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Numerous factors contribute to the low adherence to lung cancer screening (LCS) programs. A theory-informed approach to identifying the obstacles and facilitators to LCS uptake is required. This study aimed to identify, assess, and synthesize the available literature at the individual and healthcare provider (HCP) levels based on a social-ecological model and identify gaps to improve practice and policy decision-making. Systematic searches were conducted in nine electronic databases from inception to December 31, 2020. We also searched Google Scholar and manually examined the reference lists of systematic reviews to include relevant articles. Primary studies were scored for quality assessment. Among 3938 potentially relevant articles, 36 studies, including 25 quantitative and 11 qualitative studies, were identified for inclusion in the review. Fifteen common factors were extracted from 34 studies, including nine barriers and six facilitators. The barriers included individual factors (n = 5), health system factors (n = 3), and social/environmental factors (n = 1). The facilitators included only individual factors (n = 6). However, two factors, age and screening harm, remain mixed. This systematic review identified and combined barriers and facilitators to LCS uptake at the individual and HCP levels. The interaction mechanisms among these factors should be further explored, which will allow the construction of tailored LCS recommendations or interventions for the Chinese context.

Demoralization is a prevalent psychological problem among cancer patients and reflects a sense of subjective incompetence. This systematic review aims to identify factors influencing demoralization among cancer patients.Eleven databases were systematically searched from database inception to 31 December 2020. Google Scholar and relevant reference lists were supplementarily searched. Studies reporting demoralization measured by Demoralization Scale and its influencing factors among cancer patients were included. A qualitative synthesis was conducted owing to the heterogeneity of the study outcome.A total of 49 studies involving 10,712 participants were included in this review. The results showed substantial effect size variation, but the psychological factors showed the strongest magnitude of association. Among the biological factors, the number of physical symptoms (mean r values [rs]: 0.331) was associated with increased demoralization. Among the psychological factors, negative psychological factors include hopelessness (mean rs: 0.633), desire for death (mean rs: 0.620), dignity-related distress (mean rs: 0.595), depression (mean rs: 0.593), anxiety (mean rs: 0.589), psychological distress (mean rs: 0.465), and suicidal ideation (mean rs: 0.460) were related to increased demoralization; whereas positive psychological factors including hope (mean rs: -0.565), attachment security (mean rs: -0.530), and sense of coherence (mean rs: -0.453) were related to decreased demoralization. Among the social factors, social support (mean rs: -0.330) was negatively related to demoralization, and the demographic factors were still controversial. Quality of life was considered to be at the intersection of biopsychosocial factors and negatively associated with demoralization (mean rs: -0.599).Demoralization is a consequence of the interaction of physical, psychological, and social factors among cancer patients. Factors with a significant effect should not be overlooked when designing an intervention to reduce demoralization. It is necessary to distinguish demoralization from other negative psychological states and further explore positive psychological factors influencing demoralization among cancer patients.

Lung adenocarcinoma (LUAD) is a heterogeneous disease. Our study aimed to understand the unique molecular features of preinvasive to invasive LUAD subtypes. We retrospectively analyzed the clinical, histopathological, and molecular data of 3,254 Chinese patients with preinvasive lesions (n = 252), minimally invasive adenocarcinomas (n = 479), and invasive LUAD (n = 2,523). Molecular data were elucidated using a targeted 68-gene next-generation sequencing panel. Our findings revealed four preinvasive lesion-predominant gene mutations, including MAP2K1 insertion-deletions (indels), BRAF non-V600E kinase mutations, and exon 20 insertions (20ins) in both EGFR and ERBB2, which we referred to as mutations enriched in AIS (MEA). The detection rate of MEA in invasive tumors was relatively lower. MAP2K1 missense mutations, which were likely passenger mutations, co-occurred with oncogenic driver mutations, while small indels were mutually exclusive from other genes regardless of the invasion level. BRAF non-V600E kinase-mutant invasive adenocarcinomas (IAC) had significantly higher mutation rates in tumor suppressor genes but lower frequency of co-occurring oncogenic driver mutations than non-kinase-mutant IAC, suggesting the potential oncogenic activity of BRAF non-V600E kinase mutations albeit weaker than BRAF V600E. Moreover, similar to the extremely low frequency of MAP2K1 indels in IAC, BRAF non-V600E kinase domain mutations co-occurring with TSC1 mutations were exclusively found in preinvasive lesions. Compared with EGFR L858R and exon 19 deletion, patients with preinvasive lesions harboring 20ins in either EGFR or ERBB2 were significantly younger, while those with IAC had similar age. Furthermore, our study demonstrated distinct mutational features for subtypes of oncogene mutations favored by different invasion patterns in adenocarcinomas. In conclusion, our data demonstrate distinct mutational features between preinvasive lesions and invasive tumors with MEA, suggesting the involvement of MEA in the early stages of tumorigenesis. Further pre-clinical studies are required to establish the role of these genes in the malignant transformation of LUAD.

Considerable attention has focused on the role of omega-3 polyunsaturated fatty acids (PUFA) in the prevention of cardiometabolic diseases, which has led to dietary recommendations to increase omega-3 fatty acid intake. A meta-analysis was conducted to summarize evidence from prospective studies regarding associations between omega-3 PUFA biomarkers and risk of developing major chronic diseases.Four electronic databases were searched for articles from inception to March 1, 2022. Random-effects model was used to estimate the pooled relative risk (RR) and 95% confidence intervals (CIs) for the association of omega-3 PUFAs, including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), with risk of developing type 2 diabetes (T2D), cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke, cancer, and mortality. The Grades of Recommendation, Assessment, Development and Evaluation assessment tool was used to rates the confidence in estimates.A total of 67 prospective studies comprised of 310,955 participants were identified. Individual omega-3 PUFAs showed divergent associations with the study outcomes of interest. A significant inverse association with T2D risk was observed across categories of ALA (relative risk [RR]: 0.89, 95% confidence interval [CI]: 0.82-0.96), EPA (RR: 0.85, 95% CI: 0.72-0.99) and DPA (RR: 0.84, 95% CI: 0.73-0.96) biomarkers. The marine-origin omega-3 fatty acids biomarkers but not ALA was significantly associated with lower risks of total CVD, CHD, and overall mortality, with RRs ranging from 0.70 for DHA-CHD association to 0.85 for EPA-CHD association. A lower risk of colorectal cancer was observed at higher levels of DPA (RR: 0.76, 95% CI: 0.59-0.98) and DHA (RR: 0.80; 95% CI: 0.65-0.99), whereas no association was noted for other outcomes. In addition, a dose-response relationship was observed between an increasing level of EPA, DPA, or DHA biomarker and lower risk of CVD.Higher concentrations of marine-derived omega-3 PUFA biomarkers were associated with a significantly reduced risk of total CVD, CHD, and total mortality. Levels of ALA were inversely associated with a lower risk of T2D but not CVD-related outcomes. These data support the dietary recommendations advocating the role of omega-3 PUFAs in maintaining an overall lower risk of developing cardiovascular disease and premature deaths.

The hygiene area is one of the most important facilities in a space station. If its environmental lighting is appropriately designed, it can significantly reduce the psychological pressure on astronauts. This study investigates the effect of correlated colour temperature (CCT) on heart rate, galvanic skin response, emotion and satisfaction in the hygiene area of a space station. Forty subjects participated in experiments in a hygiene area simulator with a controlled lighting environment. The lighting conditions included 2700 K, 3300 K, 3600 K, 5000 K and 6300 K; physiological responses (heart rate, galvanic skin response), as well as emotion and satisfaction, were recorded. The results showed that CCT significantly influenced the participants’ physiological and subjective responses in the space station hygiene area. 6300 K led to the best emotion and satisfaction levels, the highest galvanic skin response and the lowest heart rate. The opposite was true for 2700 K.

The unique characteristics of camelid heavy-chain only antibody (HCAb) derived nanobodies (Nbs) have facilitated their employment as tools for research and application in extensive fields including food safety inspection, diagnosis and therapy of diseases, etc., to develop immune detecting techniques or alternative candidates of conventional antibodies as diagnostic and therapeutic reagents. The wide application in the fields of food allergen inspection and immunotherapy has not been addressed as not much results published in the literature. The robust properties and straightforward selecting strategy of Nbs impel the advantageous employment compared with monoclonal antibodies (mAbs) to establish immunoassay and serve as blocking antibodies to compete immunoglobulin E (IgE) binding epitopes on food allergens. More and more efforts have been invested to develop specific Nbs against food allergen proteins, such as macadamia allergen of Mac i 1, peanut allergen of Ara h 3, and lupine allergen of Lup an 1, which demonstrated the potential of Nbs for research and application in food allergen surveillance. Meanwhile, the paratopes of Nbs preferably targeting the unique epitopes of food allergens can provide more possibilities to serve as blocking antibodies to shield IgE binding epitopes for food allergy immunotherapy. Regardless, the research and application of Nbs in the field of food allergen and allergic reactions are expected to attract dramatic focus and produce promising research outputs.

