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Guo-Ming Zhang,1,2,* Jing Liu,1,2,* Xu-Xiao Guo,3 Fu-Meng Yang4 1Department of Laboratory Medicine, Shuyang Hospital, Shuyang, People’s Republic of China; 2Department of Laboratory Medicine, the Affiliated Shuyang Hospital of Xuzhou Medical University, Shuyang, People’s Republic of China; 3Department of Laboratory Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of China; 4Department of Laboratory Medicine, the Second People’s Hospital of Lianyungang, Lianyungang, People’s Republic of China*The authors contributed equally to this workCorrespondence: Guo-Ming Zhang, Department of Laboratory Medicine, Shuyang Hospital, No. 9, Yingbin Road, Shuyang, People’s Republic of China, Email gm@xzhmu.edu.cn; zly52120@163.comBackground: LDLC equations have varying levels of underestimation for the calculated LDLC. Therefore, underestimating LDLC should be avoided as much as possible. We need to establish LDLC equations that underestimate LDLC as little as possible.Methods: We established the equations with a healthy cohort from Shuyang Hospital and validated the equations with an unselected patient cohort from The Second People’s Hospital of Lianyungang. We established the novel LDLC equations by using the regression equation. The relationship between two markers was analysed using Pearson’s approach. The 95% limits of measuring agreement within ± 2 SD for the LDLC equations was performed using Bland‒Altman analysis. ROC curve analysis was used to predict LDLC levels and the accuracy of the LDLC equation for determining the direct LDLC levels at LDLC cut-offs was assessed.Results: We obtained two novel LDLC equations (LDL_nonHDLC equation=− 0.899+1.195*nonHDLC-0.00347*nonHDLC2 and LDL_TC(total cholesterol) equation=− 2.775+1.29*TC − 0.00990* TC 2). The correlation coefficient between the novel LDLC equation and the direct LDLC measurements is not lower than that between the LDL_NIH equation and the direct LDLC measurements. The AUCs of our novel LDLC equations were greater than those of the LDL_NIH equation and the LDL_F equation at the LDLC cut-offs for clinical decision-making. The measuring agreement in the methods of the LDL_nonHDL equation is superior to that of the LDL_NIH equation.Conclusion: LDLC calculated by the novel LDL_nonHDL equation exhibited superiority over the LDL_NIH equation. Combining the LDL_NIH equation and our novel LDLC equation may improve accuracy and avoid undertreatment of high LDLC levels.Keywords: low-density lipoprotein cholesterol, NIH LDL-C equation, friedewald equation, novel LDLC equation

BackgroundProviders are often unaware of poor adherence to prescribed medications for their patients with chronic diseases.ObjectiveTo develop brief, computer-administered patient-reported measures in English and Spanish assessing adherence behaviors and barriers. Design, Participants, and Main Measures: Item pools were constructed from existing measures of medication adherence behaviors and barriers, which informed development of a patient concept elicitation interview guide to identify medication adherence behavior and barrier-related concepts. Two hundred six patients either living with HIV (PLWH) or without were interviewed. Interviews were coded, concepts matched to item pool content, and new items were developed for novel concepts. A provider/investigator team highlighted clinically relevant items. Cognitive interviews were conducted with patients on final candidate items (n = 37). The instruments were administered to 2081 PLWH.Key resultsBehavioral themes from concept elicitation interviews included routines incorporating time of day, placement, visual cues, and intentionality to miss or skip doses. Barrier themes included health-related (e.g. depressed mood, feeling ill), attitudes/beliefs (e.g., need for medication), access (e.g., cost/insurance problems), and circumstantial barriers (e.g., lack of privacy, disruption of daily routine). The final instruments included 6 behavior items, and 1 barrier item with up to 23 response options. PLWH endorsed a mean (SD) of 3.5 (1.1) behaviors. The 201 PLWH who missed ≥2 doses in the previous week endorsed a mean (SD) of 3.1 (2.5) barriers. The intraclass correlation coefficient (ICC) for the numbers of behaviors endorsed in 61 PLWH after 4-16 days was 0.54 and for the number of barriers for the 20 PLWH with ≥2 missed doses the ICC was 0.89, representing fair and excellent test-retest reliability.ConclusionMeasures of medication adherence behaviors and barriers were developed for use with patients living with chronic diseases focusing on clinical relevance, brevity, and content validity for use in clinical care.

IntroductionRates of sexually transmitted infection (STI) are rising in the USA, yet STI risk remains under-addressed by providers, even in HIV care, and with high-risk patients. We interviewed primary care patients living with and without HIV regarding circumstances surrounding sexual risk behavior to identify opportunities for providers to address and reduce STI risk.MethodsWe conducted semi-structured 1:1 interviews with patients living with and without HIV reporting ≥ 1 sex partner and varying STI exposure risk in the past 12 months from four geographically diverse US HIV and primary care clinics. We audio-recorded, transcribed, and coded interviews by circumstance type, using double-coding to ensure inter-coder reliability. We used Fisher's exact and T tests to determine associations with demographic/risk factors.ResultsPatients (n = 91) identified a mean of 3 of 11 circumstances. These included substance use (54%), desire for physical/emotional intimacy (48%), lack of HIV/STI status disclosure (44%), psychological drivers (i.e., coping, depression; 38%), personal dislike of condoms (22%), partner condom dislike/refusal (19%), receiving payment for sex (13%), and condom unavailability (9%). Higher proportions of those who were high STI-exposure risk patients, defined as those with ≥ 2 sex partners in the past 3 months reporting never or sometimes using condoms, reported disliking condoms (p = .006); higher proportions of the high-risk and moderate-risk (≥ 2 partners and condom use "most of the time") groups reported substance use as a circumstance (p = .04).ConclusionCircumstances surrounding perceived STI exposure risk were diverse, often overlapping, and dependent on internal, environmental, and partner-related factors and inadequate communication. Meaningful care-based interventions regarding HIV/STI transmission behavior must address the diversity and interplay of these factors.

BackgroundLow health literacy is associated with poor medication adherence and poor health outcomes. Limited understanding of prescribed medications may decrease validity of patient-reported adherence measures.ObjectivesTo assess knowledge of names and purposes of prescribed medications among patients with multiple chronic conditions.MethodsIndividual interviews were conducted with a convenience sample of patients from six U.S. primary care clinics. Participants (n = 57) were English and/or Spanish-speaking patients prescribed 3+ medications for chronic conditions, for which non-adherence may lead to disability or death. In individual interviews, patients were asked to name their medications, explain the purpose of each, and to explain how they distinguish them from one another. Interviews were audio recorded, transcribed, and coded; coded content was quantified by 1) whether or not the patient could name medications; 2) method of categorizing medications; 3) whether or not the purpose of the medication was understood. Descriptive statistics were compiled using Fisher's exact test to determine the relationship between patient knowledge and medication characteristics.ResultsThirty percent of patients could not name at least one of their medications; 19% did not know their purpose; 30% held misconceptions about the purpose of one or more medications. There was no significant difference in ability to name medications or state their medication's purpose between patients using medi-sets, pre-packaged rolls, or blister packs, and patients who stored pills in their original containers (p = 0.56 and p = 0.73, respectively), or across demographic groups (p = 0.085 to 0.767).ConclusionsMany patients demonstrated difficulty identifying the name and purpose of prescribed medications; this did not differ by demographic group or medication storage type. Patients may benefit from routine review of medications with their provider in order to improve health literacy, outcomes, and patient-reported adherence measurement.

