Mulberry and Hippophae-based solid beverage promotes weight loss in rats by antagonizing white adipose tissue PPARγ and FGFR1 signaling.

Obesity, a multifactorial disease with many complications, has become a global epidemic. Weight management, including dietary supplementation, has been confirmed to provide relevant health benefits. However, experimental evidence and mechanistic elucidation of dietary supplements in this regard are limited. Here, the weight loss efficacy of MHP, a commercial solid beverage consisting of mulberry leaf aqueous extract and Hippophae protein peptides, was evaluated in a high-fat high-fructose (HFF) diet-induced rat model of obesity. Body component analysis and histopathologic examination confirmed that MHP was effective to facilitate weight loss and adiposity decrease. Pathway enrichment analysis with differential metabolites generated by serum metabolomic profiling suggests that PPAR signal pathway was significantly altered when the rats were challenged by HFF diet but it was rectified after MHP intervention. RNA-Seq based transcriptome data also indicates that MHP intervention rectified the alterations of white adipose tissue mRNA expressions in HFF-induced obese rats. Integrated omics reveals that the efficacy of MHP against obesogenic adipogenesis was potentially associated with its regulation of PPARγ and FGFR1 signaling pathway. Collectively, our findings suggest that MHP could improve obesity, providing an insight into the use of MHP in body weight management.

Transcriptomic insights into the lipotoxicity of high-fat high-fructose diet in rat and mouse.

Along with the increasing prevalence of obesity worldwide, the deleterious effects of high-calorie diet are gradually recognized through more and more epidemiological studies. However, the concealed and chronic causality whitewashes its unhealthy character. Given an ingenious mechanism orchestrates the metabolic adaptation to high-fat high-fructose (HFF) diet and connive its lipotoxicity, in this study, an experimental rat/mouse model of obesity was induced and a comparative transcriptomic analysis was performed to probe the mystery. Our results demonstrated that HFF diet consumption altered the transcriptomic pattern as well as different high-calorie diet fed rat/mouse manifested distinct hepatic transcriptome. Validation with RT-qPCR and Western blotting confirmed that SREBP1-FASN involved in de novo lipogenesis partly mediated metabolic self-adaption. Moreover, hepatic ACSL1-CPT1A-CPT2 pathway involved in fatty acids ß-oxidation, played a key role in the metabolic adaption to HFF. Collectively, our findings enrich the knowledge of the chronic adaptation mechanisms and also shed light on future investigations. Meanwhile, our results also suggest that efforts to restore the fatty acids metabolic fate could be a promising avenue to fight against obesity and associated steatosis and insulin resistance challenged by HFF diet.

Ambulatory blood pressure levels in individuals with uncontrolled clinic hypertension across Bangladesh, Pakistan, and Sri Lanka.

Hypertension is a leading risk factor for cardiovascular disease in South Asia. The authors aimed to assess the cross-country differences in 24-h ambulatory, daytime, and nighttime systolic blood pressure (SBP) among rural population with uncontrolled clinic hypertension in Bangladesh, Pakistan, and Sri Lanka. The authors studied patients with uncontrolled clinic hypertension (clinic BP ≥ 140/90 mmHg) who underwent ambulatory blood pressure monitoring (ABPM) during the baseline assessment as part of a community-based trial. The authors compared the distribution of ABPM profiles of patients across the three countries, specifically evaluating ambulatory SBP levels with multivariable models that adjusted for patient characteristics. Among the 382 patients (mean age, 58.3 years; 64.7% women), 56.5% exhibited ambulatory hypertension (24-h ambulatory BP ≥ 130/80 mmHg), with wide variation across countries: 72.6% (Bangladesh), 50.0% (Pakistan), and 51.0% (Sri Lanka; P < .05). Compared to Sri Lanka, adjusted mean 24-h ambulatory, daytime, and nighttime SBP were higher by 12.24 mmHg (95% CI 4.28-20.20), 11.96 mmHg (3.87-20.06), and 12.76 mmHg (4.51-21.01) in Bangladesh, separately. However, no significant differences were observed between Pakistan and Sri Lanka (P > .05). Additionally, clinic SBP was significantly associated with 24-h ambulatory (mean 0.38, 95% CI 0.28-0.47), daytime (0.37, 0.27-0.47), and nighttime SBP (0.40, 0.29-0.50) per 1 mmHg increase. The authors observed substantial cross-country differences in the distribution of ABPM profiles among patients with uncontrolled clinic hypertension in rural South Asia. The authors findings indicated the need to incorporate 24-h BP monitoring to mitigate cardiovascular risk, particularly in Bangladesh.