Oxysterol metabolism plays an important role in the initiation and development of various tumors. However, little is known that the metabolic alternation can promote the metastasis of hepatocellular carcinoma (HCC). In this study, we identify the sulfotransferase family 2A member 1 (SULT2A1) to 27-hydroxycholesterol (27-OHC) metabolic axis as playing a critical role in HCC metastasis. The level of 27-OHC closely corresponded with HCC metastasis instead of proliferation in vitro and in vivo. Also, the expression of SULT2A1 is extremely downregulated in human HCC tissues and is correlated with poor prognosis and tumor metastasis. Gain- and loss-of-function studies reveal that SULT2A1 suppresses the metastasis of HCC by regulating the level of 27-OHC. Further mechanistic studies indicated that SULT2A1-dependent alternation of 27-OHC activates the nuclear factor-κB signaling pathway and promotes HCC metastasis by enhancing Twist1 expression and epithelial-mesenchymal transition. In conclusion, our findings indicate the relationship between the metabolism of 27-OHC and the metastasis of HCC. Moreover, SULT2A1 could act as a potential prognostic biomarker and a therapeutic target for preventing HCC metastasis.

Autism spectrum disorder (ASD) has become one of the most common neurological developmental disorders in children. However, the study of ASD diagnostic markers faces significant challenges due to the existence of heterogeneity. In this study, genetic testing was performed on children who were clinically diagnosed with ASD. Children with ASD susceptibility genes and healthy controls were studied. The proteomics of plasma and peripheral blood mononuclear cells (PBMCs) as well as plasma metabolomics were carried out. The results showed that although there was genetic heterogeneity in children with ASD, the differentially expressed proteins (DEPs) in plasma, peripheral blood mononuclear cells, and differential metabolites in plasma could still effectively distinguish autistic children from controls. The mechanism associated with them focuses on several common and previously reported mechanisms of ASD. The biomarkers for ASD diagnosis could be found by taking differentially expressed proteins and differential metabolites into consideration. Integrating omics data, glycerophospholipid metabolism and N-glycan biosynthesis might play a critical role in the pathogenesis of ASD.

Scars are nearly impossible to avoid after a skin injury, but despite advancements in the treatment modalities, they remain a clinical problem, especially hypertrophic scars (HS). Many studies include the mechanism of formation and inhibition of HS, but it is not fully understood yet. Circular RNA HECTD1 (circHECTD1), for the first time, has been found to have roles in HS physiology. We determined the relative circHECTD1 levels in HS fibrous cells and tissues by RT-qPCR. Afterward, the effect of circHECTD1 knockdown on the proliferation, migration, invasion, fibrosis, and Transforming Growth Factor-beta/small mothers against decapentaplegic (TGF-β/Smad) signaling was studied using CCK-8, wound healing, Transwell, and western blot assays. After the role of circHECTD1 was clarified, its targeted micro RNA (miR) was predicted using the Starbase database, and we constructed a miR-142-3p mimic to study the details of its regulation mechanism. We used the TargetScan database to predict the downstream target high mobility group box 1 (HMGB1) of miR-142-3p, and the luciferase report assay verified the binding, and then its effect was determined by RT-qPCR. circHECTD1 is highly expressed in HS tissues and human skin hypertrophic scar fibroblasts (HSF); its loss of function inhibits cell proliferation, migration, invasion, fibrosis, and TGF-β/Smad signaling. However, miR-142-3p inhibitor reverses the effect of circHECTD1 on all the above-mentioned aspects, including HMGB1 expression. In conclusion, circHECTD1 knockdown interrupts TGF-β/Smad signaling through miR-142-3p/HMGB1 and suppresses scar fibrosis.

Objective We aimed to evaluate the long-term outcome of gamma knife radiosurgery (GKRS) for the treatment of sporadic cerebral cavernous malformation (CCM), especially the influence of lesion volume on annual hemorrhage rate (AHR) of CCM patients after GKRS. Methods Fifty-one single-lesion patients with a history of hemorrhage who underwent radiosurgery at our institution were included and divided into two groups (A and B), based on their lesion volume. Group A included 25 patients with lesion volumes > 1cm3, whereas Group B included 26 patients with lesion volumes ≤1 cm3. The clinical data of the patients were retrospectively analyzed. Results All patients were followed up for more than 4 years after GKRS. The calculated AHR before GKRS was 18.49% in Group A and 10.16% in Group B. The calculated AHR after GKRS was 5.43% and 0.99% for Groups A and B respectively. Significant differences in AHR after GKRS were identified between Group A and Group B (p = 0.011). Thirty-seven sporadic CCM patients (14 in Group A, 23 in Group B) experienced symptom improvement and significant differences in symptom improvement were observed between Group A and Group B (p=0.009). Conclusions GKRS decreased the risk of hemorrhage and was beneficial for symptomatic improvement in sporadic CCM patients with a history of hemorrhage. The long-term clinical outcomes for sporadic CCM patients with small lesion volumes (≤1 cm3) were better than those of sporadic CCM patients with large lesion volumes (>1 cm3).

Pre-existing renal dysfunction is an independent risk factor for cardiac surgery-associated acute kidney injury (AKI). We aimed to investigate whether the improvement of postoperative cardiac function after coronary artery bypass grafting (CABG) surgery would affect the risk of AKI in patients with different levels of baseline renal function.Data were collected from patients who underwent CABG surgery from January 2018 to April 2019. Patients were divided into normal (GFR ≥ 90 ml/min/1.73 mA total of 1365 patients were enrolled, including 793 (58.1%) in the normal group, 476 (34.9%) in the non-CKD group, and 96 (7.0%) in the CKD group. The AKI incidence in the normal, non-CKD, and CKD groups was 22.2%, 28.4%, and 40.6%, respectively. Patients with improved cardiac function in the non-CKD and CKD groups had significantly lower AKI incidence than those without improved cardiac function (22.8% vs. 36.9%, p = .002% and 32.8% vs. 54.3%, p = .037, respectively). For non-CKD patients with improved cardiac function, the serum creatinine at discharge was significantly lower than its preoperative serum creatinine (0.8 ± 0.5 vs 1.2 ± 0.9 mg/dl, p = .002). Multivariate logistic regression analysis showed that the improvement in cardiac function could reduce the risk for postoperative AKI in non-CKD patients but not in CKD patients.For patients with renal dysfunction and mildly reduced eGFR (60≤GFR 90 ml/min/1.73 m

Existing data demonstrate a significant correlation between autism spectrum disorder (ASD) and the status of biologically essential and toxic trace elements. However, there is still a lack of data on the steady state of trace elements in ASD. We performed a case-control study to explore the association between the risk of ASD and 23 trace elements in plasma. The results showed that children with ASD had considerably decreased lithium (Li), manganese (Mn), selenium (Se), barium (Ba), mercury (Hg), and tin (Sn) levels when compared to their age- and sex-matched controls. Meanwhile, children with ASD had considerably increased plasma chromium (Cr) and vanadium (V) concentrations. We also divided each group into subgroups based on age and gender and created element-related networks for each subgroup. We detected significant element correlations within or between subgroups, as well as changes in correlations that included all elements examined. Finally, more element correlations were observed among males, which may open a new avenue for understanding the complicated process behind the sex ratio of children with ASD. Overall, our data revealed a novel relationship between elements and ASD, which may extend current understanding about ASD.