PurposeTo evaluate psychometric characteristics and cross-sectional and longitudinal validity of the 7-item PROMIS® Fatigue Short Form and additional fatigue items among people living with HIV (PLWH) in a nationally distributed network of clinics collecting patient reported data at the time of routine clinical care.MethodsCross-sectional and longitudinal fatigue data were collected from September 2012 through April 2013 across clinics participating in the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS). We analyzed data regarding psychometric characteristics including simulated computerized adaptive testing and differential item functioning, and regarding associations with clinical characteristics.ResultsWe analyzed data from 1597 PLWH. Fatigue was common in this cohort. Scores from the PROMIS® Fatigue Short Form and from the item bank had acceptable psychometric characteristics and strong evidence for validity, but neither performed better than shorter instruments already integrated in CNICS.ConclusionsThe PROMIS® Fatigue Item Bank is a valid approach to measuring fatigue in clinical care settings among PLWH, but in our analyses did not perform better than instruments associated with less respondent burden.

Cancer represents a profound challenge to healthcare systems and individuals worldwide. The development of multiple drug resistance is a major problem in cancer therapy and can result in progression of the disease. In our previous studies, we developed small-molecule inhibitors targeting ubiquitin-specific peptidase 24 (USP24) to combat drug-resistant lung cancer. Recently, we found that the USP24 inhibitor NCI677397 induced ferroptosis, a type of programmed cell death, in drug-resistant cancer cells by increasing lipid reactive oxygen species (ROS) levels. In the present study, we investigated the molecular mechanisms and found that the targeting of USP24 by NCI677397 increased gene expression of most lipogenesis-related genes, such as acyl-CoA synthetase long-chain family member 4 (ACSL4), and activated autophagy. In addition, the activity of several antioxidant enzymes, such as glutathione peroxidase 4 (GPX4) and dihydrofolate reductase (DHFR), was inhibited by NCI677397 treatment via an increase in protein degradation, thereby inducing lipid ROS production and lipid peroxidation. In summary, we demonstrated that NCI677397 induced a marked increase in lipid ROS levels, subsequently causing lipid peroxidation and leading to the ferroptotic death of drug-resistant cancer cells. Our study provides new insights into the clinical use of USP24 inhibitors as ferroptosis inducers (FINs) to block drug resistance during chemotherapy., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Current biodiversity loss is generally considered to have been caused by anthropogenic disturbance, but it is unclear when anthropogenic activities began to affect biodiversity loss. One hypothesis suggests it began with the Industrial Revolution, whereas others propose that anthropogenic disturbance has been associated with biodiversity decline since the early Holocene. To test these hypotheses, we examined the unique vegetation of evergreen broadleaved forests (EBLFs) in East Asia, where humans have affected landscapes since the early Holocene. We adopted a genomic approach to infer the demographic history of a dominant tree (Litsea elongata) of EBLFs. We used Holocene temperature and anthropogenic disturbance factors to calculate the correlation between these variables and the historical effective population size of L. elongata with Spearman statistics and integrated the maximum-entropy niche model to determine the impact of climate change and anthropogenic disturbance on fluctuation in its effective population size. We identified 9 well-defined geographic clades for the populations of L. elongata. Based on the estimated historical population sizes of these clades, all the populations contracted, indicating persistent population decline over the last 11,000 years. Demographic history of L. elongata and human population change, change in cropland use, and change in irrigated rice area were significantly negatively correlated, whereas climate change in the Holocene was not correlated with demographic history. Our results support the early human impact hypothesis and provide comprehensive evidence that early anthropogenic disturbance may contribute to the current biodiversity crisis in East Asia., (© 2023 Society for Conservation Biology.)

Objective: The etiology, clinical presentation, diagnosis, and treatment strategies of chronic pancreatitis (CP) vary significantly between countries. Specifically, the etiology and surgical approaches to treating CP differ between China and Western countries. Therefore, this study aims to compare the disparities in CP profiles and management based on our single-center experience and recent data from the West., Methods: From January 2007 to December 2017, a total of 130 consecutive patients with histologically confirmed chronic pancreatitis (CP) underwent surgical treatment at the First Affiliated Hospital of Nanjing Medical University. The clinical features, etiology, risk factors, and operative procedures of these CP patients were analyzed and compared with recent data from Western countries., Results: Our patient cohort was predominantly male (3.19:1), with a median age of 50.2 ± 9.8 years. Upper abdominal pain was the most common symptom, present in 102 patients (78.5%). The most common etiology was obstructive factors (47.7%), followed by alcohol (34.6%). The incidence of genic mutation was 2%, significantly lower than rates reported in Western research. Steatorrhea, weight loss, and jaundice were present in 6.9%, 18.5%, and 17.7% of patients, respectively. Pancreatic cysts or pseudocysts were diagnosed in 7 patients (5.4%). The following procedures were performed: Partington procedure in 33 patients (25.4%), Frey procedure in 17 patients (13.2%), Berne procedure in 5 patients (3.9%), Beger procedure in 1 patient (0.8%), pancreaticoduodenectomy in 17 patients (13.1%), pylorus-preserving pancreaticoduodenectomy in 18 patients (13.9%), middle pancreatectomy in 1 patient (0.8%), and distal pancreatectomy in 9 patients (6.9%). Choledochojejunostomy was performed in 14 patients (10.8%), gastroenterostomy in 2 (1.5%), and 15 patients (11.5%) underwent aspiration biopsy., Conclusion: Our study confirms that, etiologically, obstructive chronic pancreatitis (CP) is more frequent in the Chinese population than in Western populations. Although diagnostic instruments and operative procedures in China and Western countries are roughly comparable, slight differences exist in relation to diagnostic flowcharts/criteria and the indications and optimal timing of surgery.

The effective treatment of breast cancer remains a profound clinical challenge, especially due to drug resistance and metastasis which unfortunately arise in many patients. The transcription inhibitor 5,6-dichloro-1-beta-D-ribofuranosyl-benzimidazole (DRB), as a selective inhibitor of cyclin-dependent kinase 9, was shown to be effective in inducing apoptosis in various hematopoietic malignancies. However, the anticancer efficacy of DRB against breast cancer is still unclear. Herein, we demonstrated that administration of DRB to the breast cancer cell line led to the inhibition of cellular proliferation and induction of the typical signs of apoptotic cells, including the increases in Annexin V-positive cells, DNA fragmentation, and activation of caspase-7, caspase-9, and poly (ADP ribose) polymerase (PARP). Treatment of DRB resulted in a rapid decline in the myeloid cell leukemia 1 (Mcl-1) protein, whereas levels of other antiapoptotic proteins did not change. Overexpression of Mcl-1 decreased the DRB-induced PARP cleavage, whereas knockdown of Mcl-1 enhanced the effects of DRB on PARP activation, indicating that loss of Mcl-1 accounts for the DRB-mediated apoptosis in MCF-7 cells, but not in T-47D. Furthermore, we found that co-treatment of MCF-7 cells with an inhibitor of AKT (LY294002) or an inhibitor of the proteasome (MG-132) significantly augmented the DRB-induced apoptosis. These data suggested that DRB in combination with LY294002 or MG-132 may have a greater therapeutic potency against breast cancer cells., (© 2023. Springer Nature Limited.)

Rheumatoid arthritis (RA) is an autoimmune disease that generally affects the joints. In the face of inflammation-induced cartilage and bone damage, RA treatment remains insufficient. While research evidence indicates that acupuncture can exert anti-inflammatory and analgesic effects, improve the joint function of RA patients, and delay the disease, data on whether it can promote RA repair are lacking. Findings from the present work demonstrated that both the antigen-induced arthritis (AIA) and collagen-induced arthritis (CIA) models can simulate joint swelling of RA. The AIA model was more stable than the CIA model, with a higher incidence of successful arthritis modeling. Moreover, the AIA mice model could simulate the signal molecules and related pathological processes of the autoimmune response in RA, as well as major pathways related to RA and antigen immune response mechanisms. Manual acupuncture (MA) at Zusanli (ST36) significantly improved paw redness and swelling, pain, and inflammatory cell infiltration in the joints in AIA mice. The therapeutic effect of MA on AIA is achieved primarily through the regulation of steroid hormone biosynthesis, cell metabolism, and tissue repair processes. MA at ST36 can increase the gene contents of tissue repair growth factors, including PEG3 , GADD45A , GDF5 , FGF5 , SOX2 , and ATP6V1C2 in the inflammatory side joints of AIA mice, as well as the gene expression of the anti-inflammatory cytokine IL-10 . In conclusion, acupuncture may alleviate RA in the joints via modulating the tissue healing process., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Wang, Gong, Yang, Wang, Liu, Gui, Xie, Xu and Guo.)

