SUVmax values of primary tumors, lymph node metastasis, bone metastases, and tumor-muscle ratios were 19.71 ± 16.52, 5.11, 31.30 ± 29.85, and 44.77 ± 22.29, respectively. The mean SUVmax of tumors in patients with PSA > 10 ng/mL was significantly higher than that in patients with PSA ≤ 10 ng/mL (25.97 ± 18.64 vs. 10.33 ± 3.74). Meanwhile, the mean SUVmax of tumors in patients with a Gleason score ≥ 8 was significantly higher than that in patients with a Gleason score < 8 (31.85 ± 22.09 vs. 13.18 ± 11.58). The kidneys received the highest estimated dose of 0.098 ± 0.006 mGy/MBq, and the effective dose was calculated as 0.0128 ± 0.007 mGy/MBq. CONCLUSION: The novel qualified PSMA-targeted radiotracer Al18F-PSMA-Q was conveniently prepared with favorable yield and SA. The results of preclinical and pilot clinical studies exhibited a high specific uptake in PCa lesions and an excellent tumor-to-background ratio with a reasonable radiation exposure, which indicated the great potential of Al18F-PSMA-Q for PCa imaging. TRIAL REGISTRATION: Chinese Clinical trial registry ChiCTR2100053507, Registered 23 November 2021, retrospectively registered.

18F-FDG and 68 Ga-FAPI PET/CT for the evaluation of periprosthetic joint infection and aseptic loosening in rabbit models.

PURPOSE: We built a joint replacement loosening model based on the original rabbit model of infection and evaluated the performance characteristics of 18F-FDG and 68 Ga-FAPI in evaluating infection and loosening. METHODS: After surgery, the rabbits were divided into four groups, with six individuals in the control group and 10 each in the aseptic loosening, S. aureus and S. epidermidis groups. PET/CT and serological examination were performed three times at two-week intervals. After the rabbits were euthanized, micro-CT, tissue pathology, pullout tests and scanning electron microscopy (SEM) were performed. RESULTS: The pullout test and SEM showed the feasibility of the aseptic loosening model. 18F-FDG showed similar performance in the control and loosening groups. The SUVmax of the S. aureus group was consistently higher than that of the S. epidermidis group. As for 68 Ga-FAPI, the SUVmax of the control group was lowest in the second week and gradually increased over subsequent weeks. The SUVmax of the loosening group began to exceed that of the control group after the second week. The SUVmax of the S. aureus group in the second week was the lowest among the four groups and increased as the number of weeks increased. The pathology results showed concordance with the performance of PET/CT. Linear regressions between SUVmax and serology showed that 18F-FDG was positively correlated with CRP and IL-6, while 68 Ga-FAPI revealed negative correlations with CRP and IL-6 in the second week and positive correlations in the sixth week. In addition, the SUVmax and MT(target)V of both 18F-FDG and 68 Ga-FAPI were negatively correlated with bone volume/trabecular volume (TV) and bone surface area/TV. CONCLUSION: In this longitudinal observation, 68 Ga-FAPI showed greater sensitivity than 18F-FDG in detecting diseases, and 68 Ga-FAPI had no intestinal or muscular uptake. The MT(target)V of 68 Ga-FAPI was larger than that of 18F-FDG, which meant that 68 Ga-FAPI had the potential to define the scope of lesions more accurately. Finally, the SUVmax of 68 Ga-FAPI could not differentiate between loosening and infection; further study of the diagnostic criteria is warranted.

Etiologic classification of infantile spasms using positron emission/magnetic resonance imaging and the efficacy of adrenocorticotropic hormone therapy.