Purpose The present study identified predictors of intrahepatic progression-free survival (ihPFS) after ultrasound (US)-guided percutaneous microwave ablation (MWA) for colorectal liver metastases (CRLMs) and developed a nomogram to predict ihPFS. Methods From January 2013 to December 2018, a total of 314 patients (224 men and 90 women; mean age, 57.1 ± 11.8 years; range, 23–86 years) with 645 CRLMs (mean diameter, 16.6 ± 6.5 mm; range, 6.0–45.0 mm) treated with US-guided percutaneous MWA were included and analyzed. The average number of CRLMs per patient treated was 2 (range, 1–8). A nomogram to predict ihPFS was developed based on a multivariable Cox model. Validation of the nomogram was performed using the concordance index (C-index), calibration curves, and decision curve analyses. Results The 1-, 2-, and 3-year cumulative ihPFS rates were 59.0%, 38.9%, and 30.8%, respectively. Maximal CRLM size, number of CRLMs, ablative margin, primary tumor lymph node status, and chemotherapy were five independent prognostic factors for ihPFS. The C-index of the nomogram was 0.702 (CI: 0.681–0.723). A risk classification system that perfectly classified the patients into three risk groups was constructed. The median ihPFS of patients in the low-, intermediate-, and high-risk groups was 36.3 months (95% CI: 21.4–51.1), 13.4 months (95% CI: 12.1–14.6), and 3.8 months (95% CI: 2.3–5.3), respectively. Conclusion The nomogram and risk classification system will facilitate the personalized assessment of ihPFS for patients receiving US-guided percutaneous MWA for CRLMs.

A novel hydrophilic porous biocomposite was fabricated by incorporating graphene oxide (GO) @chitosan (CS) foam substrate (GO@CS@ZIF-8 foam) with ZIF-8 crystals in situ via a facile stirring method for simultaneous enrichment of glycopeptides and phosphopeptides from complex biological samples. The experimental results demonstrated that GO@CS@ZIF-8 foam exhibited favorable specificity for simultaneous enrichment of N-glycopeptides and phosphopeptides under the same condition for HRP and β-casein tryptic digest mixtures. The novel material was further applied to enriching both glycopeptides and phosphopeptides simultaneously from 4 μL complex human serum, and 423 N-glycopeptides and 40 phosphopeptides corresponding to 133 glycoproteins and 29 phosphoproteins were identified, respectively.

Central nervous system-penetrant therapies with intracranial efficacy against non-small cell lung cancer (NSCLC) brain metastases are urgently needed. We report preclinical studies investigating brain penetration and intracranial activity of the MET inhibitor tepotinib. After intravenous infusion of tepotinib in Wistar rats (n = 3), mean (±standard deviation) total tepotinib concentration was 2.87-fold higher in brain (505 ± 22 ng/g) than plasma (177 ± 20 ng/mL). In equilibrium dialysis experiments performed in triplicate, mean tepotinib unbound fraction was 0.35% at 0.3 and 3.0 µM tepotinib in rat brain tissue, and 4.0% at 0.3 and 1.0 µM tepotinib in rat plasma. The calculated unbound brain-to-plasma ratio was 0.25, indicating brain penetration sufficient for intracranial target inhibition. Of 20 screened subcutaneous patient-derived xenograft (PDX) models from lung cancer brain metastases (n = 1), two NSCLC brain metastases models (LU5349 and LU5406) were sensitive to the suboptimal dose of tepotinib of 30 mg/kg/qd (tumor volume change [%TV]: -12% and -88%, respectively). Molecular profiling (nCounter®; NanoString) revealed high-level MET amplification in both tumors (mean MET gene copy number: 11.2 and 24.2, respectively). Tepotinib sensitivity was confirmed for both subcutaneous models at a clinically relevant dose (125 mg/kg/qd; n = 5). LU5349 and LU5406 were orthotopically implanted into brains of mice and monitored by magnetic resonance imaging (MRI). Tepotinib 125 mg/kg/qd induced pronounced tumor regression, including complete or near-complete regressions, compared with vehicle in both orthotopic models (n = 10; median %TV: LU5349, -84%; LU5406, -63%). Intracranial antitumor activity of tepotinib did not appear to correlate with blood-brain barrier leakiness assessed in T1-weighted gadolinium contrast-enhanced MRI.

Background:. Nitinol-containing devices are widely used in clinical practice. However, there are concerns about nickel release after nitinol-containing device implantation. This study aimed to compare the efficacy and safety of a parylene-coated occluder vs. a traditional nitinol-containing device for atrial septal defect (ASD). Methods:. One-hundred-and-eight patients with ASD were prospectively enrolled and randomly assigned to either the trial group to receive a parylene-coated occluder (n = 54) or the control group to receive a traditional occluder (n = 54). The plugging success rate at 6 months after device implantation and the pre- and post-implantation serum nickel levels were compared between the two groups. A non-inferiority design was used to prove that the therapeutic effect of the parylene-coated device was non-inferior to that of the traditional device. The Cochran–Mantel–Haenszel chi-squared test with adjustment for central effects was used for the comparison between groups. Results:. At 6 months after implantation, successful ASD closure was achieved in 52 of 53 patients (98.11%) in both the trial and control groups (95% confidence interval (CI): [−4.90, 5.16]) based on per-protocol set analysis. The absolute value of the lower limit of the 95% CI was 4.90%, which was less than the specified non-inferiority margin of 8%. No deaths or severe complications occurred during 6 months of follow-up. The serum nickel levels were significantly increased at 2 weeks and reached the maximum value at 1 month after implantation in the control group (P 0.05). Conclusions:. The efficacy of a parylene-coated ASD occluder is non-inferior to that of a traditional uncoated ASD occluder. The parylene-coated occluder prevents nickel release after device implantation and may be an alternative for ASD, especially in patients with a nickel allergy.

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a secretory serine protease that plays multiple biological functions in the regulation of physiological and pathological processes. PCSK9 inhibitors decrease the circulating LDL-cholesterol level with well-known preventive and therapeutic effects on atherosclerosis (AS). Still, increasing evidence shows that the direct impact of PCSK9 on the vascular wall also plays an important role in atherosclerotic progression. Compared with other vascular cells, a large proportion of PCSK9 is originated from vascular smooth muscle cells (VSMC). Therefore, defining the effect of VSMC-derived PCSK9 on response changes, such as phenotypic switch, apoptosis, autophagy, inflammation, foam cell formation, and calcification of VSMC, helps us better understand the “pleiotropic” effects of VSMC on the atherosclerotic process. In addition, our understanding of the mechanisms of PCSK9 controlling VSMC functions in vivo is far from enough. This review aims to holistically evaluate and analyze the current state of our knowledge regarding PCSK9 actions affecting VSMC functions and its mechanism in atherosclerotic lesion development. A mechanistic understanding of PCSK9 effects on VSMC will further underpin the success of a new therapeutic strategy targeting AS.

Background Early identification of massive middle cerebral artery infarction (MCAI) at risk for malignant MCAI (m-MCAI) may be useful in selecting patients for aggressive therapies. The aim of this study was to determine whether CYP metabolites may help to predict impending m-MCAI. Methods This is a prospective, two-center observational study in 256 patients with acute massive MCAI. Plasma levels of 20-hydroxyeicosatetraenoic acid (20-HETE), epoxyeicosatrienoic acids, and dihydroxyeicosatrienoic acids were measured at admission. Brain computed tomography (CT) was performed at admission and repeated between day 3 and 7, or earlier if there was neurological deterioration. The primary outcome was m-MCAI. The m-MCAI was diagnosed when follow-up brain CT detected a more than two-thirds space-occupying MCAI with midline shift, compression of the basal cisterns, and neurological worsening. Results In total of 256 enrolled patients, 77 (30.1%) patients developed m-MCAI. Among the 77 patients with m-MCAI, 60 (77.9%) patients died during 3 months of stroke onset. 20-HETE level on admission was significantly higher in patients with m-MCAI than those without m-MCAI. There was an increase in the risk of m-MCAI with increase of 20-HETE levels. The third and fourth quartiles of 20-HETE levels were independent predictors of m-MCAI (OR: 2.86; 95% CI: 1.16 – 6.68; P = 0.025, and OR: 4.23; 95% CI: 1.35 – 8.26; P = 0.002, respectively). Conclusions Incidence of m-MCAI was high in patients with massive MCAI and the prognosis of m-MCAI is very poor. Elevated plasma 20-HETE may be as a predictor for m-MCAI in acute massive MCAI, and it might useful in clinical practice in therapeutic decision making.

Herein, we report the discovery of a novel class of quinazoline carboxamides as dual p70S6k/Akt inhibitors for the treatment of tumors driven by alterations to the PI3K/Akt/mTOR (PAM) pathway. Through the screening of in-house proprietary kinase library, 4-benzylamino-quinazoline-8-carboxylic acid amide 1 stood out, with sub-micromolar p70S6k biochemical activity, as the starting point for a structurally enabled p70S6K/Akt dual inhibitor program that led to the discovery of M2698, a dual p70S6k/Akt inhibitor. M2698 is kinase selective, possesses favorable physical, chemical, and DMPK profiles, is orally available and well tolerated, and displayed tumor control in multiple in vivo studies of PAM pathway-driven tumors.