House dust mites (HDMs) are a common source of respiratory allergens responsible for allergic asthma and innate immune responses in human diseases. Since HDMs are critical factors in the triggering of allergen-induced airway mucosa from allergic asthma, we aimed to investigate the mechanisms of Toll-like receptors (TLR) in the signaling of the HDM extract that is involved in mucus hypersecretion and airway inflammation through the engagement of innate immunity. Previously, we reported that the somatic nuclear autoantigenic sperm protein (sNASP)/tumor necrosis factor receptor-associated factor 6 (TRAF6) axis controls the initiation of TLRs to maintain the homeostasis of the innate immune response. The present study showed that the HDM extract stimulated the biogenesis of Mucin 5AC (MUC5AC) in bronchial epithelial cells via the TLR2/4 signaling pathway involving MyD88 and TRAF6. Specifically, sNASP binds to TRAF6 in unstimulated bronchial epithelial cells to prevent the activation of TRAF6-depenedent kinases. Upon on HDMs' stimulation, sNASP is phosphorylated, leading to the activation of TRAF6 downstream of the p38 MAPK and NF-κB signaling pathways. Further, NASP-knockdown enhanced TRAF6 signaling and MUC5AC biogenesis. In the HDM-induced mouse asthma model, we found that the HDM extract promoted airway hyperresponsiveness (AHR), MUC5AC, and allergen-specific IgE production as well as IL-5 and IL-13 for recruiting inflammatory cells. Treatment with the PEP-NASP peptide, a selective TRAF6-blocking peptide, ameliorated HDM-induced asthma in mice. In conclusion, this study indicated that the sNASP/TRAF6 axis plays a regulatory role in asthma by modulating mucus overproduction, and the PEP-NASP peptide might be a potential target for asthma treatment.

The neuroactive alkaloids in betel quid (BQ) can induce BQ addiction. We conducted a case-control study to investigate the effects of BQ-associated DSM-5 symptoms, pathological behaviors, and BQ use disorder (BUD) on oral squamous cell carcinoma (OSCC) risk. A total of 233 patients with newly diagnosed and histopathologically confirmed OSCC and 301 sex- and age-matched controls were included. BQ-related DSM-5 symptoms in the 12 months prior to disease onset were used to measure psychiatric characteristics and BUD. Compared with nonchewers, chewers with the symptoms of unsuccessful cutdown of BQ consumption, neglecting major roles, social or interpersonal problems, abandoning or limiting activities, hazardous use, and continued use despite the awareness of the dangers had a 54.8-, 49.3-, 49.9-, 40.4-, 86.2-, and 42.9-fold higher risk of developing OSCC, respectively. Mild-to-moderate and severe BUD were, respectively, associated with a 8.2-8.5- and 42.3-fold higher OSCC risk, compared with BQ nonuse. Risky BQ use of pathological behavior was associated with a 12.5-fold higher OSCC risk in chewers with no BUD or mild BUD and a 65.0-fold higher risk in chewers with moderate-to-severe BUD ( p for risk heterogeneity between the two BUD groups, 0.041). In conclusion, BQ-associated DSM-5 symptoms, pathological behaviors, and BUD severity are associated with the impact of BQ chewing on OSCC development. The pathological behavior of risky BQ use enhances OSCC risk in chewers with moderate-to-severe BUD. Preventing BUD in new BQ users and treating BUD in chewers who already have the disorder are two priorities in areas where BQ chewing is prevalent.

Innate anti-inflammatory mechanisms are essential for immune homeostasis and can present opportunities to intervene inflammatory diseases. In this report, we found that YAP isoform 9 (YAP9) is an essential negative regulator of the potent inflammatory stimuli such as TNFα, IL-1β, and LPS. YAP9 constitutively interacts with another anti-inflammatory regulator A20 (TNFAIP3) to suppress inflammatory responses, but A20 and YAP can function only in the presence of the other. YAP9 uses a short stretch of amino acids in the proline-rich domain (PRD) and transactivation domain (TAD) suppress the inflammatory signaling while A20 mainly uses the zinc finger domain 7 (ZF7). Cell-penetrating synthetic PRD, TAD, and ZF7 peptides act as YAP9 and A20 mimetics respectively to suppress the proinflammatory responses at the cellular level and in mice. Our data uncover a novel anti-inflammatory axis and anti-inflammatory agents that can be developed to treat acute or chronic conditions where TNFα, IL-1β, or LPS plays a key role in initiating and/or perpetuating inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Shen, Fan, Bai, Li and Lee.)

Activated effector T cells (Teff) and/or compromised regulatory T cells (Treg) underlie many chronic inflammatory diseases. We discovered a novel pathway to regulate survival and expansion of Teff without compromising Treg survival and a potential therapeutic to treat these diseases. We found dimethylguanidino valeric acid (DMGV) as a rheostat for Teff survival: while cell-intrinsic DMGV generated by Alanine-Glyoxylate Aminotransferase 2 (AGXT2) is essential for survival and expansion by inducing mitochondrial ROS and regulation of glycolysis, an excessive (or exogenous) DMGV level inhibits activated Teff survival, thereby the AGXT2-DMGV-ROS axis functioning as a switch to turn on and off Teff expansion. DMGV-induced ROS is essential for glycolysis in Teff, and paradoxically DMGV induces ROS only when glycolysis is active. Mechanistically, DMGV rapidly activates mitochondrial calcium uniporter (MCU), causing a surge in mitochondrial Ca 2+ without provoking calcium influx to the cytosol. The mitochondrial Ca 2+ surge in turn triggers the mitochondrial Na + /Ca 2+ exchanger (NCLX) and the subsequent mitochondrial Na + import induces ROS by uncoupling the Coenzyme Q cycle in Complex III of the electron transport chain. In preclinical studies, DMGV administration significantly diminished the number of inflammatory T cells, effectively suppressing chronic inflammation in mouse models of colitis and rheumatoid arthritis. DMGV also suppressed expansion of cancer cells in vitro and in a mouse T cell leukemic model by the same mechanism. Our data provide a new pathway regulating T cell survival and a novel mode to treat autoimmune diseases and cancers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Shen, Fan, Chen and Lee.)

Background: Georgia has one of the highest maternal mortality rates within the US. This study describes the qualitative needs assessment undertaken to understand the needs of rural and underserved women and their perspectives on implementing a self monitoring application during pregnancy and postpartum., Methods: Qualitative methodology was used to conduct the needs assessment of 12 health care providers (nurses, nurse-midwives, patient care coordinators, and physicians) and 25 women from rural and underserved populations in Georgia was conducted to ascertain common themes on three topics: pregnancy care experiences, comfort with technology, and initial perspectives on the proposed VidaRPM application. Transcription, coding, and consensus were conducted using content analysis and a Cohen's Kappa coefficient was calculated to identify level of overall agreement between raters for the representative quotes identified for each theme., Results: The overall agreement for the representative quotes that were chosen for each theme was in strong agreement (κ = 0.832). The major provider feedback included the following regarding the VidaRPM app: inclusion of questions to monitor physical well-being, embedded valid and reliable educational resources, and multiple modalities. The overall feedback from the mothers regarding the VidaRPM application was the virtual aspect helped overcome the barriers to accessing care, comfort with both WiFi and technology, and sustainable utility., Discussion: The needs of rural and underserved pregnant women and their providers were assessed to develop and refine the VidaRPM app. This qualitative study on the VidaRPM app is the first step towards closing the gap between providers and patients during prenatal and postpartum periods by empowering and educating women into the first-year postpartum living in rural and underserved areas., Competing Interests: The authors have declared that no competing interests exist.

