Citations

Abstract Background Self‐efficacy, or the beliefs learners hold about what they can do, develops largely from how learners perceive and interpret four main sources of information: mastery experiences, vicarious experiences, social persuasions and physiological and affective states. Although the relationship between these sources and self‐efficacy is well‐established, less is known about the factors that may influence how early adolescent learners perceive and interpret information from these sources. Aims The purpose of this study was to investigate how the predisposition of perfectionism might predict how learners perceive efficacy‐relevant information in the domain of math. Methods Using a correlational design, this study considered whether perfectionism was associated with how middle school students ( N = 1683) perceive information from the four hypothesized sources of self‐efficacy. Participants completed a paper‐based survey at two time points. Perfectionism was measured at Time 1. Self‐efficacy and its sources were measured at Time 2. Structural equation modelling techniques were used to examine the relationship between factors. Results and Conclusions Students who held themselves to high standards (i.e., greater self‐oriented perfectionism) reported higher levels of mastery experiences, vicarious experiences, social messages and self‐efficacy. Conversely, students who felt external pressure to be perfect (i.e., socially prescribed perfectionism) reported lower levels of mastery experiences, vicarious experiences and self‐efficacy, as well as higher levels of negative physiological and affective states. The relationship between perfectionism and self‐efficacy was partially mediated by students' perceptions of mastery. This study extends the current literature on the sources of math self‐efficacy in early adolescence by showing how a predisposition like perfectionism is associated with how adolescent learners perceive and interpret efficacy‐relevant information.

Introduction: The atrial natriuretic peptide (ANP) regulates blood pressure (BP) and cardiorenal homeostasis via activation of guanylyl cyclase A (GC-A) receptor and second messenger cGMP. We recently demonstrated the safety, tolerability, and BP-lowering properties of MANP, an ANP analog and best-in-class GC-A activator, in subjects with essential hypertension (HTN). However, the effects of MANP on human metabolome during HTN remains undefined. Hypothesis: A single subcutaneous (SQ) administration of MANP can trigger metabolomic changes in humans. Methods: Twenty-two patients with HTN and metabolic syndrome (MetS) were randomized to receive placebo (N=5) or MANP (N=17, 2.5 μg/kg). Untargeted liquid chromatography mass spectrometry-based metabolomics and informatics were conducted on plasma of all subjects at baseline, 1 h post injection (hpi), and 6 hpi. Top circulating metabolites associated with MANP treatment were identified via a comparison of abundance between before and after MANP administration. Results: Compared to placebo, MANP resulted in the most prominent cGMP increase at 1 hpi and BP lowering effect at 6 hpi. With untargeted approach, we identified totally 1384 circulating metabolites. Principal component analysis supported distinct metabolic signatures at baseline, 1 hpi and 6 hpi in subjects receiving MANP. In MANP group, we found 31 metabolites at 1 hpi and 148 metabolites at 6 hpi showing significant change in abundance (adjusted P value < 0.05) compared to baseline. By contrast, <10 metabolites with difference in circulating abundance at either 1 hpi or 6 hpi compared to baseline were found in placebo group. Specifically, 8 annotated metabolites were identified with significant and progressive changes at both 1 and 6 hpi after treatment of MANP but not placebo, which included spisulosine, paecilaminol, quinine ethyl carbonate, thyrotropin releasing hormone, 3-epideoxycholic acid, hellicoside, pentanorvitamin D3, and tetracosanal. Conclusion: SQ administration of MANP triggers changes in a wide range of circulating metabolites beyond cGMP activation and BP reduction in humans. The biological outcome and clinical impact of these MANP-associated metabolites may help guide a precision medicine approach in HTN with MetS.

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease globally in tandem with the growing obesity epidemic. However, there is a lack of data on the relationship between historical weight changes 10 years ago and at present on NAFLD prevalence at the population level. Therefore, we sought to evaluate the relationship between weight classes and the prevalence of NAFLD. Methods: Data were used from the United States National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Univariate and multivariate general linear model analyses were used to obtain risk ratio (RR) estimations of NAFLD events. Results: In total, 34,486 individuals were analysed, with those who were lean at both time points as the control group. Overweight (RR: 14.73, 95%CI: 11.94 to 18.18, p < 0.01) or obese (RR: 31.51, 95%CI: 25.30 to 39.25, p < 0.01) individuals at both timepoints were more likely to develop NAFLD. Residual risk exists where previously obese individuals became overweight (RR: 14.72, 95%CI: 12.36 to 17.52, p < 0.01) or lean (RR: 2.46, 95%CI: 1.40 to 4.31, p = 0.02), and previously overweight individuals who became lean (RR 2.24, 95%CI 1.42 to 3.54, p = 0.01) had persistent elevated risk of developing NAFLD despite weight regression. Sensitivity analysis identified that a higher proportion of individuals with regression in weight class were diabetics and Mexican Americans, while fewer African Americans saw weight-class regression. Conclusions: Residual risk exists in patients who lost weight despite the smaller magnitude of effect, and targeted weight reductions should still be used to mitigate the risk of NAFLD at the population level.