Rationale: Acute kidney injury (AKI) is associated with aberrant generation of oxidative species and inflammation, leading to high mortality of in-hospitalized patients. Although N-acetylcysteine (NAC) showed positive effects in alleviating contrast-induced AKI, the clinical applications are strongly restrained due to the low bioavailability, low renal accumulation, short renal retention time, and high dosage-induced toxicity. Methods: We addressed the clinical dilemma of NAC by developing ultrasmall gold nanoclusters (1-2 nm) capped with NAC (denoted as Au NCs-NAC) as a nanozyme-based antioxidant defense system for AKI alleviation. Rhabdomyolysis-induced AKI mice model was developed, and the same dose of free NAC (as a control) and NAC onto Au NCs (Au NCs-NAC) was used for in vivo investigation of AKI restoration. Results: The as-developed gold nanozyme exhibited high bioavailability and good physicochemical stability as compared to NAC. Meanwhile, Au NCs-NAC showed broad-spectrum antioxidant activity of Au NCs-NAC, offering in vitro renoprotective effects, as well as macrophages by relieving inflammation under hydrogen peroxide or lipopolysaccharide stimulation. Notably, owing to the smaller size than kidney threshold (5.5 nm), Au NCs-NAC displayed preferential renal enrichment (< 2 h) and longer retention (> 24 h) in AKI mice as revealed by fluorescence imaging, thereby largely enhancing the restoration of renal function in AKI mice than free NAC by protecting the kidneys from oxidative injury and inflammation without systemic toxicity, as demonstrated by tissues staining, inflammatory cytokines and biomarkers detection, and mice survival rate. Conclusion: Owing to the synergistic anti-inflammatory/antioxidative effects, and enhanced bioavailability and renal accumulation/retention, Au NCs-NAC displayed far superior therapeutic performance than NAC alone. This work will facilitate the development of high-performance antioxidative nanoplatforms, as well as overcome the clinical limitations of small molecular drugs for AKI treatment and other inflammatory diseases.

Background Blood samples indicative of jaundice, lipemia, hemolysis, and others are often encountered in the laboratory, and such features impact greatly on the detection of coagulation items. To understand the anti-interference ability of the magnetic bead method automatic coagulation instrument and the optical method automatic coagulation instrument against jaundice, lipemia, and hemolysis, anti-interference experiments of prolonged prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB) were conducted using ExC810 (magnetic bead method) and CS5100 (optical method). Methods Interference samples were prepared with bilirubin, hemoglobin, and lipids, while control samples were prepared with NaOH and distilled water. The samples contained different values of PT, APTT, TT, and FIB and were detected by magnetic bead method and optical method, respectively. The relative deviation was calculated according to the formula. Results In the anti-interference experiment of PT, APTT, TT, and FIB (jaundice, lipemia, hemolysis), the deviation between the test results and the control results with the addition of interfering substances tested by ExC810 was lower overall than that of CS5100. However, after the addition of interfering substances, most of the items were not detected by CS5100 in the anti-lipidemia experiment. Conclusions When testing coagulation function, the magnetic bead method has better anti-interference recognition of jaundice, lipemia, and hemolysis than the optical method, and its anti-lipemic interference has a particularly obvious advantage.

Background Second head and neck neuroendocrine carcinoma (NEC) after radical radiotherapy for nasopharyngeal carcinoma (NPC) treatment is rarely reported. The prognosis of second cancer is poor, and our research focuses on finding a breakthrough in the treatment. In this study, we aimed to investigate clinicopathological characteristics and to identify the genomic landscape of second head and neck NECs. Methods We collected five second head and neck NEC cases in the recent three years from our patient database. Clinicopathological data and images were obtained. Genomic analysis was performed using high-throughput second generation sequencing. KEGG pathway enrichment analyses between high-frequency mutations were performed using the STRING database. Results All patients had been diagnosed with second NEC, according to the pathological observations. The interval between diagnosis of NPC and NEC ranged from 10 to 18 years. Two patients had brain or liver metastasis at three and nine months, respectively, after the diagnosis of NEC. Three patients died of the disease with the overall survival time ranging from three to nine months. Commonly altered genes (50%) in second head and neck NECs included TP53, RB1, NOTCH2, PTEN, POLG, KMT2C, U2AF1, EPPK1, ELAC2, DAXX, COL22A1, and ABL1. Those genetic lesions might affect p53 signaling, MAPK signaling, PI3K-Akt signaling, sphingolipid signaling, and neurotrophin signaling pathways. Conclusions Second head and neck NECs had poor prognosis. We revealed, for the first time, the mutational landscape, high-frequency somatic mutations, and potential signaling pathways of second head and neck NECs. Its optimal treatment model needs to be further studied in future clinical trials.

s Purpose To explore the distinct expression and diverse roles of IL-36 cytokines in dry eye disease using an in vitro hyperosmolarity model of human corneal epithelial cells (HCECs). Methods Primary HCECs were cultured from fresh donor limbal explants. Hyperosmolarity model was established by switching HCECs from isosmotic (312 mOsM) to hyperosmotic medium (350–500 mOsM) alone or with addition of rhIL-36RA or rhIL-38 for 2–48 h. Some cultures were treated with IL-36α (1–10 ng/ml) with or without rhIL-36RA or rhIL-38. Gene expression was detected by RT-qPCR; and protein production and barrier disruption were evaluated by ELISA and/or immunofluorescent staining. Results IL-36 cytokines were differential expressed in primary HCECs. Among 3 pro-inflammatory agonists, IL-36α, but not IL-36β and IL-36γ, was distinctly induced at osmolarity-dependent manner while two antagonist IL-36RA and IL-38 were significantly suppressed in HCECs exposed to hyperosmotic stress. IL-36α increased to 4.4-fold in mRNA and 6.9-fold at protein levels (116.0 ± 36.33 pg/ml vs 16.79 ± 6.51 pg/ml in controls) by 450 mOsM, but dramatically inhibited by addition of rhIL-36RA or rhIL-38. Exogenous rhIL-36α stimulated expression of TNF-α and IL-1β at mRNA and protein levels and disrupted tight junction proteins ZO-1 and occludin. However, rhIL-36RA or rhIL-38 suppressed TNF-α and IL-1β production and protected HCECs from barrier disruption in response to IL-36α or hyperosmolarity. Conclusions Our findings demonstrate that the stimulated pro-inflammatory IL-36α with the suppressed antagonists IL-36RA and IL-38 is a novel mechanism by which hyperosmolarity induces inflammation in dry eye. IL-36RA and IL-38 may have a therapeutic potential in dry eye.

Objectives. Observational studies indicate that insomnia may increase risk of peptic ulcer disease (PUD). Our purpose is to clarify the possible causal relationship between insomnia and PUD by Mendelian randomization analyses. Methods. We carried out analyses using summary statistics data for genetic variants reported from a GWAS of insomnia ( N = up to 1,331,010 individuals) and from a GWAS of PUD ( N = up to 456,327 individuals). Three Mendelian randomization approaches were used to explore whether insomnia might play a causal role in PUD, and pathway and functional enrichment analyses were conducted to anticipate the underlying mechanisms. Results. Conventional Mendelian randomization analysis showed clear causality between insomnia and PUD; 1 SD increased insomnia incident was related to a 19% higher risk of PUD ( P = 6.69 × 10 − 16 ; OR, 1.19 (95% CI, 1.14-1.24)). The associations between insomnia and PUD were consistent in the other two analyses performed using the weighted median method ( P = 7.75 × 10 − 7 ; OR, 1.16 (95% CI, 1.09-1.23)) and MR-Egger regression ( P = 5.00 × 10 − 3 ; OR, 1.27 (95% CI, 1.07-1.50)). Moreover, no evidence indicated a reverse causality between PUD events and insomnia symptoms. Pathway and functional enrichment analyses indicated that the mechanisms of insomnia effect on PUD may be through various ways, such as the immune system and oxidative stress. Conclusions. This Mendelian randomization study suggests insomnia as a causal risk factor for PUD. The potential mechanisms included may be immune and oxidative stress. These findings indicate that improving sleep quality could have substantial health benefits.