There is a great need for a diagnostic tool using simple clinical information collected from patients to diagnose uric acid (UA) stones in nephrolithiasis. We built a predictive model making use of machine learning (ML) methodologies entering simple parameters easily obtained at the initial clinical visit. Socio-demographic, health, and clinical data from two cohorts (A and B), both diagnosed with nephrolithiasis, one between 2012 and 2016 and the other between June and December 2020, were collected before nephrolithiasis treatment. A ML-based model for predicting UA stones in nephrolithiasis was developed using eight simple parameters-sex, age, gout, diabetes mellitus, body mass index, estimated glomerular filtration rate, bacteriuria, and urine pH. Data from Cohort A were used for model training and validation (ratio 3:2), while data from Cohort B were used only for validation. One hundred and forty-six (13.3%) out of 1098 patients in Cohort A and 3 (4.23%) out of 71 patients in Cohort B had pure UA stones. For Cohort A, our model achieved a validation AUC (area under ROC curve) of 0.842, with 0.8475 sensitivity and 0.748 specificity. For Cohort B, our model achieved 0.936 AUC, with 1.0 sensitivity, and 0.912 specificity. This ML-based model provides a convenient and reliable method for diagnosing urolithiasis. Using only eight readily available clinical parameters, including information about metabolic disorder and obesity, it distinguished pure uric acid stones from other stones before treatment.

Acute lung injury (ALI) is a severe inflammatory lung disease associated with macrophages. Somatic nuclear autoantigenic sperm protein (sNASP) is a negative regulator of Toll-like receptor (TLR) signaling that targets tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) in macrophages, which is required to maintain homeostasis of the innate immune response. In the present study, we generated a cell permeable PEP-sNASP peptide using the sNASP protein N-terminal domain, and examined its potential therapeutic effect in a mouse model of ALI induced by the intranasal administration of lipopolysaccharide (LPS) and elucidated the underlying molecular mechanisms in RAW 264.7 cells. In vivo , PEP-sNASP peptide treatment markedly ameliorated pathological injury, reduced the wet/dry (W/D) weight ratio of the lungs and the production of proinflammatory cytokines (interleukin (IL)-1β, IL-6, and TNF-α). In vitro , we demonstrated that when the PEP-sNASP peptide was transduced into RAW 264.7 cells, it bound to TRAF6, which markedly decreased LPS-induced proinflammatory cytokines by inhibiting TRAF6 autoubiquitination, nuclear factor (NF)-κB activation, reactive oxygen species (ROS) and cellular nitric oxide (NO) levels. Furthermore, the PEP-sNASP peptide also inhibited NLR family pyrin domain containing 3 (NLRP3) inflammasome activation. Our results therefore suggest that the PEP-sNASP may provide a potential protein therapy against oxidative stress and pulmonary inflammation via selective TRAF6 signaling., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Hsu, Hu, Lan, Yeh and Yang.)

Recognition of invading pathogens by Toll-like receptors (TLRs) activates innate immunity through signaling pathways that involved multiple protein kinases and phosphatases. We previously demonstrated that somatic nuclear autoantigenic sperm protein (sNASP) binds to TNF receptor-associated factor 6 (TRAF6) in the resting state. Upon TLR4 activation, a signaling complex consisting of TRAF6, sNASP, interleukin (IL)-1 receptor-associated kinase 4, and casein kinase 2 (CK2) is formed. CK2 then phosphorylates sNASP to release phospho-sNASP (p-sNASP) from TRAF6, initiating downstream signaling pathways. Here, we showed that protein phosphatase 4 (PP4) is the specific sNASP phosphatase that negatively regulates TLR4-induced TRAF6 activation and its downstream signaling pathway. Mechanistically, PP4 is directly recruited by phosphorylated sNASP to dephosphorylate p-sNASP to terminate TRAF6 activation. Ectopic expression of PP4 specifically inhibited sNASP-dependent proinflammatory cytokine production and downstream signaling following bacterial lipopolysaccharide (LPS) treatment, whereas silencing PP4 had the opposite effect. Primary macrophages and mice infected with recombinant adenovirus carrying a gene encoding PP4 (Ad-PP4) showed significant reduction in IL-6 and TNF-α production. Survival of Ad-PP4-infected mice was markedly increased due to a better ability to clear bacteria in a sepsis model. These results indicate that the serine/threonine phosphatase PP4 functions as a negative regulator of innate immunity by regulating the binding of sNASP to TRAF6., Competing Interests: The authors declare no competing interest.

Rheumatoid arthritis (RA) is characterized by joint leukocyte infiltration, synovial inflammation and bone damage result from osteoclastogenesis. Bruton's tyrosine kinase (BTK) is a key regulator of B cell receptor (BCR) and Fc gamma receptor (FcγR) signaling involved in the pathobiology of RA and other autoimmune disorders. SOMCL-17-016 is a potent and selective tricyclic BTK inhibitor, structurally distinct from other known BTK inhibitors. In present study we investigated the therapeutic efficacy of SOMCL-17-016 in a mouse collagen-induced arthritis (CIA) model and underlying mechanisms. CIA mice were administered SOMCL-17-016 (6.25, 12.5, 25 mg·kg -1 ·d -1 , ig), or ibrutinib (25 mg·kg -1 ·d -1 , ig) or acalabrutinib (25 mg·kg -1 ·d -1 , ig) for 15 days. We showed that oral administration of SOMCL-17-016 dose-dependently ameliorated arthritis severity and bone damage in CIA mice; it displayed a higher in vivo efficacy than ibrutinib and acalabrutinib at the corresponding dosage. We found that SOMCL-17-016 administration dose-dependently inhibited anti-IgM-induced proliferation and activation of B cells from CIA mice, and significantly decreased anti-IgM/anti-CD40-stimulated RANKL expression in memory B cells from RA patients. In RANKL/M-CSF-stimulated RAW264.7 cells, SOMCL-17-016 prevented osteoclast differentiation and abolished RANK-BTK-PLCγ2-NFATc1 signaling. In summary, this study demonstrates that SOMCL-17-016 presents distinguished therapeutic effects in the CIA model. SOMCL-17-016 exerts a dual inhibition of B cell function and osteoclastogenesis, suggesting that it to be a promising drug candidate for RA treatment., (© 2020. The Author(s), under exclusive licence to CPS and SIMM.)

Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface characterized by manifestations of dryness and irritation. Although the pathogenesis is not fully illuminated, it is recognized that inflammation has a prominent role in the development and deterioration of DED. β-aminoarteether maleate (SM934) is a water-soluble artemisinin derivative with anti-inflammatory and immunosuppressive activities. In this study, we established scopolamine hydrobromide (SCOP)-induced rodent model as well as benzalkonium chloride (BAC)-induced rat model to investigate the therapeutic potential of SM934 for DED. We showed that topical application of SM934 (0.1%, 0.5%) significantly increased tear secretion, maintained the number of conjunctival goblet cells, reduced corneal damage, and decreased the levels of inflammatory mediators (TNF-α, IL-6, IL-10, or IL-1β) in conjunctiva in SCOP-induced and BAC-induced DED models. Moreover, SM934 treatment reduced the accumulation of TLR4-expressing macrophages in conjunctiva, and suppressed the expression of inflammasome components, i.e., myeloid differentiation factor88 (MyD88), Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and cleaved caspase 1. In LPS-treated RAW 264.7 cells, we demonstrated that pretreatment with SM934 (10 μM) impeded the upregulation of TLR4 and downstream NF-κB/NLRP3 signaling proteins. Collectively, artemisinin analog SM934 exerts therapeutic benefits on DED by simultaneously reserving the structural integrity of ocular surface and preventing the corneal and conjunctival inflammation, suggested a further application of SM934 in ophthalmic therapy, especially for DED.