PURPOSE: The aim of this study was to investigate if the etiologic classification of infantile spasm (IS) using positron emission tomography/magnetic resonance imaging (PET/MR) is feasible. Based on the classified etiologic groups, we further evaluated the efficacy of adrenocorticotropic hormone (ACTH) therapy in different IS groups. MATERIALS AND METHODS: One hundred fifty-five children diagnosed with IS were included in this study. A qualitative assessment of the PET/MR images was performed. The abnormal lesions localized with both MR and PET images were considered to be epileptic foci, and the patients with these lesions were classified into the structural-metabolic group. For the remaining patients, quantitative analyses were further performed on whole-brain T1-weighted (T1WI) and PET images, based on the asymmetry index of bilateral volumes and metabolic quantifications. Patients with asymmetry indices above a certain threshold (15%) were classified into the structural-metabolic group. The patients without positive finding from either qualitative or quantitative analyses were assigned to the unknown etiology group. The efficacy of ACTH therapy was evaluated in the different IS groups. RESULTS: Among the 155 children with IS, 18 genetic cases were first diagnosed by the genetic testing. In the remaining 137 cases, 49 cases were identified with structural-metabolic etiology using qualitative PET/MR assessments. Fifty-two cases were newly diagnosed with quantitative analysis. The remaining 36 cases were classified into the unknown etiology group. The efficacy of ACTH therapy was statistically different for the different etiology groups (p < 0.001). The respective efficacy rates for the genetic, qualitative structural-metabolic, quantitative structural-metabolic, and unknown etiology groups were 27.8% (5/18), 30.61% (15/49), 34.62% (18/52), and 72.22% (26/36), respectively. CONCLUSIONS: The combination of PET and MR provides additional diagnostic information for IS. Quantitative analysis can further improve patient etiologic classifications and the predication of therapy efficacies.

PET image denoising using unsupervised deep learning.

PURPOSE: Image quality of positron emission tomography (PET) is limited by various physical degradation factors. Our study aims to perform PET image denoising by utilizing prior information from the same patient. The proposed method is based on unsupervised deep learning, where no training pairs are needed. METHODS: In this method, the prior high-quality image from the patient was employed as the network input and the noisy PET image itself was treated as the training label. Constrained by the network structure and the prior image input, the network was trained to learn the intrinsic structure information from the noisy image and output a restored PET image. To validate the performance of the proposed method, a computer simulation study based on the BrainWeb phantom was first performed. A 68Ga-PRGD2 PET/CT dataset containing 10 patients and a 18F-FDG PET/MR dataset containing 30 patients were later on used for clinical data evaluation. The Gaussian, non-local mean (NLM) using CT/MR image as priors, BM4D, and Deep Decoder methods were included as reference methods. The contrast-to-noise ratio (CNR) improvements were used to rank different methods based on Wilcoxon signed-rank test. RESULTS: For the simulation study, contrast recovery coefficient (CRC) vs. standard deviation (STD) curves showed that the proposed method achieved the best performance regarding the bias-variance tradeoff. For the clinical PET/CT dataset, the proposed method achieved the highest CNR improvement ratio (53.35% ± 21.78%), compared with the Gaussian (12.64% ± 6.15%, P = 0.002), NLM guided by CT (24.35% ± 16.30%, P = 0.002), BM4D (38.31% ± 20.26%, P = 0.002), and Deep Decoder (41.67% ± 22.28%, P = 0.002) methods. For the clinical PET/MR dataset, the CNR improvement ratio of the proposed method achieved 46.80% ± 25.23%, higher than the Gaussian (18.16% ± 10.02%, P < 0.0001), NLM guided by MR (25.36% ± 19.48%, P < 0.0001), BM4D (37.02% ± 21.38%, P < 0.0001), and Deep Decoder (30.03% ± 20.64%, P < 0.0001) methods. Restored images for all the datasets demonstrate that the proposed method can effectively smooth out the noise while recovering image details. CONCLUSION: The proposed unsupervised deep learning framework provides excellent image restoration effects, outperforming the Gaussian, NLM methods, BM4D, and Deep Decoder methods.

Low- and high-frequency transcutaneous electrical acupoint stimulation induces different effects on cerebral µ-opioid receptor availability in rhesus monkeys.