Mediating and moderating effects of authoritative parenting styles on adolescent behavioral problems.

Introduction: This study aimed to analyze how authoritative parenting affects behavioral problems among primary, junior high, and secondary high school students. Today, parental educational anxiety and parent-child relationship conflicts are common in China and are resulting in a high incidence of child behavioral problems. High-quality family education is becoming increasingly important in China. This study sought to provide a reference for developing responsive family education services. Methods: A total of 10,441 parents in Hubei Province, including urban and rural areas, were evaluated using the Parents' Education Anxiety Questionnaire, Parental Authority Parenting Questionnaire, Parent-Child Relationship Scale, and Self-Made Behavior Problem Scale to determine the internal mechanisms of child behavioral problems in the family system. To make the sample more representative, this study collected data from primary and secondary schools representative of the southeast, northwest, and center of Hubei Province; further, the number of parents involved in each school was controlled at approximately 300 to ensure that the final sample had analytical value. Results: Educational anxiety directly affected children's behavioral problems and indirectly affected them through the conflicts between parent and child. This conflict partially mediated educational anxiety and child behavioral problems, and authoritative parenting played a significant regulatory role in this relationship. Discussion: Higher levels of educational anxiety among parents increased the likelihood of a depressed family environment. This can lead to deteriorating parent-child relationships, which can result in children's problem behaviors. Parents can address these problems by changing their approach to education and adjusting their emotions accordingly.

A Novel Ultrafiltrate Extract of Propolis Exerts Anti-inflammatory Activity through Metabolic Rewiring.

Thousands of years ago, humans started to use propolis because of its medicinal properties, and modern science has successfully identified several bioactive molecules within this resinous bee product. However, a natural propolis extract which has been removed the adhesive glue and preserved propolis bioactive compounds is urgently needed to maximise the therapeutic opportunities. In this study, a novel ultrafiltrate fraction from Brazilian green propolis, termed P30K, was demonstrated with anti-inflammatory properties, both in vitro and in vivo. Total flavonoids and total phenolic acids content in P30K were 244.6 mg/g and 275.8 mg/g respectively, while the IC50 value of inhibition of cyclooxygenase-2 (COX-2) was 8.30 µg/mL. The anti-inflammatory activity of P30K was furtherly corroborated in experimental models of lipopolysaccharides (LPS)-induced acute liver and lung injury. Mechanistically, integrated GC-MS and LC-MS based serum metabolomics analysis revealed that P30K modulated citrate cycle (TCA), pyruvate, glyoxylate and dicarboxylate metabolism pathways to inhibit secretion of pro-inflammatory cytokines. Results of network pharmacology and molecular docking suggested that P30K targeted catechol-O-methyltransferases (COMT), 11ß-hydroxysteroid dehydrogenases (HSD11B1), and monoamine oxidases (MAOA and MAOB) to promote cellular metabolomic rewiring. Collectively, our work reveals P30K as an efficient therapeutic agent against inflammatory conditions and its efficacy is related to metabolic rewiring.

A deep learning fusion network trained with clinical and high-frequency ultrasound images in the multi-classification of skin diseases in comparison with dermatologists: a prospective and multicenter study.