During the last decade, immune checkpoint inhibition (ICI) has become a pillar of cancer therapy. Antibodies targeting CTLA-4 or PD-1/PD-L1 have been approved in several malignancies, with thousands of clinical trials currently underway. While the majority of cancer immunotherapies have traditionally focused on enhancing cytotoxic responses by CD8 + or NK cells, there are clear evidences that CD4 + T cell responses can modulate the immune response against tumors and influence the efficacy of ICI therapy. CD4 + T cells can differentiate into several subsets of helper T cells (Th) or regulatory T cells (Treg), with a wide range of effector and/or regulatory functions. Importantly, different Th subsets may have different and sometimes contrasting roles in the clinical response to ICI therapy, which in addition may vary depending on the organ and tumor niche. In this review, we discuss recent evidence that highlights how ICI therapy impacts Th1, Th9, and Th17 cells and vice versa . These data might be important designing better interventions that unleash the full potential of immune response against cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lee, Lozano-Ruiz, Yang, Fan, Shen and González-Navajas.)

Although cancers arise from genetic mutations enabling cells to proliferate uncontrollably, they cannot thrive without failure of the anticancer immunity due in a large part to the tumor environment's influence on effector and regulatory T cells. The field of immune checkpoint inhibitor (ICI) therapy for cancer was born out of the fact that tumor environments paralyze the immune cells that are supposed to clear them by activating the immune checkpoint molecules such as PD-1. While various subsets of effector T cells work collaboratively to eliminate cancers, Tregs enriched in the tumor environment can suppress not only the native anticancer immunity but also diminish the efficacy of ICI therapies. Because of their essential role in suppressing autoimmunity, various attempts to specifically deplete tumor-associated Tregs are currently underway to boost the efficacy of ICI therapies without causing systemic autoimmune responses. A better understanding the roles of Tregs in the anti-cancer immunity and ICI therapies should provide more specific targets to deplete intratumoral Tregs. Here, we review the current understanding on how Tregs inhibit the anti-cancer immunity and ICI therapies as well as the advances in the targeted depletion of intratumoral Tregs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 González-Navajas, Fan, Yang, Yang, Lozano-Ruiz, Shen and Lee.)

Betel-quid (BQ) is a commonly used psychoactive substance that renders a specific cardiotoxicity. The purpose of this study was to investigate the association between BQ chewing and premature ventricular contractions (PVC) in patients with cardiopulmonary symptoms, and examine the potential influences of cardiovascular and chronic diseases on such relationship. Participants were 146 patients with cardiopulmonary symptoms who participated in 24-h Holter electrocardiogram monitoring during 2012-2018 in a hospital serving residents that lived in a BQ high prevalence area. Data on substance uses and medical histories for cardiovascular and chronic diseases were collected. Baron-Kenny method was employed to evaluate possible mediation. In patients with cardiopulmonary symptoms, 36.3% were BQ users and 63.7% were nonusers. Adjusting for covariates, BQ chewing was significantly associated with heart failure and diabetes mellitus (adjusted odds ratio (aOR) = 3.4 and 2.3, respectively), but only heart failure was significantly correlated with a low and high level of PVC. Additionally controlling for the effect of heart failure, the risk of high PVC for BQ users reduced from 3.60 to 2.88; however, the risk for BQ chewers remained significant (95% CI: 1.06-7.84). Heart failure was found to explain 27.7% of the excessive effect of BQ use on high PVC. In conclusion, BQ use is directly associated with an elevated risk of high PVC in patients with cardiopulmonary symptoms. The higher risk might be elevated among patients who suffered heart failure. Given several research limitations, the findings from this study offer future opportunities for validation.

BACKGROUND Studies have found that many published life sciences research results are irreproducible. Our goal was to provide comprehensive risk estimates of familiar reproducibility deficiencies to support quality improvement in research. MATERIAL AND METHODS Reports included were peer-reviewed, published between 1980 and 2016, and presented frequency data of basic biomedical research deficiencies. Manual and electronic literature searches were performed in seven bibliographic databases. For deficiency concepts with at least four frequency studies and with a sample size of at least 15 units in each, a meta-analysis was performed. RESULTS Overall, 68 publications met our inclusion criteria. The study identified several major groups of research quality defects: study design, cell lines, statistical analysis, and reporting. In the study design group of 3 deficiencies, missing power calculation was the most frequent (82.3% [95% Confidence Interval (CI): 69.9-94.6]). Among the 6 cell line deficiencies, mixed contamination was the most frequent (22.4% [95% CI: 10.4-34.3]). Among the 3 statistical analysis deficiencies, the use of chi-square test when expected cells frequency was <5 was the most prevalent (15.7% [95% CI: -3.2-34.7]). In the reporting group of 12 deficiencies, failure to state the number of tails was the most frequent (65% [95% CI: 39.3-90.8]). CONCLUSIONS The results of this study could serve as a general reference when consistently measurable sources of deficiencies need to be identified in research quality improvement.

Human visual acuity is anatomically determined by the retinal fovea. The ontogenetic development of the fovea can be seriously hindered by oculocutaneous albinism (OCA), which is characterized by a disorder of melanin synthesis. Although people of all ethnic backgrounds can be affected, no efficient treatments for OCA have been developed thus far, due partly to the lack of effective animal models. Rhesus macaques are genetically homologous to humans and, most importantly, exhibit structures of the macula and fovea that are similar to those of humans; thus, rhesus macaques present special advantages in the modeling and study of human macular and foveal diseases. In this study, we identified rhesus macaque models with clinical characteristics consistent with those of OCA patients according to observations of ocular behavior, fundus examination, and optical coherence tomography. Genomic sequencing revealed a biallelic p.L312I mutation in TYR and a homozygous p.S788L mutation in OCA2 , both of which were further confirmed to affect melanin biosynthesis via in vitro assays. These rhesus macaque models of OCA will be useful animal resources for studying foveal development and for preclinical trials of new therapies for OCA., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Kun-Chao Wu et al.)

Objective: To investigate the association between single nucleotide polymorphisms (SNP) of IL-17A (rs2275913) and IL-17F (rs763780) genes and susceptibility to knee osteoarthritis (KOA) in Chinese Han and Tibetan populations. Methods: A case-control study was conducted. Total of 122 Han KOA patients and 124 Han healthy controls and 76 Tibetan KOA patients and 68 Tibetan healthy controls in Qinghai Province were selected between 2015 and 2017. SNP typing was performed on four groups of rs2275913 and rs763780 polymorphisms by polymerease chain reaction (PCR)-sequencing to detect IL-17A and IL-17 F genotype frequencies and allele frequencies. The t test was used to compare data between groups. Results: The genotype AA frequency of IL-17A (rs2275913) was significantly different between the Han KOA and the control group ( OR= 2.625, P= 0.016). Compared with the frequency of allele A in healthy control group, the allele A frequency in Han KOA group was significantly higher( OR= 1.445, P= 0.047); the genotype frequency of IL-17A,however,was comparable between the KOA and the healthy control in Tibetan population ( OR= 1.696, 1.355, both P> 0.05); there were also not difference in the IL-17F (rs763780) genotype frequency and allele frequency between the Han KOA and Tibetan KOA groups and two control groups,respectively ( OR= 1.346, 1.126, both P> 0.05). Conclusion: It is highly likely that the pathogenesis of KOA in Chinese Han population is positively related to the genotype AA and allele A of IL-17A (rs2275913).