Although systematic studies have demonstrated that acupuncture or electroacupuncture (EA) analgesia is based on their accelerating endogenous opioid release to activate opioid receptors and that EA of different frequencies is mediated by different opioid receptors in specific areas of the central nervous system, there is little direct, real-time evidence to confirm this in vivo. The present study was designed to investigate the effects of transcutaneous electrical acupoint stimulation (TEAS), an analogue of EA, at low and high frequencies on µ-opioid receptor (MOR) availability in the brain of rhesus monkeys. Monkeys underwent 95-min positron emission tomography (PET) with (11) C-carfentanil three times randomly while receiving 0, 2, or 100 Hz TEAS, respectively. Each TEAS was administered in the middle 30 min during the 95-min PET scan, and each session of PET and TEAS was separated by at least 2 weeks. The results revealed that 2 Hz but not 100 Hz TEAS evoked a significant increase in MOR binding potential in the anterior cingulate cortex, the caudate nucleus, the putamen, the temporal lobe, the somatosensory cortex, and the amygdala compared with 0 Hz TEAS. The effect remained after the end of TEAS in the anterior cingulate cortex and the temporal lobe. The selective increase in MOR availability in multiple brain regions related to pain and sensory processes may play a role in mediating low-frequency TEAS efficacy.

Standardized uptake value based evaluation of lymphoma by FDG and FLT PET/CT.

Although (18) F-FDG PET/CT imaging is the conventional method for evaluating lymphoma, PET/CT imaging with radiopharmaceuticals other than FDG is being investigated. We evaluated the utility of different standardized uptake value (SUV) measurements in (18) F-FLT PET/CT scans compared with PET/CT scans performed with FDG. Two scans, each using one of the radiopharmaceuticals, were performed on each of 114 patients with histologically proven lymphoma. Maximum and mean SUV (SUV(max)) and (SUV(mean)) of all visualized lesions, with backgrounds of mediastinal blood pool, liver, spleen and vertebra were calculated. The ratios of the SUVs of the lesions to those of each reference region were statistically analyzed. Using receiver operating characteristic curves, we analyzed the differences in uptake of the two agents in aggressive and indolent B-cell non-Hodgkin lymphoma. We found that the SUV(max) measurements of FDG were significantly different between aggressive and indolent B-cell non-Hodgkin lymphoma. The receiver operating characteristic curve of SUV(max) of tumour/liver for FDG studies resulted in the most area under the curve. The SUV(max) of the tumour/mediastinum ratio for FLT studies resulted in the most area under the curve (0.781). There was no significant correlation between FDG and FLT uptake in most types of lymphoma we studied. Further studies of the characteristics of (18) F-FLT should employ the tumour/mediastinum SUV(max) ratio for accurate uptake measurement.

Comparison of dual-biomarker PIB-PET and dual-tracer PET in AD diagnosis.

OBJECTIVES: To identify the optimal time window for capturing perfusion information from early (11)C-PIB imaging frames (perfusion PIB, (11)C-pPIB) and to compare the performance of (18)F-FDG PET and "dual biomarker" (11)C-PIB PET [(11)C-pPIB and amyloid PIB ((11)C-aPIB)] for classification of AD, MCI and CN subjects. METHODS: Forty subjects (14 CN, 12 MCI and 14 AD patients) underwent (18)F-FDG and (11)C-PIB PET studies. Pearson correlation between the (18)F-FDG image and sum of early (11)C-PIB frames was maximised to identify the optimal time window for (11)C-pPIB. The classification power of imaging parameters was evaluated with a leave-one-out validation. RESULTS: A 7-min time window yielded the highest correlation between (18)F-FDG and (11)C-pPIB. (11)C-pPIB and (18)F-FDG images shared a similar radioactive distribution pattern. (18)F-FDG performed better than (11)C-pPIB for the classification of both AD vs. CN and MCI vs. CN. (11)C-pPIB + (11)C-aPIB and (18)F-FDG + (11)C-aPIB yielded the highest classification accuracy for the classification of AD vs. CN, and (18)F-FDG + (11)C-aPIB had the best classification performance for the classification of MCI vs. CN CONCLUSION: C-pPIB could serve as a useful biomarker of rCBF for measuring neural activity and improve the diagnostic power of PET for AD in conjunction with (11)C-aPIB. (18)F-FDG and (11)C-PIB dual-tracer PET examination could better detect MCI. KEY POINTS: • Dual-tracer PET examination provides neurofunctional and neuropathological information for AD diagnosis. • The identified optimal 11C-pPIB time frames had highest correlation with 18F-FDG. • 11C-pPIB images shared a similar radioactive distribution pattern with 18F-FDG images. • 11C-pPIB can provide neurofunctional information. • Dual-tracer PET examination could better detect MCI.