Background: Clinical appearance and high-frequency ultrasound (HFUS) are indispensable for diagnosing skin diseases by providing internal and external information. However, their complex combination brings challenges for primary care physicians and dermatologists. Thus, we developed a deep multimodal fusion network (DMFN) model combining analysis of clinical close-up and HFUS images for binary and multiclass classification in skin diseases. Methods: Between Jan 10, 2017, and Dec 31, 2020, the DMFN model was trained and validated using 1269 close-ups and 11,852 HFUS images from 1351 skin lesions. The monomodal convolutional neural network (CNN) model was trained and validated with the same close-up images for comparison. Subsequently, we did a prospective and multicenter study in China. Both CNN models were tested prospectively on 422 cases from 4 hospitals and compared with the results from human raters (general practitioners, general dermatologists, and dermatologists specialized in HFUS). The performance of binary classification (benign vs. malignant) and multiclass classification (the specific diagnoses of 17 types of skin diseases) measured by the area under the receiver operating characteristic curve (AUC) were evaluated. This study is registered with www.chictr.org.cn (ChiCTR2300074765). Findings: The performance of the DMFN model (AUC, 0.876) was superior to that of the monomodal CNN model (AUC, 0.697) in the binary classification (P = 0.0063), which was also better than that of the general practitioner (AUC, 0.651, P = 0.0025) and general dermatologists (AUC, 0.838; P = 0.0038). By integrating close-up and HFUS images, the DMFN model attained an almost identical performance in comparison to dermatologists (AUC, 0.876 vs. AUC, 0.891; P = 0.0080). For the multiclass classification, the DMFN model (AUC, 0.707) exhibited superior prediction performance compared with general dermatologists (AUC, 0.514; P = 0.0043) and dermatologists specialized in HFUS (AUC, 0.640; P = 0.0083), respectively. Compared to dermatologists specialized in HFUS, the DMFN model showed better or comparable performance in diagnosing 9 of the 17 skin diseases. Interpretation: The DMFN model combining analysis of clinical close-up and HFUS images exhibited satisfactory performance in the binary and multiclass classification compared with the dermatologists. It may be a valuable tool for general dermatologists and primary care providers. Funding: This work was supported in part by the National Natural Science Foundation of China and the Clinical research project of Shanghai Skin Disease Hospital.

Assessment of the Diagnostic Performance of Clinical Examinations and High-Frequency Ultrasound in Patients With Pigmented Skin Tumors.

OBJECTIVES: To investigate whether the integration of high-frequency ultrasound (HFUS) to routine clinical examinations could improve diagnostic performance and management decision for pigmented skin tumors. METHODS: Three general practitioners trained previously and a dermatologist independently assessed pigmented skin tumors and rendered management decision based on clinical examinations alone or clinical examinations integrating HFUS. RESULTS: After integrating HFUS, the diagnostic area under the curve (AUC) (0.658-0.693 versus 0.848, all P < .05) and specificity (46.6-58.6% versus 89.7%, all P < .05) for pigmented skin malignancies were improved for general practitioners, meanwhile unnecessary biopsy rate reduced (42.9-53.6% versus 10.7%, P < .001). To the dermatologist, the diagnostic AUC (0.822 versus 0.949, P < .001), sensitivity (81.7% versus 96.7%, P = .012) and specificity (0.828 versus 0.931, P = .031) improved significantly, meanwhile both missed biopsy rate (14.5% versus 4.8%, P = .031) and unnecessary biopsy rate (19.6% versus 7.1%, P = .016) decreased. Additionally, the diagnostic performance of the general practitioner with integrating HFUS could be comparable with the dermatologist based on clinical examinations alone (all P > .05). CONCLUSIONS: As a complementary tool of clinical examinations, HFUS could help physicians differentiate pigmented skin malignancies and manage decision.

Accurate Detection of Multiple Tumor Mutations in Formalin-Fixed Paraffin-Embedded Tissues by Coupling Sequence Artifacts Elimination and Mutation Enrichment With MeltArray.