Objective: In this work, the relationship between octamer binding transcription factor 4 (OCT-4) expression and the clinicopathological features of cervical cancer (CC) is evaluated in detail. Methods: The library databases Pubmed, Embase, Cochrane library, Wan Fang and Chinese National Knowledge Infrastructure (CNKI) were searched for research related to these concepts published from the time the databases were established until May 2018. The obtained studies are screened, extracted, and evaluated according to the inclusion and exclusion criteria, and meta-analysis is carried out via RevMan 5.3. Results: Ten case-control studies, including 408 cases of CC, 164 cases of cervical intraepithelial neoplasia (CIN), and 148 cases of normal cervix, are included in the analysis. Results show that OCT-4 levels are statistically significantly different between the CC and normal cervical tissue groups (odds ratio (OR) = 15.59, 95% confidence interval (CI): 8.70, 27.94), the CC and CIN groups (OR = 5.64, 95% CI: 3.23, 9.86), the CIN and normal cervical tissues groups (OR = 7.13, 95% CI: 2.41, 21.05), and the CC well/moderately differentiated and poorly differentiated groups (OR = 0.44, 95% CI: 0.24, 0.81). OCT-4 is not statistically significantly different between CIN I + II and CIN III tissues (OR = 0.40, 95% CI: -0.02, 0.81), the CC lymphatic and non-lymphatic metastasis groups (OR = 1.93, 95% CI: 0.83, 4.47), the FIGO I and FIGO II groups (OR = 0.79, 95% CI: 0.29, 2.13), and the adenocarcinoma and squamous cell carcinoma groups (OR = 1.55, 95% CI: 0.70, 3.44). Conclusions: The available evidence suggests that OCT-4 expression is associated with CC malignancy and histological differentiation. This finding, however, is subject to quantitative studies and quality tests., (© 2019 The Author(s).)

Glaucoma is an optic neuropathy characterized by progressive degeneration of retinal ganglion cells (RGCs). Aberrations in several cytoskeletal proteins, such as tau have been implicated in the pathogenesis of neurodegenerative diseases, could be initiating factors in glaucoma progression and occurring prior to axon degeneration. Developmentally regulated brain protein (Drebrin or DBN1) is an evolutionarily conserved actin-binding protein playing a prominent role in neurons and is implicated in neurodegenerative diseases. However, the relationship between circulating DBN1 levels and RGC degeneration in glaucoma patients remains unclear. In our preliminary study, we detected drebrin protein in the plasma of glaucoma patients using proteomic analysis. Subsequently, we recruited a total of 232 patients including primary angle-closure glaucoma (PACG), primary open-angle glaucoma (POAG) and Posner-Schlossman syndrome (PS) and measured its DBN1 plasma levels. We observed elevated DBN1 plasma levels in patients with primary glaucoma but not in patients with PS compared to nonaxonopathic controls. Interestingly, in contrast to tau plasma levels increased in all groups of patients, elevated drebrin plasma levels correlated with retinal nerve fiber layer defect (RNFLD) in glaucoma patients. To further explore the expression of DBN1 in neurodegeneration, we conducted experiment of optic nerve crush (ONC) models, and observed increased expression of DBN1 in the serum as well as in the retina and then decreased after ONC. This result reinforces the potentiality of circulating DBN1 levels are increased in glaucoma patients with neurodegeneration. Taken together, our findings suggest that circulating DBN1 levels correlated with RNFLD and may reflect the severity of RGCs injury in glaucoma patients. Combining measurement of circulating drebrin and tau levels may be a useful indicator for monitoring progression of neurodegenerative diseases.

Non-small cell lung cancer (NSCLC) is one of the most common aggressive malignancies. miRNAs have been identified as important biomarkers and regulators of NSCLC. However, the functional contributions of miR-1260b to NSCLC cell proliferation and apoptosis have not been studied. In this study, miR-1260b was upregulated in NSCLC plasma, tissues, and cell lines, and its high expression was correlated with tumor size and progression. Functionally, miR-1260b overexpression promoted cell proliferation and cell cycle, conversely inhibited cell apoptosis and senescence. Mechanically, miR-1260b negatively regulated SOCS6 by directly binding to its 3'-UTR. Furthermore, miR-1260b-mediated suppression of SOCS6 activated KIT signaling. Moreover, YY1 was an upstream regulator of miR-1260b. This study is the first to illustrate that miR-1260b, mediated by YY1, activates KIT signaling by targeting SOCS6 to regulate NSCLC cell proliferation and apoptosis, and is a potential biomarker and therapeutic target for NSCLC. In sum, our work provides new insights into the molecular mechanisms of NSCLC involved in cell proliferation and apoptosis.

Aim: To establish a rotavirus (RV)-induced diarrhea model using RV SA11 in neonatal rhesus monkeys for the study of the pathogenic and immune mechanisms of RV infection and evaluation of candidate vaccines., Methods: Neonatal rhesus monkeys with an average age of 15-20 d and an average weight of 500 g ± 150 g received intragastric administration of varying doses of SA11 RV ( 10 7 PFUs/mL, 10 6 PFUs/mL, or 10 5 PFUs/mL, 10 mL/animal) to determine whether the SA11 strain can effectively infect these animals by observing their clinical symptoms, fecal shedding of virus antigen by ELISA, distribution of RV antigen in the organs by immunofluorescence, variations of viral RNA load in the organs by qRT-PCR, histopathological changes in the small intestine by HE staining, and apoptosis of small intestinal epithelial cells by TUNEL assay., Results: The RV monkey model showed typical clinical diarrhea symptoms in the 10 8 PFUs SA11 group, where we observed diarrhea 1-4 d post infection (dpi) and viral antigen shed in the feces from 1-7 dpi. RV was found in jejunal epithelial cells. We observed a viral load of approximately 5.85 × 10 3 copies per 100 mg in the jejunum at 2 dpi, which was increased to 1.09 × 10 5 copies per 100 mg at 3 dpi. A relatively high viral load was also seen in mesenteric lymph nodes at 2 dpi and 3 dpi. The following histopathological changes were observed in the small intestine following intragastric administration of SA11 RV: vacuolization, edema, and atrophy. Apoptosis in the jejunal villus epithelium was also detectable at 3 dpi., Conclusion: Our results indicate that we have successfully established a RV SA11 strain diarrhea model in neonatal rhesus monkeys. Future studies will elucidate the mechanisms underlying the pathogenesis of RV infection, and we will use the model to evaluate the protective effect of candidate vaccines., Competing Interests: Conflict-of-interest statement: The authors do not have a commercial or other association that might pose a conflict of interest.

Background: Patient-provider sexual risk behavior discussions occur infrequently but may be facilitated by high-quality sexual risk screening tools., Objective: To develop the Sexual Risk Behavior Inventory (SRBI), a brief computer-administered patient-reported measure., Design: Qualitative item development/quantitative instrument validation., Participants: We developed SRBI items based on patient interviews (n = 128) at four geographically diverse US primary care clinics. Patients were diverse in gender identity, sex, sexual orientation, age, race/ethnicity, and HIV status. We compared sexual risk behavior identified by the SRBI and the Risk Assessment Battery (RAB) among patients (n = 422)., Approach: We constructed an item pool based on validated measures of sexual risk, developed an in-depth interview guide based on pool content, and used interviews to elicit new sexual risk concepts. We coded concepts, matched them to item pool content, and developed new content where needed. A provider team evaluated item clinical relevance. We conducted cognitive interviews to assess item comprehensibility. We administered the SRBI and the RAB to patients., Key Results: Common, clinically relevant concepts in the SRBI included number of sex partners; partner HIV status; partner use of antiretroviral medication (ART)/pre-exposure prophylaxis (PrEP); and recent sex without barrier protection, direction of anal sex, and concern regarding HIV/STI exposure. While 90% reported inconsistent condom use on the RAB, same-day SRBI administration revealed that for over one third, all their partners were on ART/PrEP., Conclusion: The SRBI is a brief, skip-patterned, clinically relevant measure that ascertains sexual risk behavior across sex, sexual orientation, gender identity, partner HIV serostatus, and partner treatment status, furnishing providers with context to determine gradations of risk for HIV/STI.