[Validation of standardized uptake values for ¹8F-FDG in normal organs: comparison of whole-body PET/CT and PET/MRI].

OBJECTIVE: To validate whether PET/MR could provide a semi-quantitative measurement (SUV(max)) comparable to that produced by PET/CT in normal organs. METHODS: 277 subjects underwent an ordinary ¹8F-FDG PET/CT followed by a PET/MR scan with a 25-45 min interval. Region of interest (ROIs) were drawn in 4 reference normal organs/tissues in both MRAC-PET and CTAC-PET images and the liver and erector spinae in the dual-time point PET/CT images. RESULTS: 259 malignant and 21 benign lesions, pathologically confirmed, were detected in the 220 subjects. SUV(max) derived from PET/CT (SUV(max)-CT) and PET/MR (SUV(max)-MRI) was highly correlated over the reference organ ROIs (r = 0.62-0.73), except lung (r = 0.44). The SUV(max)-MRI was significantly lower than the respective SUV(max)-CT in all 4 organs and after delay-correction in liver and muscle. CONCLUSION: The results indicate that PET/MR can provide reliable measurement in physiological organs.

Iliopsoas fibrosis after revision of total hip arthroplasty revealed by 68Ga-FAPI PET/CT: a case report.

Background: Total hip arthroplasty (THA) is a well-established surgical procedure that has been extensively validated to alleviate pain, enhance joint function, improve the ability to perform daily activities, and enhance overall quality of life. However, this procedure is associated with certain complications, among which skeletal muscle fibrosis is a frequently overlooked but significant complication that can lead to persistent pain. Currently, there is no effective method for diagnosing skeletal muscle fibrosis following total hip arthroplasty. Case report: We report a 75-year-old male patient who complained of left groin pain after revision total hip arthroplasty. Serological examinations, X-rays, and bone scan results were all normal. However, during the 68Ga-FAPI PET/CT examination, we observed significant radiotracer uptake along the iliopsoas muscle. This abnormal uptake pattern suggested potential biological activity in this specific area. Combined with physical examination, the patient was diagnosed with iliopsoas fibrosis. Conclusions: The presented images indicated that the uptake pattern was an important indicator for diagnosis, and the prospect of fibroblast activation protein in the diagnosis of skeletal muscle fibrosis has shown certain application value.

Social network analysis of a decade-long collaborative innovation network between hospitals and the biomedical industry in China.

Collaborative innovation between hospitals and biomedical enterprises is crucial for ensuring breakthroughs in their development. This study explores the structural characteristics and examines the main roles of associated key actors of collaborative innovation between hospitals and biomedical enterprises in China. Using the jointly owned patent data within the country's healthcare industry, a decade-long collaborative innovation network between hospitals and biomedical enterprises in China was established and analyzed through social network analysis. The results revealed that the overall levels of collaborative innovation network density, collaborative frequency, and network connectivity were significantly low, especially in less-developed regions. In terms of actors with higher degree centrality, hospitals accounted for the majority, whereas a biomedical enterprise in Shenzhen had the highest degree centrality. Organizations in underdeveloped and northwest regions and small players were more likely to implement collaborative innovation. In conclusion, a collaborative innovation network between hospitals and biomedical enterprises in China demonstrated high dispersion and poor development levels. Stimulating organizations' initiatives for collaborative innovation may enhance quality and quantity of such innovation. Policy support and economic investments, strategic collaborative help, and resource and partnership optimization, especially for small players and in less-developed and northwest regions, should be encouraged to enhance collaborative innovation between hospitals and the biomedical industry in China and other similar countries or regions.