The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. Robust identification of clinically and biologically relevant molecular subtypes from nongenomic high-throughput sequencing data remains challenging. We established the largest multicenter AML cohort (n = 655) in China, with all patients subjected to RNA sequencing (RNA-Seq) and 619 (94.5%) to targeted or whole-exome sequencing (TES/WES). Based on an enhanced consensus clustering, eight stable gene expression subgroups (G1–G8) with unique clinical and biological significance were identified, including two unreported (G5 and G8) and three redefined ones (G4, G6, and G7). Apart from four well-known low-risk subgroups including PML::RARA (G1), CBFB::MYH11 (G2), RUNX1::RUNX1T1 (G3), biallelic CEBPA mutations or -like (G4), four meta-subgroups with poor outcomes were recognized. The G5 (myelodysplasia-related/-like) subgroup enriched clinical, cytogenetic and genetic features mimicking secondary AML, and hotspot mutations of IKZF1 (p.N159S) (n = 7). In contrast, most NPM1 mutations and KMT2A and NUP98 fusions clustered into G6–G8, showing high expression of HOXA / B genes and diverse differentiation stages, from hematopoietic stem/progenitor cell down to monocyte, namely HOX -primitive (G7) , HOX -mixed (G8), and HOX -committed (G6). Through constructing prediction models, the eight gene expression subgroups could be reproduced in the Cancer Genome Atlas (TCGA) and Beat AML cohorts. Each subgroup was associated with distinct prognosis and drug sensitivities, supporting the clinical applicability of this transcriptome-based classification of AML. These molecular subgroups illuminate the complex molecular network of AML, which may promote systematic studies of disease pathogenesis and foster the screening of targeted agents based on omics.

BACKGROUND This study aimed to explore the features of cognitive impairment in patients with neurosyphilis at the early stage of mild cognitive impairment (MCI). MATERIAL AND METHODS A total of 18 patients with asymptomatic neurosyphilis (ANS), 19 patients with neurosyphilis at the MCI stage (neurosyphilis-MCI), and 15 patients with neurosyphilis at the dementia stage (neurosyphilis-dementia) were enrolled. Cognitive function was evaluated using comprehensive rating scales. Tests of syphilis in blood and cerebrospinal fluid (CSF) were conducted, and white blood cell (WBC) counts and protein levels in CSF were measured. RESULTS Overall cognitive function and individual cognitive domains, including memory, language, visuospatial skill, and attention/executive function, were all significantly impaired in the neurosyphilis-MCI group compared with the ANS group, and were further impaired in the neurosyphilis-dementia group. Although there was no difference in serum rapid plasma regain (RPR) titer among the 3 groups, the number of patients with serum RPR titer ≥1: 32 in the neurosyphilis-MCI group was much higher than that in the ANS group. CSF RPR positive rate in the neurosyphilis-MCI group was significantly higher than that in the ANS group. The WBC count, protein level, and the rate of elevated protein level or increased WBC count in CSF did not differ among the 3 groups. CONCLUSIONS The feature of cognitive impairment of neurosyphilis-MCI patients displayed multiple-domain amnestic MCI. Perhaps there were extensive brain areas involved at the early stage, and a continuous neuroinflammatory process was through the different stages of neurosyphilis. Early diagnosis and treatment are very important for preventing the progression of general paresis of the insane.

Background Synchronous multiple primary lung cancers associated with small non-dominant nodules are commonly encountered. However, the incidence, follow-up, and treatment of small non-dominant tumors have been but little studied. We explored the prevalence and management of small non-dominant tumors and factors associated with interval growth. Methods This observational, consecutive, retrospective single-center study enrolled patients diagnosed with synchronous multiple primary lung cancers and small non-dominant tumors (≤ 6 mm in diameter) who underwent resection of the dominant tumor. The incidence, follow-up, and management of small non-dominant tumors and predictors of nodule growth were analyzed. Results There were 88 patients (12% of all lung cancer patients) with pathological diagnoses of synchronous multiple primary lung cancers. A total of 131 (18%) patients were clinically diagnosed with at least one small (≤ 6 mm in diameter) multiple primary lung cancer non-dominant tumor. 94 patients with 125 small-nodule non-dominant tumors clinically diagnosed as multiple primary lung cancers were followed-up for at least 6 months. A total of 29 (29/125, 23.2%) evidenced small pulmonary nodules (≤ 6 mm in diameter) that exhibited interval growth on follow-up computed tomography (CT). On multivariate analysis, a part-solid nodule (compared to a pGGN) (OR 1.23; 95% CI 1.08–1.40) or a solid nodule (compared to a pGGN) (OR 3.50; 95% CI 1.94–6.30) predicted small nodule interval growth. Conclusion We found a relatively high incidence of multiple primary lung cancers with small non-dominant tumors exhibiting interval growth on follow-up CT, suggesting that resection of non-dominant tumors at the time of dominant tumor resection, especially when the nodules are part-solid or solid, is the optimal treatment.

Geographical, environmental and pollution conditions affect facial skin health, but their effects on skin appearance have not been elucidated. This study aimed to describe the skin barrier and skin tone characteristics of Chinese subjects according to lifestyle and environmental conditions using in vitro measurements. In total, 1092 women aged 22–42 years were recruited from 7 representative Chinese cities. Eight skin parameters (hydration, sebum, pH, transdermal water loss, individual type angle, melanin index, erythema index, yellowness) were measured using noninvasive instruments; individual lifestyle data were also collected. Data on four meteorological factors (air temperature, relative humidity, sunshine duration, wind speed) and seven air pollution indicators (air quality index, fine particulate matter, breathable particulate matter, sulfur dioxide, nitrogen dioxide, carbon monoxide and ozone) were collected in each city from the China Meteorological Administration. Facial skin characteristics differed significantly between cities. Facial skin barrier characteristics and skin tones showed regional differences, with a better skin barrier associated with the western region, as indicated by high skin hydration and sebum secretion and a low pH value. According to the value of transdermal water loss, lighter and darker skin tones were found in the western and southern regions, respectively. Environmental conditions affected facial skin status. Air pollution induced facial skin issues, with fine particulate matter and nitrogen dioxide contributing the most. Individual lifestyles affected the facial skin barrier and skin tone.

Objective Blood glucose is related to early neurological deterioration in acute ischemic stroke, but multiple mechanisms are involved in early neurological deterioration, such as progressive infarction. This study aimed to determine whether fasting blood glucose (FBG) is an independent predictor of progressive infarction. Methods From April 2017 to December 2020, we retrospectively enrolled 477 patients with acute ischemic stroke within 48 hours of onset. Demographic characteristics, clinical information, neuroimaging characteristics, and laboratory data were collected after admission. Results We found that 147 (30.8%) patients had progressive infarction. Multiple regression analysis showed that high FBG concentrations (>7.66 mmol/L) were independently associated with progressive infarction. Sex subgroup analysis showed that high FBG concentrations were an independent predictor of progressive infarction in male patients (odds ratio, 2.559; 95% confidence interval, 1.279–5.121). In a receiver operating characteristic curve analysis, FBG concentrations were a predictor of progressive infarction in all cases, especially in male patients. The cutoff value of FBG in all patients and men was 7.155 mmol/L. Conclusions FBG is an independent predictor of progressive infarction in patients with acute ischemic stroke within 48 hours of onset, especially in men. Patients with FBG concentrations ≥7.155 mmol/L are more likely to develop progressive infarction.

BackgroundThe Family Health Climate (FHC) is a family environment attribute postulated to influence the health behaviors of family members. It can be measured by domain scales for physical activity (FHC-PA) and nutrition (FHC-NU), which have been validated and used to identify health climate patterns in families in Western populations. To extend the use of the scales to Asian settings, this study aimed to adapt and validate the instruments for use in the multi-ethnic population of Singapore, accounting for language and cultural differences.MethodsIn Part A (n = 40) to adapt the scales for the Singapore population, we performed cognitive interviews, face validity testing and pre-testing of the instruments (n = 40). Besides English, the scales were translated into Chinese and Malay. In Part B (n = 400), we performed exploratory and confirmatory factor analyses respectively on two random samples. We also tested for item discriminant validity, internal consistency reliability, construct validity, and measurement invariance.ResultsThe findings from the cognitive interviews in Part A led to scale adaptations to accommodate cultural and linguistic factors. In Part B, EFA on Sample I resulted in a three-factor model for the PA scale (accounting for 71.2% variance) and a four-factor model for the NU scale (accounting for 72.8% variance). CFA on Sample II indicated acceptable model fits: FHC-PA: χ2 = 192.29, df = 101, p < 0.001, χ2/df = 1.90; SRMR = 0.049; RMSEA = 0.067; CFI = 0.969; TLI = 0.963; FHC-NU: χ2 = 170.46, df = 98, p < 0.001, χ2/df = 1.74; SRMR = 0.036; RMSEA = 0.061; CFI = 0.967; TLI = 0.960. The scores of family members demonstrated significant agreement on the FHC-PA (Sg) [ICC(2, 2) = 0.77] and FHC-NU (Sg) [ICC(2, 2) = 0.75] scales. Findings suggest good evidence for item discriminant validity, internal consistency reliability, construct validity, and measurement invariance. Short versions of the scales were also developed.ConclusionWe adapted, translated and validated the scales for assessing the health climate of families in Singapore, including the development of short versions. The results showed good psychometric properties and the constructs had significant relationships with health behaviors and routines. Improving our understanding of family influences on individual health behavior will be important in developing multi-level strategies for health promotion and chronic disease prevention.