Formalin-fixed paraffin-embedded (FFPE) tissues are the primary source of DNA for companion diagnostics (CDx) of cancers. Degradation of FFPE tissue DNA and inherent tumor heterogeneity constitute serious challenges in current CDx assays. To address these limitations, we introduced sequence artifact elimination and mutation enrichment to MeltArray, a highly multiplexed PCR approach, to establish an integrated protocol that provides accuracy, ease of use, and rapidness. Using PIK3CA mutations as a model, we established a MeltArray protocol that could eliminate sequence artifacts completely and enrich mutations from 23.5- to 59.4-fold via a single-reaction pretreatment step comprising uracil-DNA-glycosylase excision and PCR clamping. The entire protocol could identify 13 PIK3CA hotspot mutations of 0.05% to 0.5% mutant allele fractions within 5 hours. Evaluation of 106 breast cancer and 40 matched normal FFPE tissue samples showed that all 47 PIK3CA mutant samples were from the cancer tissue, and no false-positive results were detected in the normal samples. Further evaluation of 105 colorectal and 40 matched normal FFPE tissue samples revealed that 11 PIK3CA mutants were solely from the cancer sample. The detection results of our protocol were consistent with those of the droplet digital PCR assays that underwent sequence artifact elimination. Of the 60 colorectal samples with next-generation sequencing results, the MeltArray protocol detected 2 additional mutant samples with low mutant allele fractions. We conclude that the new protocol provides an improved alternative to current CDx assays for detecting tumor mutations in FFPE tissue DNA.

Social Determinants of Health and Disparities in Hypertension and Cardiovascular Diseases.

High blood pressure causes over 10 million preventable deaths annually globally. Populations in low- and middle-income countries suffer the most, experiencing increased uncontrolled blood pressure and cardiovascular disease (CVD) deaths. Despite improvements in high-income countries, disparities persist, notably in the United States, where Black individuals face up to 4× higher CVD mortality than White individuals. Social determinants of health encompass complex, multidimensional factors linked to an individual's birthplace, upbringing, activities, residence, workplaces, socioeconomic and environmental structures, and significantly affect health outcomes, including hypertension and CVD. This review explored how social determinants of health drive disparities in hypertension and related CVD morbidity from a socioecological and life course perspective. We present evidence-based strategies, emphasizing interventions tailored to specific community needs and cross-sector collaboration to address health inequalities rooted in social factors, which are key elements toward achieving the United Nations' Sustainable Development Goal 3.4 for reducing premature CVD mortality by 30% by 2030.

Ethanol Extract of Rosa rugosa Ameliorates Acetaminophen-Induced Liver Injury via Upregulating Sirt1 and Subsequent Potentiation of LKB1/AMPK/Nrf2 Cascade in Hepatocytes.

Acetaminophen (APAP)-induced liver injury is a common hepatic disease resulting from drug abuse. Few targeted treatments are available clinically nowadays. The flower bud of Rosa rugosa has a wide range of biological activities. However, it is unclear whether it alleviates liver injury caused by APAP. Here, we prepared an ethanol extract of Rosa rugosa (ERS) and analyzed its chemical profile. Furthermore, we revealed that ERS significantly ameliorated APAP-induced apoptosis and ferroptosis in AML-12 hepatocytes and dampened APAP-mediated cytotoxicity. In AML-12 cells, ERS elevated Sirt1 expression, boosted the LKB1/AMPK/Nrf2 axis, and thereby crippled APAP-induced intracellular oxidative stress. Both EX527 and NAM, which are chemically unrelated inhibitors of Sirt1, blocked ERS-induced activation of LKB1/AMPK/Nrf2 signaling. The protection of ERS against APAP-triggered toxicity in AML-12 cells was subsequently abolished. As expression of LKB1 was knocked down, ERS still upregulated Sirt1 but failed to activate AMPK/Nrf2 cascade or suppress cytotoxicity provoked by APAP. Results of in vivo experiments showed that ERS attenuated APAP-caused hepatocyte apoptosis and ferroptosis and improved liver injury and inflammation. Consistently, ERS boosted Sirt1 expression, increased phosphorylations of LKB1 and AMPK, and promoted Nrf2 nuclear translocation in the livers of APAP-intoxicated mice. Hepatic transcriptions of HO-1 and GCLC, which are downstream antioxidant genes of Nrf2, were also significantly increased in response to ERS. Our results collectively indicated that ERS effectively attenuates APAP-induced liver injury by activating LKB1/AMPK/Nrf2 cascade. Upregulated expression of Sirt1 plays a crucial role in ERS-mediated activation of LKB1.

Theaflavine inhibits hepatic stellate cell activation by modulating the PKA/LKB1/AMPK/GSK3ß cascade and subsequently enhancing Nrf2 signaling.