Characteristics and influencing factors of caregivers' healthcare preferences for young children under COVID-19 lockdown: a cross-sectional study in Shanghai, China.

BACKGROUND: Missed or delayed child healthcare caused by the COVID-19 lockdown has threatened young children's health and has had an unpredictable influence on caregivers' child healthcare preferences. This study investigated caregivers' child healthcare preferences and the factors that influence them among families with young children (0-3 years) during the lockdown in Shanghai. METHODS: Participants in this cross-sectional study were enrolled through random encounter sampling. Questionnaires were distributed online from June 1 to November 10, 2022, in Shanghai. A total of 477 valid questionnaires were received. The demographics of caregivers and their families, children's characteristics, COVID-19-related information, and caregivers' healthcare preferences were analyzed. The statistical analyses included frequency and percentage, chi-square tests, and multinomial logistic regression. RESULTS: Caregivers preferred child healthcare professionals in the community health service system (CHS; 47.6%) followed by hospital pediatricians (40.0%) during lockdown. Caregivers with the following characteristics preferred CHS: those with an annual household income of CNY 200,000-300,000, those whose youngest children were aged 8-12 months, and those who experienced early childhood physical development issues. Caregivers preferred hospitals if they had experienced healthcare-seeking-related difficulties in accessing professional guidance from hospital pediatricians. CONCLUSIONS: During pandemic lockdowns, policymakers should allocate more resources to CHS to meet caregivers' childcare demands. Moreover, special attention should be given to the healthcare needs for CHS among families with specific demographics. TRIAL REGISTRATION: Approval was obtained from the Ethics Committee of Shanghai Jiao Tong University School of Medicine School of Public Health (SJUPN-202,109; June 1, 2022).

Thorough molecular configuration analysis of noncanonical AAV genomes in AAV vector preparations.

The unique palindromic inverted terminal repeats (ITRs) and single-stranded nature of adeno-associated virus (AAV) DNA are major hurdles to current sequencing technologies. Due to these characteristics, sequencing noncanonical AAV genomes present in AAV vector preparations remains challenging. To address this limitation, we developed thorough molecule configuration analysis of noncanonical AAV genomes (TMCA-AAV-seq). TMCA-AAV-seq takes advantage of the documented AAV packaging mechanism in which encapsidation initiates from its 3' ITR, for AAV-seq library construction. Any AAV genome with a 3' ITR is converted to a template suitable to adapter addition by a Bst DNA polymerase-mediated extension reaction. This extension reaction helps fix ITR heterogeneity in the AAV population and allows efficient adapter addition to even noncanonical AAV genomes. The resulting library maintains the original AAV genome configurations without introducing undesired changes. Subsequently, long-read sequencing can be performed by the Pacific Biosciences (PacBio) single-molecule, real-time (SMRT) sequencing technology platform. Finally, through comprehensive data analysis, we can recover canonical, noncanonical AAV DNA, and non-AAV vector DNA sequences, along with their molecular configurations. Our method is a robust tool for profiling thorough AAV-population genomes. TMCA-AAVseq can be further extended to all parvoviruses and their derivative vectors.

Effective dose of intranasal remimazolam for preoperative sedation in preschool children: a dose-finding study using Dixon's up-and-down method.