Overexpressing human NAD(iP/i)H:quinone oxidoreductase 1 (hNQO1) in lung cancer tissues is deemed to be an attractive biomarker, which is directly connected to cancerous pathological processes. Monitoring of hNQO1 activity is crucial to early diagnosis and prognosis of lung cancer. In this study, an activatable hemi-cyanine dye-based probe (denoted as the LET-10 probe) was synthesized for near-infrared fluorescence (NIRF) and ratiometric photoacoustic (RPA) imaging of hNQO1. LET-10 can realize the NIRF and PA signal opening in the presence of hNQO1. Taking the octabutoxy naphthalocyanine in the LET-10 probe as a built-in reference signal, the LET-10 probe further demonstrated a double-signal self-calibration process for RPA imaging. Finally, the LET-10 probe was successfully applied for NIRF/RPA duplex imaging in the hNQO1-positive A549 lung cancer model, which suggests that the LET-10 probe is a promising tool for in vivo hNQO1 detection, especially for lung cancer diagnosis.

Photodynamic therapy (PDT) has attained extensive attention as a noninvasive tumor treatment modality. However, the hypoxia in solid tumors, skin phototoxicity of "always on" photosensitizers (PSs), and abundant supply of glutathione (GSH) in cancer cells severely hampered the clinical applications of PDT. Herein, a self-oxygenation nanoplatform (denoted as CZCH) with GSH depletion ability was encapsulated into the hyaluronic acid microneedle patch (MN-CZCH) to simultaneously improve the biosafety and therapeutic efficacy of PDT. The Cu

Glucose and lactate play important roles for tumor growth. How to simultaneously deprive tumors of glucose and lactate is a big challenge. We have developed a cascade catalytic system (denoted as FPGLC) based on fluorinated polymer (FP) with co-loading of glucose oxidase (GOx), lactate oxidase (LOx), and catalase (CAT). GOx and LOx deprive glucose and lactate, respectively, resulting in abundant hydrogen peroxide (Hsub2/subOsub2/sub) generation. Meanwhile, CAT catalyzes Hsub2/subOsub2/subinto Osub2/sub, which not only promotes catalytic reactions of GOx and LOx for consuming more glucose and lactate, but also alleviates tumor hypoxia. Benefiting from the excellent cross-membrane and transmucosal penetration capacities of FP, FPGLC rapidly accumulated in tumors and subsequently mediated enhanced cascade catalytic therapy under the guidance of photoacoustic imaging. These results demonstrate that the dual depletion of glucose and lactate with Osub2/subsupply is a promising strategy for efficient antitumor starvation therapy.

Post-treatment apical periodontitis (PoAP) occurs when root canal treatment has not adequately eliminated bacterial invasion and infection. Yet little is known about the bacterial composition and changes related to the etiology and pathogenesis of PoAP. In this study, clinical samples classified as root apex (HARD) and periapical granulation tissues (SOFT) were separately collected from 10 patients with PoAP. The microbiota of each sample was characterized by 16S rRNA gene sequencing, and the obtained dataset was coanalyzed with 20 NCBI sequence read archive (SRA) datasets of healthy oral (HO) and primary apical periodontitis (PAP). We observed 2522 operational taxonomic units (OTUs) belonging to 29 phyla, and all samples shared 86.5% of the sequence reads. The OTUs affiliated with Bacteroidetes, Firmicutes, Proteobacteria, Fusobacteria, and Actinobacteria, were identified as core microbiota, which accounted for nearly 90% of 16S rRNA sequences in all samples. However, the principal coordinates analysis (PCoA) of the beta diversity demonstrated that the three periapical statuses have distinct microbial compositions. Compared with HO and PoAP, Actinomyces has a significantly increased abundance in PAP. The microbial diversities in PoAP were significantly lower than those in the HO and PAP (p

Thoracic endovascular aortic repair (TEVAR) has been accepted as the mainstream treatment for type B aortic dissection, but post-TEVAR biomechanical-related complications are still a major drawback. Unfortunately, the stent-graft (SG) configuration after implantation and biomechanical interactions between the SG and local aorta are usually unknown prior to a TEVAR procedure. The ability to obtain such information via personalised computational simulation would greatly assist clinicians in pre-surgical planning. In this study, a virtual SG deployment simulation framework was developed for the treatment for a complicated aortic dissection case. It incorporates patient-specific anatomical information based on pre-TEVAR CT angiographic images, details of the SG design and the mechanical properties of the stent wire, graft and dissected aorta. Hyperelastic material parameters for the aortic wall were determined based on uniaxial tensile testing performed on aortic tissue samples taken from type B aortic dissection patients. Pre-stress conditions of the aortic wall and the action of blood pressure were also accounted for. The simulated post-TEVAR configuration was compared with follow-up CT scans, demonstrating good agreement with mean deviations of 5.8% in local open area and 4.6 mm in stent strut position. Deployment of the SG increased the maximum principal stress by 24.30 kPa in the narrowed true lumen but reduced the stress by 31.38 kPa in the entry tear region where there was an aneurysmal expansion. Comparisons of simulation results with different levels of model complexity suggested that pre-stress of the aortic wall and blood pressure inside the SG should be included in order to accurately predict the deformation of the deployed SG.

Key points The corticoreticulospinal tract (CReST) is a descending motor pathway that reorganizes after corticospinal tract (CST) injury in animals. In humans, the pattern of CReST innervation to upper limb muscles has not been carefully examined in healthy individuals or individuals with CST injury. In this study we assessed CReST projections to an arm and hand muscle on the same side of the body in healthy and chronic stoke subjects using transcranial magnetic stimulation. We show that CReST connection strength to the muscles differs between healthy and stroke subjects, with stronger connections to hand than arm in healthy subjects, and stronger connections to the arm than hand in stroke subjects. These results help us better understand CReST innervation patterns in the upper limb, and may point to its role in normal motor function and motor recovery in humans. Abstract The corticoreticulospinal tract (CReST) is a major descending motor pathway in many animals, but little is known about its innervation patterns in proximal and distal upper extremity (UE) muscles in humans. The contralesional CReST furthermore reorganizes after corticospinal tract (CST) injury in animals, but it is less clear whether CReST innervation changes after stroke in humans. We thus examined CReST functional connectivity, connection strength, and modulation in an arm and hand muscle of healthy (n = 15) and chronic stroke (n = 16) subjects. We delivered transcranial magnetic stimulation to the contralesional hemisphere (assigned in healthy subjects) to elicit ipsilateral motor evoked potentials (iMEPs) from the paretic biceps (BIC) and first dorsal interosseous (FDI) muscle. We operationalized CReST functional connectivity as iMEP presence/absence, CReST projection strength as iMEP size, and CReST modulation as change in iMEP size by head rotation. We found comparable CReST functional connectivity to the BICs and FDIs in both subject groups. However, the pattern of CReST connection strength to the muscles diverged between groups, with stronger connections to FDIs than BICs in healthy subjects and stronger connections to BICs than FDIs in stroke subjects. Head rotation modulated only FDI iMEPs of healthy subjects. Our findings indicate that the healthy CReST does not have a proximal innervation bias, and its strong FDI connections may have functional relevance to finger individuation. The reversed CReST innervation pattern in stroke subjects confirms its reorganization after CST injury, and its strong BIC connections may indicate upregulation for particular UE muscles or their functional actions. This article is protected by copyright. All rights reserved.

Objective To quantify changes in respiratory and glycemic control outcomes following antenatal corticosteroids (ANCS) exposure in late preterm neonates. Design/methods The study included 500 neonates born between 34 0/7 and 36 6/7 weeks of gestation. Study population was divided into two groups: an immature group (34 0/7-35 6/7 weeks) and a mature group (36 0/7-36 6/7 weeks). Respiratory and glycemic control outcomes were analyzed for each group independently. Results In the immature group, the odds of developing respiratory distress decreased in neonates exposed to ANCS within 7 days of delivery (aOR 0.42; p = 0.02). In the mature group, ANCS exposure did not change respiratory outcomes, but decreased lowest blood glucose levels (-1.5 ± 0.66 mg/dL per dose, p = 0.02). Conclusion In our study cohort, ANCS administration was associated with improved neonatal respiratory outcomes only for infants in the immature 34 0/7-35 6/7 weeks of gestational age group. ANCS was associated with altered glycemic control only in infants in the mature 36 0/7-36 6/7 weeks of gestational age group.