Activation of hepatic stellate cells (HSCs) constitutes a crucial etiological factor leading to liver fibrosis. Theaflavine (TF) is a characteristic bioactive compound in fermented tea. Here, we found that TF attenuated the activation of LX-2 HSCs induced by transforming growth factor-ß1 (TGF-ß1). TF potentiated nuclear factor erythroid 2-related Factor 2 (Nrf2) signaling. Knockdown of Nrf2 abrogated TF-mediated resistance to TGF-ß1. Liver kinase B1 (LKB1), AMP-activated kinase (AMPK), and glycogen synthase kinase-3ß (GSK3ß) are upstream regulators of Nrf2. TF modulated the LKB1/AMPK/GSK3ß axis. Inhibition of AMPK or knockdown of LKB1 crippled TF-mediated potentiation of Nrf2. Protein kinase A (PKA) catalyzes LKB1 phosphorylation. In LX-2 cells, TF increased the LKB1/PKA interaction without affecting their contents. Inhibition of PKA abolished TF-mediated potentiation of LKB1/Nrf2 and abrogated the inhibitory effects of TF on their activation. TF also enhanced direct binding between purified catalytic subunit α of PKA (PKA-Cα) and LKB1 proteins in vitro. Molecular docking indicated that TF showed binding activity with both LKB1 and PKA-Cα proteins. In mouse primary HSCs, TF elevated LKB1/PKA-Cα binding, boosted LKB1 phosphorylation, potentiated Nrf2 and suppressed their spontaneous activation. PKA inhibition or LKB1 knockdown eliminated TF-mediated induction of Nrf2 and suppression of HSC activation. Furthermore, TF considerably alleviated CCl4-induced mouse liver fibrosis. In mouse livers, TF increased the LKB1/PKA-Cα interaction, upregulated LKB1 phosphorylation and modulated its downstream AMPK/GSK3ß/Nrf2 cascade. Our findings collectively indicated that TF suppresses HSC activation. Mechanistically, TF elevated the LKB1/PKA interaction in HSCs, which increased LKB1 phosphorylation and subsequently modulated the downstream AMPK/GSK3ß/Nrf2 axis.

The Value of Ultra-High-Frequency Ultrasound for the Differentiation between Superficial Basal Cell Carcinoma and Bowen's Disease.

BACKGROUND: The similar visual appearance of superficial basal cell carcinoma (sBCC) and Bowen's disease (BD) may cause confusion for diagnosis. OBJECTIVE: The aim of the study was to investigate the value of ultra-high-frequency ultrasound (uHFUS) in differentiating sBCC from BD. MATERIALS AND METHODS: This prospective study included a pilot cohort of 110 patients (73 BDs and 37 sBCCs) from November 2016 to October 2020 and a validation cohort of 42 patients (30 BDs and 12 sBCCs) from July 2021 to December 2021. Clinical and uHFUS features of pathologically confirmed sBCC and BD were assessed. A predictive model was developed based on the uHFUS features of the pilot cohort. Subsequently, the model was validated and compared with clinical diagnosis in the validation cohort. RESULTS: uHFUS features with significant differences between sBCC and BD included lesion surface, skin layer involvement, hyperkeratosis, and hyperechoic spots (all p < 0.05). A prediction model based on the above features was established to identify sBCC and BD in the pilot and validation cohorts with areas under the curve (AUC) of 0.908 and 0.923, sensitivity of 82.3% and 83.3%, specificity of 91.9% and 91.7%, and accuracy of 85.5% and 85.7%, respectively, which were significantly higher than those obtained by clinical diagnosis based on photographic pictures of lesions, with the AUC of 0.692, sensitivity of 63.3%, specificity of 75.3%, and accuracy of 66.7% (all p < 0.05). CONCLUSION: uHFUS provides detailed internal features of sBCC and BD, which facilitates the differentiation between sBCC and BD, and its diagnostic performance is superior to clinical diagnosis.

Purification Process and In Vitro and In Vivo Bioactivity Evaluation of Pectolinarin and Linarin from Cirsium japonicum.