Many Toll-like receptors (TLRs) signal through TNF receptor-associated factor 6 (TRAF6) to activate innate immune responses. Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways. In sNasp S158A knockin (S158A-KI) mice, LPS-treated macrophages could not phosphorylate sNASP, which remained bound to TRAF6. S158A-KI mice were more susceptible to sepsis due to a marked reduction in IL-1β, TNF-α, and IFN-γ production accompanied by an inability to clear bacteria and recruit leukocytes. Furthermore, phosphorylation-regulated release of sNASP from TRAF6 is observed following activation of TLR-1, -2, -4, -5, and -6. Thus, sNASP is a negative regulator of TLR signaling to modulate the innate immune response.

Numerous epidemiological studies have shown that male patients with uric acid nephrolithiasis outnumber female patients. To our knowledge, no research exists evaluating the reasons gender affects the development of uric acid nephrolithiasis. We hereby used a novel application of structural equation modeling to analyze the mediators of the effects of gender on uric acid nephrolithiasis. In 1,098 patients with nephrolithiasis between 2012 and 2016, male gender was found to have a statistically significant positive indirect effect on the development of uric acid nephrolithiasis, which was mediated by lower urine pH (estimate: 0.010, standard error: 0.005, critical ratio: 2.135, 95% confidence interval: 0.002-0.023, P = 0.017), lower estimated glomerular filtration rate (estimate: 0.014, standard error: 0.005, critical ratio: 2.993, 95% confidence interval: 0.006-0.025, P < 0.001), and higher incidence rate of gout (estimate: 0.009, standard error: 0.005, critical ratio: 2.028, 95% confidence interval: 0.002-0.021, P = 0.009). We conclude that low urine pH, impaired renal function, and gout are the mediators of the effect of male gender on the development of uric acid nephrolithiasis. The survey, treatment, and follow-up of kidney diseases, acidic urine, and uric acid metabolism disorders should be considered in men with uric acid nephrolithiasis.

G-quadruplex has attracted considerable attention due to their prevalent distribution in functional genomic regions and transcripts, which can importantly influence biological processes such as regulation of telomere maintenance, gene transcription and gene translation. Artificial receptor study has been developed for accurate identification of G-quadruplex from DNA species, since it is important for the G-quadruplex related basic research, clinical diagnosis, and therapy. Herein, fluorescent dye ThT-E, a derivative of the known fluorescence probe Thioflavin T (ThT), was designed and synthesized to effectively differentiate various G-quadruplex structures from other nucleic acid forms. Compared with methyl groups in ThT, three ethyl groups were introduced to ThT-E, which leads to strengthened affinity, selectivity and little inducing effect on the G-quadruplex formation. More importantly, ThT-E could be served as a visual tool to directly differentiate G-quadruplex solution even with naked eyes under illumination of ultraviolet light. Thus, this probe reported herein may hold great promise for high-throughput assay to screen G-quadruplex, which may widely apply to G-quadruplex-based potential diagnosis and therapy.

Objective: To examine factors that are associated with the apprehension levels of oncology nurses toward hospice care. Factors examined in this study included demographics, nursing experience, education levels, title and post, personal experiences, and attitudes toward end-of-life care., Methods: Questionnaires were provided to nurses (n=201) from three first-tier hospitals in China. A quantitative scale, Professional End-of-life Care Attitude Scale (PEAS), was used to assess personal and professional apprehension levels toward hospice care. The PEAS was translated to Chinese with terms adapted to the cultural environment in China. Statistical analyses were performed to examine the relationships between the apprehension levels and various factors., Results: The total PEAS scores exhibited internal consistency and reliability, with a Cronbach α =0.897 and Pearson's r =0.9030. Of the 201 nurses, 184 provided a valid response (91.5%). Education level was significantly correlated with personal ( P <0.01) and professional apprehension levels ( P <0.05). Higher apprehension level was found in nurses with less education., Conclusion: The PEAS quantitative survey is useful for evaluating apprehension levels of nurses toward hospice care. Nurses with more education experienced less anxiety when providing care for terminally ill patients. The findings suggested that education programs on hospice care could be strengthened to help nurses cope with negative attitudes toward end-of-life care., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

SUMO protease SENP1 is elevated in multiple carcinomas including prostate cancer (PCa). SENP1 exhibits carcinogenic properties; it promotes androgen receptor-dependent and -independent cell proliferation, stabilizes HIF1α, increases VEGF, and supports angiogenesis. However, mice expressing an androgen-responsive promoter driven SENP1-transgene (SENP1-Tg) develop high-grade prostatic intraepithelial neoplasia, but not carcinoma. We now show that tumor suppressive PTEN signaling is induced in SENP1-Tg to enhance prostate epithelial cell apoptosis. SENP1 blocks SUMO1-dependent ubiquitylation and degradation of PTEN. In the absence of SENP1, SUMO1-modified PTEN is sequestered in the cytosol, where binding to ubiquitin-E3 ligase WWP2 occurs. Concurrently, WWP2 is also SUMOylated, which potentiates its interaction with PTEN. Thus, SENP1 directs ubiquitin-E3-substrate association to control PTEN stability. PTEN serves as a barrier for SENP1-mediated prostate carcinogenesis as SENP1-Tg mice develop invasive carcinomas only after PTEN reduction. Hence, SENP1 modulates multiple facets of carcinogenesis and may serve as a target specifically for aggressive PTEN-deficient PCa.

Objective: By the detection of HBV infection, AFP and AST, the targets of biological behavior and the gene expression of multi-drug resistance gene 1 (MDR1) in hepatocellular carcinoma (HCC), we investigate characteristics of the expression of MDR1 in HCC and its relationship with HCC biological behavior., Methods: Using real-time fluorescence quantitative PCR (FQ-PCR) to detect the expressions of MDR1 in 102 samples of HCC tissue and 20 samples of non-cancerous tissue, we analyze the relationship between expressions of MDR1 and biological characteristics of HCC., Results: The expression of MDR1 in HCC is 0.55 ± 0.27, and in normal liver tissues is 0.23 ± 0.10, respectively. The expression in HCC is higher than it in normal liver tissue, the difference is statistically significant (P<0.05) and the difference between the expression and the HCC envelopes is statistically significant, and the expression increases along with the increase of Edmondson classification (P<0.05). HBV infection, AFP positive, the rise of AST, all these factors have positive correlations with the expression (r=0.463, 0.473, 0.299). In MDR1 expressions of HCC patients, the survival curve of the negative is higher than that of the positive, but the difference is not statistically significant., Conclusion: There are drug resistance phenomena in HCC, MDR1 expression may play an important role in primary HCC drug resistance. HBV infection can be detected as a reference indicator of HCC chemotherapy resistance, plasma levels of AFP, AST can be used as a reference index change dynamic monitoring of MDR1 expression.

Item response theory (IRT) is an important method of assessing the validity of measurement scales that is underutilized in the field of psychiatry. IRT describes the relationship between a latent trait (e.g., the construct that the scale proposes to assess), the properties of the items in the scale, and respondents' answers to the individual items. This paper introduces the basic premise, assumptions, and methods of IRT. To help explain these concepts we generate a hypothetical scale using three items from a modified, binary (yes/no) response version of the Center for Epidemiological Studies-Depression scale that was administered to 19,399 respondents. We first conducted a factor analysis to confirm the unidimensionality of the three items and then proceeded with Mplus software to construct the 2-Parameter Logic (2-PL) IRT model of the data, a method which allows for estimates of both item discrimination and item difficulty. The utility of this information both for clinical purposes and for scale construction purposes is discussed.