AbstractPeripheral nerve injury‐induced spinal microglial proliferation plays a pivotal role in neuropathic pain. So far, key intracellular druggable molecules involved in this process are not identified. The nuclear factor of activated T‐cells (NFAT1) is a master regulator of immune cell proliferation. Whether and how NFAT1 modulates spinal microglial proliferation during neuropathic pain remain unknown. Here it is reported that NFAT1 is persistently upregulated in microglia after spinal nerve ligation (SNL), which is regulated by TET2‐mediated DNA demethylation. Global or microglia‐specific deletion of Nfat1 attenuates SNL‐induced pain and decreases excitatory synaptic transmission of lamina II neurons. Furthermore, deletion of Nfat1 decreases microglial proliferation and the expression of multiple microglia‐related genes, such as cytokines, transmembrane signaling receptors, and transcription factors. Particularly, SNL increases the binding of NFAT1 with the promoter of Itgam, Tnf, Il‐1b, and c‐Myc in the spinal cord. Microglia‐specific overexpression of c‐MYC induces pain hypersensitivity and microglial proliferation. Finally, inhibiting NFAT1 and c‐MYC by intrathecal injection of inhibitor or siRNA alleviates SNL‐induced neuropathic pain. Collectively, NFAT1 is a hub transcription factor that regulates microglial proliferation via c‐MYC and guides the expression of the activated microglia genome. Thus, NFAT1 may be an effective target for treating neuropathic pain.

Background: Aldosterone is a critical pathological driver for cardiac and renal diseases. We recently discovered that mutant atrial natriuretic peptide (MANP), a novel atrial natriuretic peptide (ANP) analog, possessed more potent aldosterone inhibitory action than ANP in vivo. MANP and natriuretic peptide (NP)-augmenting therapy sacubitril/valsartan are under investigations for human hypertension treatment. Understanding the elusive mechanism of aldosterone inhibition by NPs remains to be a priority. Conflicting results were reported on the roles of the pGC-A (particulate guanylyl cyclase A receptor) and NP clearance receptor in aldosterone inhibition. Furthermore, the function of PKG (protein kinase G) and PDEs (phosphodiesterases) on aldosterone regulation are not clear. Methods: In the present study, we investigated the molecular mechanism of aldosterone regulation in a human adrenocortical cell line H295R and in mice. Results: We first provided evidence to show that pGC-A, not NP clearance receptor, mediates aldosterone inhibition. Next, we confirmed that MANP inhibits aldosterone via PDE2 (phosphodiesterase 2) not PKG, with specific agonists, antagonists, siRNA silencing, and fluorescence resonance energy transfer experiments. Further, the inhibitory effect is mediated by a reduction of intracellular Ca2+ levels. We then illustrated that MANP directly reduces aldosterone synthase CYP11B2 (cytochrome p450 family 11 subfamily b member 2) expression via PDE2. Last, in PDE2 knockout mice, consistent with in vitro findings, embryonic adrenal CYP11B2 is markedly increased. Conclusions: Our results innovatively explore and expand the NP/pGC-A/3',5', cyclic guanosine monophosphate (cGMP)/PDE2 pathway for aldosterone inhibition by MANP in vitro and in vivo. In addition, our data also support the development of MANP as a novel ANP analog drug for aldosterone excess treatment.

AbstractBackgroundMerkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy that usually occurs in the head/neck or extremities. However, there are reports of MCC developing in the lymph nodes or parotid gland without evidence of a primary cutaneous lesion.MethodsWe reviewed 415 patients with biopsy‐proven MCC. Patients with MCC of unknown primary (n = 37, 9%, MCCUP) made up the study cohort. The primary endpoints of the study were rate of recurrence, disease‐free survival, and overall survival.ResultsPatients with MCCUP presented with tumors in lymph nodes (n = 34) or parotid gland (n = 3). Nodal disease was most commonly detected in the inguinal/external iliac (n = 15) or axillary (n = 14) regions. The mean age at diagnosis was 70 years and 24% were female. Patients presented with distant metastases in 24.3% of cases. Patients with stage IIIA disease treated with regional lymph node dissection (RLND) had a lower risk of disease recurrence (hazard ratio 0.26, p = 0.046). Recurrence‐free survival was 59.3% at 5 years. Disease‐specific survival was 63.3% at 5 years.ConclusionPatients with MCCUP have a high risk of recurrence and mortality. The optimal treatment for MCCUP has yet to be elucidated, although therapeutic RLND appears beneficial for these patients.

ABSTRACT The purpose of this case series is to review the endoscopic detection of anal intraepithelial neoplasia and anal squamous cell carcinoma including the role of rectal retroflexion and narrow-band imaging. Four cases of anal intraepithelial neoplasia were incidentally discovered in women aged 55–71 years. Anal lesions identified included sessile polyps, nodular mucosa, and circumferential polyps. A fifth patient, who presented with abdominal pain, was found to have a 3 cm anal squamous cell carcinoma on diagnostic colonoscopy, despite a negative colonoscopy 21 months earlier. In the absence of contraindications, retroflexion should be performed on all patients. Suspicious anal mucosa warrants biopsy.

AbstractBackgroundReproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear.MethodsAnalyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2–like, HER2-enriched–like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided.ResultsCompared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2–like, and HER2-enriched–like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity &lt; .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity &lt; .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like.ConclusionsThis large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.