Pectolinarin and linarin are two major flavone O-glycosides of Cirsium japonicum, which has been used for thousands of years in traditional Chinese medicine. Pharmacological research on pectolinarin and linarin is meaningful and necessary. Here, a process for the purification of pectolinarin and linarin from C. japonicum was established using macroporous resin enrichment followed by prep-HPLC separation. The results show the purity of pectolinarin and linarin reached 97.39% and 96.65%, respectively. The in vitro bioactivities result shows the ORAC values of pectolinarin and linarin are 4543 and 1441 µmol TE/g, respectively, meanwhile their inhibition rate of BSA-MGO-derived AGEs is 63.58% and 19.31% at 2 mg/mL, which is 56.03% and 30.73% in the BSA-fructose system, respectively. The COX-2 inhibition rate at 50 µg/mL of linarin and pectolinarin reached 55.35% and 40.40%, respectively. Furthermore, the in vivo bioassay combining of histopathologic evaluation and biochemical analysis of liver glutamic oxaloacetic transaminase, serum creatinine and TNF-α show pectolinarin can alleviate lipopolysaccharide (LPS)-induced acute liver and kidney injury in mice. Metabolomics analysis shows that pectolinarin attenuates LPS-challenged liver and kidney stress through regulating the arachidonic acid metabolism and glutathione synthesis pathways. Collectively, our work presents a solid process for pectolinarin and linarin purification and has discovered a promising natural therapeutic agent-pectolinarin.

Treadmill exercise decreases cerebral edema in rats with local cerebral infarction by modulating AQP4 polar expression through the caveolin-1/TRPV4 signaling pathway.

Rehabilitation therapy is beneficial for patients with ischemic stroke. Our previous study showed that treadmill training is conducive to neurological function in rats that underwent middle cerebral artery occlusion (MCAO). However, whether exercise benefits cerebral edema and the underlying mechanism remain unclear. This study investigated the influence of treadmill exercise on brain edema and the mechanism of its formation and elimination. The MCAO model was established with Sprague-Dawley (SD) rats, and lentivirus-mediated caveolin-1 shRNA was used to investigate the role of caveolin-1 in brain edema. As expected, we found that treadmill exercise has a beneficial effect on brain edema after stroke. Training led to a significant increase in the expression of caveolin-1 and TRPV4; and reduced brain water content and blood-brain barrier (BBB) damage. This treatment also changed the localization of aquaporin-4 (AQP4). Moreover, the effect of treadmill training on the polar expression of AQP4 differed over time. The results showed that early treadmill training inhibited the polar expression of AQP4, and later promoted its expression. However, the rats that were injected with the caveolin-1 shRNA lentivirus exhibited enhanced edema. Caveolin-1 shRNA eliminated the protective effect induced by exercise, which is consistent with the downregulation of TRPV4 expression. The findings indicate that treadmill training improves brain edema through the caveolin-1/TRPV4/AQP4 pathway.

OsRAM2 Function in Lipid Biosynthesis Is Required for Arbuscular Mycorrhizal Symbiosis in Rice.

Arbuscular mycorrhiza (AM) is a mutualistic symbiosis formed between most land plants and Glomeromycotina fungi. During symbiosis, plants provide organic carbon to fungi in exchange for mineral nutrients. Previous legume studies showed that the required for arbuscular mycorrhization2 (RAM2) gene is necessary for transferring lipids from plants to AM fungi (AMF) and is also likely to play a "signaling" role at the root surface. To further explore RAM2 functions in other plant lineages, in this study, two rice (Oryza sativa) genes, OsRAM2 and OsRAM2L, were identified as orthologs of legume RAM2. Examining their expression patterns during symbiosis revealed that only OsRAM2 was strongly upregulated upon AMF inoculation. CRISPR/Cas9 mutagenesis was then performed to obtain three Osram2 mutant lines (-1, -2, and -3). After inoculation by AMF Rhizophagus irregularis or Funneliformis mosseae, all of the mutant lines showed extremely low colonization rates and the rarely observed arbuscules were all defective, thus supporting a conserved "nutritional" role of RAM2 between monocot and dicot lineages. As for the signaling role, although the hyphopodia numbers formed by both AMF on Osram2 mutants were indeed reduced, their morphology showed no abnormality, with fungal hyphae invading roots successfully. Promoter activities further indicated that OsRAM2 was not expressed in epidermal cells below hyphopodia or outer cortical cells enclosing fungal hyphae but instead expressed exclusively in cortical cells containing arbuscules. Therefore, this suggested an indirect role of RAM2 rather than a direct involvement in determining the symbiosis signals at the root surface.[Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 "No Rights Reserved" license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2022.