Background: Most preschool children are distressed during anesthesia induction. While current pharmacological methods are useful, there is a need for further optimization to an "ideal" standard. Remimazolam is an ultra-short-acting benzodiazepine, and intranasal remimazolam for pre-induction sedation may be promising. Methods: This study included 32 preschool children who underwent short and minor surgery between October 2022 and January 2023. After pretreatment with lidocaine, remimazolam was administered to both nostrils using a mucosal atomizer device. The University of Michigan Sedation Score (UMSS) was assessed for sedation 6, 9, 12, 15, and 20 min after intranasal atomization. We used Dixon's up-and-down method, and probit and isotonic regressions to determine the 50% effective dose (ED50) and 95% effective dose (ED95) of intranasal remimazolam for pre-induction sedation. Results: Twenty-nine pediatric patients were included in the final analysis. The ED50 and ED95 of intranasal remimazolam for successful pre-induction sedation, when processed via probit analysis, were 0.65 (95% confidence interval [CI], 0.59-0.71) and 0.78 mg/kg (95% CI, 0.72-1.07), respectively. In contrast, when processed by isotonic regression, they were 0.65 (95% CI: 0.58-0.72 mg/kg) and 0.78 mg/kg (95% CI: 0.69-1.08 mg/kg), respectively. At 6 min after intranasal remimazolam treatment, 81.2% (13/16) of "positive" participants were successfully sedated with a UMSS ≧ 1. All the "positive" participants were successfully sedated within 9 min. Conclusion: Intranasal remimazolam is feasible for preschool children with a short onset time. For successful pre-induction sedation, the ED50 and ED95 of intranasal remimazolam were 0.65 and 0.78 mg/kg, respectively.

A novel class of self-complementary AAV vectors with multiple advantages based on cceAAV lacking mutant ITR.

Self-complementary AAV vectors (scAAV) use a mutant inverted terminal repeat (mITR) for efficient packaging of complementary stranded DNA, enabling rapid transgene expression. However, inefficient resolution at the mITR leads to the packaging of monomeric or subgenomic AAV genomes. These noncanonical particles reduce transgene expression and may affect the safety of gene transfer. To address these issues, we have developed a novel class of scAAV vectors called covalently closed-end double-stranded AAV (cceAAV) that eliminate the mITR resolution step during production. Instead of using a mutant ITR, we used a 56-bp recognition sequence of protelomerase (TelN) to covalently join the top and bottom strands, allowing the vector to be generated with just a single ITR. To produce cceAAV vectors, the vector plasmid is initially digested with TelN, purified, and then subjected to a standard triple-plasmid transfection protocol followed by traditional AAV vector purification procedures. Such cceAAV vectors demonstrate yields comparable to scAAV vectors. Notably, we observed enhanced transgene expression as compared to traditional scAAV vectors. The treatment of mice with hemophilia B with cceAAV-FIX resulted in significantly enhanced long-term FIX expression. The cceAAV vectors hold several advantages over scAAV vectors, potentially leading to the development of improved human gene therapy drugs.

Activation of CD14+ Monocytes via the IFN-γ Signaling Pathway Is Associated with Immune-Related Adverse Events in Hepatocellular Carcinoma Patients Receiving PD-1 Inhibition Combination Therapy.

(1) Background: Immune-related adverse events (irAEs) are a series of unique organ-specific inflammatory toxicities observed in patients with hepatocellular carcinoma (HCC) undergoing PD-1 inhibition combination therapy. The specific underlying mechanisms remain unclear. (2) Methods: We recruited 71 patients with HCC undergoing PD-1 inhibition combination therapy. These patients were then divided into two groups based on irAE occurrence: 34 had irAEs and 37 did not. Using Olink proteomics, we analyzed the aberrant inflammation-related proteins (IRPs) in these patient groups. For single-cell RNA sequencing (scRNA-seq) analysis, we collected peripheral blood mononuclear cells (PBMCs) from two representative patients at the pretreatment, irAE occurrence, and resolution stages. (3) Results: Our study revealed distinct plasma protein signatures in HCC patients experiencing irAEs after PD-1 inhibition combination therapy. We clarified the relationship between monocyte activation and irAEs, identified a strongly associated CD14-MC-CCL3 monocyte subset, and explored the role of the IFN-γ signaling pathway in monocyte activation during irAEs. (4) Conclusions: The activation of monocytes induced by the IFN-γ signaling pathway is an important mechanism underlying the occurrence of irAEs in HCC patients receiving PD-1 inhibition combination therapy.