Background: Previous studies have shown that local anesthetics may induce apoptosis in some cell types. In this study, we investigated the apoptotic effects of local anesthetics in human breast tumor cells., Methods: Human breast cancer (MCF-7) and mammary epithelial (MCF-10A) cell lines were treated with lidocaine and/or bupivacaine. Cell viability, DNA fragmentation, and annexin V immunofluorescence staining were assessed. The effects on apoptosis-related protein expression were investigated by Western blot analysis. The findings were extended to studies in an in vivo xenograft model., Results: Treatment of breast tumor cells with lidocaine and bupivacaine resulted in inhibition of cell viability via induction of apoptosis. The effects were more prominent in MCF-7 cells than in MCF-10A cells. Treatment with local anesthetics induced caspase 7, 8, 9, and poly ADP-ribose polymerase cleavage. The cleavage of caspase 7 and poly ADP-ribose polymerase induced by local anesthetics were effectively blocked by caspase inhibitors. Furthermore, treatment of MCF-7 xenografts with local anesthetics resulted in higher expression of cleaved caspase 7 and an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining., Conclusion: Lidocaine and bupivacaine induce apoptosis of breast tumor cells at clinically relevant concentrations. Our results reveal previously unrecognized beneficial actions of local anesthetics and call for further studies to assess the oncologic advantages of their use during breast cancer surgery.

Free-space quantum communication with satellites opens a promising avenue for global secure quantum network and large-scale test of quantum foundations. Recently, numerous experimental efforts have been carried out towards this ambitious goal. However, one essential step--transmitting single photons from the satellite to the ground with high signal-to-noise ratio (SNR) at realistic environments--remains experimental challenging. Here, we report a direct experimental demonstration of the satellite-ground transmission of a quasi-single-photon source. In the experiment, single photons (~0.85 photon per pulse) are generated by reflecting weak laser pulses back to earth with a cube-corner retro-reflector on the satellite CHAMP, collected by a 600-mm diameter telescope at the ground station, and finally detected by single-photon counting modules after 400-km free-space link transmission. With the help of high accuracy time synchronization, narrow receiver field-of-view and high-repetition-rate pulses (76 MHz), a SNR of better than 16:1 is obtained, which is sufficient for a secure quantum key distribution. Our experimental results represent an important step towards satellite-ground quantum communication.

Background: Delirium (acute confusion), is a common, morbid, and costly complication of acute illness in older adults. Yet, researchers and clinicians lack short, efficient, and sensitive case identification tools for delirium. Though the Confusion Assessment Method (CAM) is the most widely used algorithm for delirium, the existing assessments that operationalize the CAM algorithm may be too long or complicated for routine clinical use. Item response theory (IRT) models help facilitate the development of short screening tools for use in clinical applications or research studies. This study utilizes IRT to identify a reduced set of optimally performing screening indicators for the four CAM features of delirium., Methods: Older adults were screened for enrollment in a large scale delirium study conducted in Boston-area post-acute facilities (n = 4,598). Trained interviewers conducted a structured delirium assessment that culminated in rating the presence or absence of four features of delirium based on the CAM. A pool of 135 indicators from established cognitive testing and delirium assessment tools were assigned by an expert panel into two indicator sets per CAM feature representing (a) direct interview questions, including cognitive testing, and (b) interviewer observations. We used IRT models to identify the best items to screen for each feature of delirium., Results: We identified 10 dimensions and chose up to five indicators per dimension. Preference was given to items with peak psychometric information in the latent trait region relevant for screening for delirium. The final set of 48 indicators, derived from 39 items, maintains fidelity to clinical constructs of delirium and maximizes psychometric information relevant for screening., Conclusions: We identified optimal indicators from a large item pool to screen for delirium. The selected indicators maintain fidelity to clinical constructs of delirium while maximizing psychometric information important for screening. This reduced item set facilitates development of short screening tools suitable for use in clinical applications or research studies. This study represents the first step in the establishment of an item bank for delirium screening with potential questions for clinical researchers to select from and tailor according to their research objectives.

The authors examined the impact of race/ethnicity on responses to the Everyday Discrimination Scale, one of the most widely used discrimination scales in epidemiologic and public health research. Participants were 3,295 middle-aged US women (African-American, Caucasian, Chinese, Hispanic, and Japanese) from the Study of Women's Health Across the Nation (SWAN) baseline examination (1996-1997). Multiple-indicator, multiple-cause models were used to examine differential item functioning (DIF) on the Everyday Discrimination Scale by race/ethnicity. After adjustment for age, education, and language of interview, meaningful DIF was observed for 3 (out of 10) items: "receiving poorer service in restaurants or stores," "being treated as if you are dishonest," and "being treated with less courtesy than other people" (all P's < 0.001). Consequently, the "profile" of everyday discrimination differed slightly for women of different racial/ethnic groups, with certain "public" experiences appearing to have more salience for African-American and Chinese women and "dishonesty" having more salience for racial/ethnic minority women overall. "Courtesy" appeared to have more salience for Hispanic women only in comparison with African-American women. Findings suggest that the Everyday Discrimination Scale could potentially be used across racial/ethnic groups as originally intended. However, researchers should use caution with items that demonstrated DIF.

Background: studies of cognitive ageing at the group level suggest that age is associated with cognitive decline; however, there may be individual differences such that not all older adults will experience cognitive decline., Objective: to evaluate patterns of cognitive decline in a cohort of older adults initially free of dementia., Design, Setting and Subjects: elderly Catholic clergy members participating in the Religious Orders Study were followed for up to 15 years. Cognitive performance was assessed annually., Methods: performance on a composite global measure of cognition was analysed using random effects models for baseline performance and change over time. A profile mixture component was used to identify subgroups with different cognitive trajectories over the study period., Results: from a sample of 1,049 participants (mean age 75 years), three subgroups were identified based on the distribution of baseline performance and change over time. The majority (65%) of participants belonged to a slow decline class that did not experience substantial cognitive decline over the observation period [-0.04 baseline total sample standard deviation (SD) units/year]. About 27% experienced moderate decline (-0.19 SD/year), and 8% belonged to a class experiencing rapid decline (-0.57 SD/year). A subsample analysis revealed that when substantial cognitive decline does occur, the magnitude and rate of decline is correlated with neuropathological processes., Conclusions: in this sample, the most common pattern of cognitive decline is extremely slow, perceptible on a time scale measured by decades, not years. While in need of cross validation, these findings suggest that cognitive changes associated with ageing may be minimal and emphasise the importance of understanding the full range of age-related pathologies that may diminish brain function.

Object naming tests are commonly included in neuropsychological test batteries. Differential item functioning (DIF) in these tests due to cultural and language differences may compromise the validity of cognitive measures in diverse populations. We evaluated 26 object naming items for DIF due to Spanish and English language translations among Latinos ( n =1,159), mean age of 70.5 years old (Standard Deviation ( SD )±7.2), using the following four item response theory -based approaches: Mplus/Multiple Indicator, Multiple Causes (Mplus/MIMIC; Muthén & Muthén, 1998-2011), Item Response Theory Likelihood Ratio Differential Item Functioning (IRTLRDIF/MULTILOG; Thissen, 1991, 2001), difwithpar/Parscale (Crane, Gibbons, Jolley, & van Belle, 2006; Muraki & Bock, 2003), and Differential Functioning of Items and Tests/MULTILOG (DFIT/MULTILOG; Flowers, Oshima, & Raju, 1999; Thissen, 1991). Overall, there was moderate to near perfect agreement across methods. Fourteen items were found to exhibit DIF and 5 items observed consistently across all methods, which were more likely to be answered correctly by individuals tested in Spanish after controlling for overall ability.