Response to Tyrosine Kinase Inhibitors in Real-World Patients With Chronic Myeloid Leukemia.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the front-line therapy for chronic myeloid leukemia (CML), where phase 3 clinical trials have demonstrated their safety and efficacy. However, trial patients may not be representative of real-world patients (RWPs). OBJECTIVE: To evaluate RWP clinical factors associated with effectiveness and safety in CML patients treated with TKIs. METHODS: Patients with CML treated with at least 30 days of imatinib, dasatinib, nilotinib, or bosutinib between 2014 and 2018 were included. Patients were stratified into categories based on the number of factors that would have precluded enrollment into pivotal TKI phase 3 trials (0, 1, ≥2). End points included complete hematologic response (CHR), early molecular response (EMR), major molecular response (MMR), adverse event (AE)-induced dose decreases, treatment interruptions, and treatment discontinuations. RESULTS: Final analyses included 174 patients. Patients with ≥2 factors had a higher risk of dose decreases (relative risk = 1.54; 95% CI = 1.02-2.34; P = 0.02) and a shorter time to dose decrease (hazard ratio = 2.43; 95% CI = 1.23-4.97; P = 0.006) compared with patients with 0 factors. Significant differences were observed in CHR at 1 month and MMR at 3 months between patients with 0 and ≥2 factors (P = 0.03 and P = 0.04, respectively). CONCLUSION AND RELEVANCE: Approximately 60% of our RWPs would have been excluded from the pivotal phase 3 TKI trials. These data suggest that RWPs require more precise dosing to achieve CML clinical milestones and to mitigate AEs, but findings should be validated prospectively.

High-frequency ultrasound for differentiation between high-risk basal cell carcinoma and cutaneous squamous cell carcinoma.

BACKGROUND: The similar visual appearance of high-risk basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) may cause confusion for diagnosis. High-frequency ultrasound (HFUS) may provide additional intralesional information and thus help to distinguish them. METHOD: In this retrospective study, we analyzed the clinical characteristics, HFUS grayscale, and color Doppler flow imaging (CDFI) features of pathologically confirmed high-risk BCC and cSCC lesions (n = 65 vs n = 68). Subsequently, discrimination models based on the significant HFUS features were established. RESULTS: Between high-risk BCC and cSCC lesions, the HFUS grayscale features of the lesion size (10.0 mm vs 17.4 mm), thickness (3.1 mm vs 5.9 mm), internal hyperechoic spots (80.0% vs 23.5%), and posterior acoustic shadowing (16.9% vs 66.2%) were statistically different (all p < 0.001). As for the CDFI features, high-risk BCC lesions mainly appeared as pattern II (47.7%), while cSCC lesions mainly appeared as pattern III (66.2%). Based on the above five features, an optimal discrimination model was established with a sensitivity of 91.2%, a specificity of 87.7%, and an accuracy of 89.5%. CONCLUSION: HFUS features, including size, thickness, internal hyperechoic spots, posterior acoustic shadowing, and Doppler vascularity pattern, are useful for differential diagnosis between high-risk BCC and cSCC.

Improving the quality of breast ultrasound examination performed by inexperienced ultrasound doctors with synchronous tele-ultrasound: a prospective, parallel controlled trial.