Background Although existing studies have described patterns of social media use in healthcare, most are focused on health professionals in one discipline. Population health requires a multi-disciplinary approach to ensure diversity and to include diverse stakeholders. To date, what is known about using social media in population health is focused on its potential as a communication tool. This study aims to investigate patterns of use and perceived value of social media usage among stakeholders in population health practice, policy, or research. Methods We conducted a web-based survey of delegates attending the Singapore Population Health Conversations and Workshop. We designed a 24-item questionnaire to assess 1) social media use in terms of type of platform and frequency of use; 2) perceptions of social media relevance and impact on population health; and 3) top three areas in population health that would benefit from social media. We used descriptive and logistic regression analyses to assess the relationships between variables. Results Of the 308 survey respondents, 97.7% reported that they use social media in some form. Messaging (96.8%) was the most dominant activity when using social media. Challenges in implementing social media for population health were time investment by health care professionals (56.2%) and patient adoption (52.9%). The top three population health areas that would benefit most from using social media were the promotion of healthy behaviors (60.7%), community engagement (47.7%), and preventive care (40.6%). Older respondents (> = 40 years) were less likely to view social media as useful for the promotion of healthy behaviors (OR = 0.34; 95% CI: 0.19–0.60). Non-social/healthcare professionals were more likely to consider social media to be useful for community engagement (OR = 1.74; 95% CI: 1.10–2.76). For preventive care, older respondents (OR = 0.51; 95% CI: 0.32–0.82) and non-social/healthcare professionals were less likely to view social media as useful (OR = 0.61; 95% CI: 0.38–0.97). Conclusions Our findings suggest that it may be important to select the specific care areas that would benefit most from using social media. The time investment needed by population health professionals should be fully addressed in planning to maximize the application and potential value of social media.

Background Abnormally elevated xanthine oxidase (XO) activity has been verified to cause various pathological processes, such as gout, oxidative stress injury and metabolic syndrome. Thus, XO activators may exhibit above potential toxicological properties. Plumbagin (PLB) is an important active compound in traditional Chinese medicine (TCM), while its obvious toxic effects have been reported, including diarrhea, skin rashes and hepatic toxicity. However, the potential toxicity associated with enhancement of XO activity has not been fully illuminated so far. Methods The present study investigated the effect of PLB on XO activity by culturing mouse liver S9 (MLS9), human liver S9 (HLS9), XO monoenzyme system with PLB and xanthine. Then, the molecular docking and biolayer interferometry analysis were adopted to study the binding properties between PLB and XO. Finally, the in vivo acceleration effect also investigated by injected intraperitoneally PLB to KM mice for 3 days. Results PLB could obviously accelerate xanthine oxidation in the above three incubation systems. Both the Vmax values and intrinsic clearance values (CLint, Vmax/Km) of XO in the three incubation systems increased along with elevated PLB concentration. In addition, the molecular docking study and label-free biolayer interferometry assay displayed that PLB was well bound to XO. In addition, the in vivo results showed that PLB (2 and 10 mg/kg) significantly increased serum uric acid levels and enhanced serum XO activity in mice. Conclusion In summary, this study outlines a potential source of toxicity for PLB due to the powerful enhancement of XO activity, which may provide the crucial reminding for the PLB-containing preparation development and clinical application.

There are over 50 SARS‐CoV‐2 candidate vaccines undergoing Phase II and III clinical trials. Several vaccines have been approved by regulatory authorities and rolled out for use in different countries. Due to concerns of potential teratogenicity or adverse effect on maternal physiology, pregnancy has been a specific exclusion criterion for most vaccine trials with only two trials not excluding pregnant women. Thus, other than limited animal studies, gradually emerging development and reproductive toxicity data, and observational data from vaccine registries, there is a paucity of reliable information to guide recommendations for the safe vaccination of pregnant women. Pregnancy is a risk factor for severe COVID‐19, especially in women with comorbidities, resulting in increased rates of preterm birth and maternal morbidity. We discuss the major SARS‐CoV‐2 vaccines, their mechanisms of action, efficacy, safety profile and possible benefits to the maternal‐fetal dyad to create a rational approach towards maternal vaccination while anticipating and mitigating vaccine‐related complications. Pregnant women with high exposure risks or co‐morbidities predisposing to severe COVID‐19 infection should be prioritised for vaccination. Those with risk factors for adverse effects should be counselled accordingly. It is essential to support patient autonomy by shared decision‐making involving a risk‐benefit discussion with the pregnant woman., Key points What is already known about this topic? COVID‐19 infection in pregnancy leads to an increase in adverse maternal outcomes.Owing to paucity of data regarding SARS‐CoV‐2 vaccine use in pregnancy there is uncertainty regarding safety of use and subsequent pregnancy outcomes. What does this study add? Provides an overview of the available SARS‐CoV‐2 vaccines, their mechanisms of action and feasibility of use in pregnancy.Summarises recommendations regarding vaccination of pregnant or lactating women.

Exosomes are often a promising source of biomarkers for cancer diagnosis in the early stages. Therefore, it is important to develop a sensitive and low-cost detection method. Here, we introduce a new substrate using gold nanorods (GNRs) on a silver-island film that produces a 360-fold AF647 molecule fluorescence enhancement compared to glass. The amplified fluorescence was proven theoretically by using finite difference time-domain simulation (FDTD). Utilizing the enhanced fluorescence from the substrate, GNRs attached with the biomolecules and created a sandwich immunoassay that can significantly detect human CD63 antigen on the exosome. By applying the method, the detection limit of mouse IgG goes down to 0.3 ng/mL, which is considerably better than the existing methods. Moreover, the sensitivity and accuracy for clinical plasma from six patients confirm its diagnostic feasibility. The proposed substrate can be uniformly extended to the identification of other biomarkers by modifying the antibodies on the surfaces of the GNRs.

Background Intermittent exotropia (IXT) is the most common form of exotropia in children. In addition to cosmetic effects and loss of stereoscopic function, IXT may negatively impact the psychological well-being of children and their parents. The purpose of this study was to assess the patient-reported outcomes of Chinese children with IXT before and after strabismus surgery. Methods The records of children with IXT who underwent strabismus surgery at the Zhongshan Ophthalmic Center of Sun Yat-sen University, China over the period from January 1, 2016 to December 31, 2018 were prospectively recruited. All children underwent ophthalmic and orthoptic examinations, including the prism and alternate cover test, fusion function by synoptophore, stereoacuity and Newcastle control score. Two patient-reported outcome measures were used: the intermittent Exotropia Questionnaire (IXTQ) to measure disease-specific health-related quality of life (HRQOL) and the Hospital Anxiety and Depression Scale (HADS) to measure anxiety and depression. Patient-reported outcome measurements were made before and after surgery with responses from children and their parents. Results A total of 389 children were eligible for inclusion (47.8% male, 52.2% female, mean + SD age = 8.17 ± 2.81). Preoperative IXTQ scores in both children (48.21 ± 26.2) and their parents (44.6 ± 25.68) were significantly correlated with near stereoacuity (P = 0.029 and P = 0.015, respectively). The angle of deviation at near vision showed a negative linear relationship with visual function (P = 0.026) and psychological (P = 0.019) scores as well as opinions regarding surgery (P = 0.024). HADS scores (anxiety scale score: 11 ± 2.92, depression scale score: 10.44 ± 2.9) were also related to near stereoacuity (P P Conclusion Children and parents’ HRQOL and HADS were associated with near stereoacuity. Parents usually attend more readily to the angle of deviation at near in their IXT children. HRQOL improved significantly after surgery and can be used as one of the indices for preoperative evaluation but is not recommended as a criterion for surgical intervention.