PURPOSE: This prospective study explored the value of synchronous tele-ultrasound (US) to aid doctors inexperienced in US with breast US examinations. METHODS: In total, 99 patients were enrolled. Two trainee doctors who were inexperienced in US (trainee A [TA] and trainee B [TB]) and one doctor who was an expert in US completed the US examinations sequentially. TA completed the US examinations independently, while TB was instructed by the expert using synchronous tele-US. Subsequently, the expert performed on-site US examinations in person. Separately, they selected the most clinically significant nodule as the target nodule. Consistency with the expert and image quality were compared between TA and TB to evaluate tele-US. Furthermore, TB and the patients evaluated tele-US through questionnaires. RESULTS: TB demonstrated higher consistency with the expert in terms of target nodule selection than TA (93.3% vs. 63.3%, P<0.001). TB achieved good inter-observer agreement (ICC, >0.75) with the expert on five US features (5/9, 55.6%), while TA only did so for one (1/9, 11.1%) (P=0.046). TB's image quality was higher than TA's in gray value, time gain compensation, depth, color Doppler adjustment, and the visibility of key information (P=0.018, P<0.001, P<0.001, P=0.033, and P=0.006, respectively). The comprehensive assessment score was higher for TB than for TA (3.96±0.82 vs. 3.09±0.87, P<0.001). Tele-US was helpful in 69.7% of US examinations and had a training effect in 68.0%. Furthermore, 63.6% of patients accepted tele-US and 60.6% were willing to pay. CONCLUSION: Tele-US can help doctors inexperienced in US to perform breast US examinations.

Quantitative assessment of crystal dissolution in gout during urate-lowering therapy with computer-aided MicroPure imaging: a cohort study.

BACKGROUND: To evaluate whether MicroPure imaging, an ultrasound (US) image-processing technique with computer-aided analysis, can quantitatively detect crystal dissolution during urate-lowering therapy (ULT) in gout. METHODS: This was a prospective study of gout patients requiring ULT. The first metatarsophalangeal joints were examined using US and MicroPure before and after 3 months of ULT. Elementary lesions of gout, including the double contour sign (DCS), aggregates, tophi, erosion, and other US features were recorded at baseline and 3 months. MicroPure imaging features were automatically calculated by a self-developed software. Patients were divided into goal-achieved and goal-not-achieved groups according to their urate levels at 3 months. The US and MicroPure imaging features of the two groups were analyzed at baseline and 3 months. RESULTS: A total of 55 consecutive patients were enrolled (25: goal-achieved group; 30: goal-not-achieved group). US findings demonstrated that the power Doppler signal grade decreased at 3 months, regardless of the group (both P<0.05). From baseline to 3 months, tophi size and the DCS reduced in the goal-achieved group (both P<0.05), while the US aggregate features showed no difference (P=0.250). However, on the MicroPure imaging, the number and density of aggregates at 3 months decreased in the goal-achieved group (both P<0.05). There were no significant changes at 3 months in any of the MicroPure imaging features in the goal-not-achieved group (all P>0.05). CONCLUSIONS: In comparison with B-mode US, computer-aided MicroPure imaging can sensitively and quantitatively detect aggregate dissolution during effective ULT after only 3 months of treatment.

Simulation of Atmospheric Visibility Impairment.

Changes in aerosol composition and its proportions can cause changes in atmospheric visibility. Vision systems deployed outdoors must take into account the negative effects brought by visibility impairment. In order to develop vision algorithms that can adapt to low atmospheric visibility conditions, a large-scale dataset containing pairs of clear images and their visibility-impaired versions (along with other annotations if necessary) is usually indispensable. However, it is almost impossible to collect large amounts of such image pairs in a real physical environment. A natural and reasonable solution is to use virtual simulation technologies, which is also the focus of this paper. In this paper, we first deeply analyze the limitations and irrationalities of the existing work specializing on simulation of atmospheric visibility impairment. We point out that many simulation schemes actually even violate the assumptions of the Koschmieder's law. Second, more importantly, based on a thorough investigation of the relevant studies in the field of atmospheric science, we present simulation strategies for five most commonly encountered visibility impairment phenomena, including mist, fog, natural haze, smog, and Asian dust. Our work establishes a direct link between the fields of atmospheric science and computer vision. In addition, as a byproduct, with the proposed simulation schemes, a large-scale synthetic dataset is established, comprising 40,000 clear source images and their 800,000 visibility-impaired versions. To make our work reproducible, source codes and the dataset have been released at https://cslinzhang.github.io/AVID/.