Saliva has significant advantages as a test medium for detection of SARS-CoV-2 infection in patients, such as ease of collection, minimal requirement of supplies and trained personnel, and safety. Comprehensive validation in a large cohort of prospectively collected specimens with unknown SARS-CoV-2 status should be performed to evaluate the potential and limitations of saliva-based testing. We developed a saliva-based testing pipeline for detection of SARS-CoV-2 nucleic acids using real-time reverse transcription PCR (RT-PCR) and droplet digital PCR (ddPCR) readouts, and measured samples from 137 outpatients tested at a curbside testing facility and 29 inpatients hospitalized for COVID-19. These measurements were compared to the nasal swab results for each patient performed by a certified microbiology laboratory. We found that our saliva testing positively detects 100% (RT-PCR) and 93.75% (ddPCR) of curbside patients that were identified as SARS-CoV-2 positive by the Emergency Use Authorization (EUA) certified nasal swab testing assay. Quantification of viral loads by ddPCR revealed an extremely wide range, with 1 million-fold difference between individual patients. Our results demonstrate for both community screening and hospital settings that saliva testing reliability is on par with that of the nasal swabs in detecting infected cases, and has potential for higher sensitivity when combined with ddPCR in detecting low-abundance viral loads that evade traditional testing methods.

This study aimed to develop a vaccine that targets mutation-derived neoantigen in Chinese non-small-cell lung cancer (NSCLC).A cohort of 1862 Chinese NSCLC patients who underwent targeted sequencing with a 1021-gene panel was investigated. HLA typing was done using OptiType v1.0 and neoantigens were predicted by netMHCpan v4.0. HLA LOH was inferred using the lohhla algorithm and TMB were quantified by counting the total number of non-synonymous ones based on our panel data. CIBERSORT was utilized to estimate the TME in differentHLA-A*11:01(42.59%) was the top one allele and HLA-A*33:03(12.94%) ranked 12th.Our study identified that

Since associations between coffee and tea consumption with cardiovascular disease (CVD) and chronic respiratory disease (CRD) remain controversial. This study aims to investigate the separate and combined associations of coffee and tea consumption with CVD, CRD, and their comorbidity.Within the UK Biobank, 390 039 participants (56.2 ± 8.1 years) free of CVD and CRD are included. Coffee and tea consumption are self-reported at baseline. During a median follow-up of 12.1 years, 31126 CVD, 34132 CRD, and 6071 CVD-CRD comorbidity cases are identified. J-shaped associations between coffee and tea consumption with CVD, CRD, and CVD-CRD comorbidity are observed (p for nonlinearity0.001). Compared with neither coffee nor tea consumption, hazard ratios (HRs) and 95% confidence intervals (CIs) of combined consumption of moderate coffee and tea (each 2-3 cups per day) are 0.88 (0.81-0.96) for CVD, 0.78 (0.72-0.84) for CRD, and 0.74 (0.61-0.91) for CVD-CRD comorbidity.Moderate consumption of coffee and tea separately or in combination are associated with lower risks of CVD, CRD, and their comorbidity.

Serum ferritin (SF) is an iron-rich protein tightly connected with iron homeostasis, and the variations are frequently observed in diseased states, including iron-deficiency anemia, inflammation, liver disease, and tumors, which renders SF level an indicator of potential malignancies in clinical practice. Nanobodies (Nbs) have been widely explored and developed into theranostic reagents. Surprisingly, no reports stated the identification of anti-SF Nbs, nor the potential of such Nbs as a diagnostic tool. In this study, we generated SF-specific Nbs and provided novel clinical diagnostic approaches to develop an immunoassay. An immune library was constructed after immunizing an alpaca with SF, and five Nbs specifically targeting human SF were retrieved. The obtained Nbs exhibited robust properties including high stability, affinity, and specificity. Then, an ELISA-based test using a heterologous Nb-pair was developed. The calibration curve demonstrated a linear range of SF between 9.0 to 1100 ng/mL, and a limit of detection (LOD) of 1.01 ng/mL. The detecting recovery and coefficient variation (CV) were determined by spiking different concentrations of SF into the serum sample, to verify the successful application of our selected Nbs for SF monitoring. In general, this study generated SF-specific Nbs and demonstrated their potential as diagnostic immunoassay tools.

The delivery of glucose oxidase (GOx) requires extra carriers, which suffers from early leakage and exposure of GOx. These issues will be of less concern if GOx itself acts as a drug carrier. However, the catalytic activity of GOx in the blood still needs to be inhibited. Herein, we found that GOx could self-assemble with hydrophobic molecules into uniform and stable nanoparticles (NPs), including sorafenib, 4'-(amino-methyl phenyl)-2,2' : 6',2''-terpyridine modified cyanin and paclitaxel. The catalytic activity of GOx in NPs was significantly inhibited due to the binding of small molecules with its hydrophobic pockets. After dissociation in the tumor acidic microenvironment, the enzyme activity of GOx could be largely recovered. This acidity-triggered "OFF-to-ON" process ensured safe intravenous administration of GOx-based NPs. In vivo experiments showed that the combined starvation therapy and ferroptosis/photothermal therapy/chemotherapy effectively inhibited 4T1 breast tumor growth.

Pyroptosis is an inflammatory form of cell death, which plays a key role in the development of auto-inflammation and cancer. This study aimed to construct a pyroptosis and inflammasome-related genes for predicting prognosis of the pancreatic ductal adenocarcinoma (PDAC). This study was based primarily on the one-way analysis of variance, univariate Cox regression analysis, Least absolute shrinkage and selection operator (LASSO) Cox regression, a risk-prognostic signature, gene set variation analysis (GSVA), and immune microenvironment analysis, using PDAC data from The Cancer Genome Atlas and International Cancer Genome Consortium databases for the analysis of the role of 676 pyroptosis and inflammasome-related genes in PDAC retrieved from the Reactome and GeneCards databases. Lastly, we collected six paired PDAC and matched normal adjacent tissue samples to verify the expression of signature genes by quantitative real-time PCR (qRT-PCR). We identified 18 candidate pyroptosis and inflammasome-related genes that differed significantly between pathologic grades (stages) of PDAC patients. The univariate Cox and LASSO analyses pointed to six genes as the best variables for constructing a prognostic signature, including ACTA2, C1QTNF9, DNAH8, GATM, LBP, and NGF. The results of the risk prognostic model indicated that the AUCs at 1, 3, and 5 years were greater than 0.62. GSVA revealed that ‘GLYCOLYSIS’, ‘P53 PATHWAY’, ‘KRAS SIGNALING UP’, and ‘INFLAMMATORY RESPONSE’ hallmark gene sets were associated with the risk score. The high-risk group was associated with poor prognosis and was characterized by a lower infiltration of cells involved in anti-tumor immunity; whereas the low-risk group with higher T cells, NK cells, and macrophages showed relatively better survival and significantly higher upregulation of cytolytic scores and inflammation scores. Additionally, crucial pyroptosis and inflammasome-related genes were further validated by qRT-PCR. Our study revealed the prognostic role of the pyroptosis and inflammasome-related genes in PDAC for the first time. Simultaneously, the biological and prognostic heterogeneity of PDAC had been demonstrated, deepening our molecular understanding of this tumor.

Purpose Emerging evidence shows that immune checkpoint inhibitors lead to durable responses in a variety of cancers, including nasopharyngeal carcinoma (NPC), however, combination approaches (i.e., stereotactic body radiation therapy, SBRT) are required to extend this benefit beyond a subset of patients. This study retrospectively evaluated eight recurrent/metastatic NPC patients, to investigate how radiation could potentiate PD-1 checkpoint inhibition therapy. Methods Between September 2016 and July 2017, eight consecutive cases with histologically confirmed PDL1-positive status, for which prior standard therapy had been ineffective (five patients), were treated at our institution and Macao Clinics and two patients had disease progression within 6 months of completion of definitive chemoradiation, or one patient refused to receive chemoradiotherapy. All received PD-1 inhibitors first, seven of them accepted SBRT with an unmodified PD-1 inhibitors regimen after first evaluation as they were unresponsive to PD-1 inhibitors alone. Treatment was discontinued as long as patients were experiencing a clinical benefit in the opinion of the physicians and at least five cycles were given before stoppage. Results Median follow-up time was 56.7 months. The confirmed objective response rate based on RECIST-v1.1 at first evaluation was 12.5% (1/8). For the seven cases who received SBRT, six of them experience an objective response (6/7, 85.7%) after SBRT. Only one patient showed rapid progress and die within 95 days after the initiation of SBRT intervention. Three patients who did not have all lesions exposed to irradiation were available to evaluate the incidence of an abscopal effect, however, it did not occur as expected. Median PFS and OS for the seven patients were 8.0 and 30.8 months after SBRT intervention, respectively. Two-year OS as indicated was 71.0%. Conclusions PD-1 inhibitors combined with SBRT demonstrated promising antitumor activity in patients with PD-L1 positive RM-NPC. Patients may benefit from continue immunotherapy beyond disease progression when SBRT was introduced.