Search

Patients with heart failure with reduced ejection fraction (HFrEF) and worsening HF events (WHFE) represent a distinct subset of patients with a substantial comorbidity burden, greater potential for intolerance to medical therapy, and high risk of subsequent death, hospitalization and excessive healthcare costs. Although multiple therapies have been shown to be efficacious and safe in this high-risk population, there are limited real-world data regarding factors that impact clinical decision-making when initiating or modifying therapy. Likewise, prior analyses of US clinical practice support major gaps in medical therapy for HFrEF and few medication changes during longitudinal follow-up, yet granular data on reasons why clinicians do not initiate or up-titrate guideline-directed medication are lacking.We designed the CHART-HF study, an observational study of approximately 1,500 patients comparing patients with and without WHFE (WHFE defined as receipt of intravenous diuretics in the inpatient, outpatient, or emergency department setting) who had an index outpatient visit in the US between 2017 and 2019. Patient-level data on clinical characteristics, clinical outcomes, and therapy will be collected from 2 data sources: a single integrated health system, and a national panel of cardiologists. Furthermore, clinician-reported rationale for treatment decisions and the factors prioritized with selection and optimization of therapies in real-world practice will be obtained. To characterize elements of clinician decision-making not documented in the medical record, the panel of cardiologists will review records of patients seen under their care to explicitly note their primary reason for initiating, discontinuing, and titrating medications specific medications, as well as the reason for not making changes to each medication during the outpatient visit.Results from CHART-HF have the potential to detail real-world US practice patterns regarding care of patients with HFrEF with versus without a recent WHFE, to examine clinician-reported reasons for use and non-use of guideline-directed medical therapy, and to characterize the magnitude and nature of clinical inertia toward evidence-based medication changes for HFrEF.

The retrovirus HIV‐1 integrates into the host genome and establishes a latent viral reservoir that escapes immune surveillance. Molecular mechanisms of HIV‐1 latency have been studied extensively to achieve a cure for the acquired immunodeficiency syndrome (AIDS). Latency‐reversing agents (LRAs) have been developed to reactivate and eliminate the latent reservoir by the immune system. To develop more promising LRAs, it is essential to evaluate new therapeutic targets. Here, we find that CBX4, a component of the Polycomb Repressive Complex 1 (PRC1), contributes to HIV‐1 latency in seven latency models and primary CD4(+) T cells. CBX4 forms nuclear bodies with liquid–liquid phase separation (LLPS) properties on the HIV‐1 long terminal repeat (LTR) and recruits EZH2, the catalytic subunit of PRC2. CBX4 SUMOylates EZH2 utilizing its SUMO E3 ligase activity, thereby enhancing the H3K27 methyltransferase activity of EZH2. Our results indicate that CBX4 acts as a bridge between the repressor complexes PRC1 and PRC2 that act synergistically to maintain HIV‐1 latency. Dissolution of phase‐separated CBX4 bodies could be a potential intervention to reactivate latent HIV‐1.

Objective To understand factors guiding overactive bladder (OAB) therapy selection and experience with combination therapy (antimuscarinics and beta-3 agonists). Methods Cross-sectional surveys of OAB patients and OAB-treating physicians in the USA were conducted. Patients receiving monotherapy with antimuscarinics were categorized by OAB treatment history: monotherapy only; third-line procedures (e.g., onabotulinumtoxinA injections) and combination therapy; third-line therapy only; and combination therapy only. The patient survey assessed therapy choice drivers and barriers, treatment satisfaction and sociodemographic/clinical characteristics. The physician survey assessed drivers of and barriers to OAB treatment choices. Results Of 200 patients, 86.5% reported involvement in treatment decision-making; doctor’s recommendation was the most frequently considered factor (84.4%). Most patients (71%) were unaware of combination therapy. The primary reason why those patients aware of combination therapy had not used it (N = 43/200; 21%) was physician recommendation of other treatments (69.8%). For physicians (N = 50), the most frequently considered factors when prescribing OAB treatment were effectiveness (92.0%) and side effects (84.0%); 70% prescribed combination therapy, primarily for symptom severity (82.9%). The main reasons for not prescribing combination therapy were cost/insurance coverage (80%) and lack of information (53.3%). Conclusions Shared decision-making guided treatment decisions; the main considerations were treatment safety and efficacy.

The current conservative and surgical treatments are not fully effective and have complications for Raynaud's phenomenon (RP) secondary to systemic sclerosis (SSc). Botulinum toxin A (BTX-A) can be used to manage RP, but the literature mostly includes case reports and case series. Thus, we performed a randomized controlled trial to explore the efficacy of BTX-A in the treatment of RP secondary to SSc. Sixteen patients with RP secondary to SSc were recruited. One hand was randomly included in the BTX-A group and the other as control. Both hands were tested before treatment and 4 weeks later using qualitative and quantitative dermatoscopic assessments and the cold water test. Reynolds score (from 6.7 ± 4.0 to 2.9 ± 3.7, p 0.001), T

Classical swine fever virus (CSFV) is a member of the genus Pestivirus in the Flaviviridae family. To date, the host factors required for CSFV entry remain poorly characterized. To identify the functional membrane protein(s) involved in CSFV infection, we analyzed the transcriptomic data from previous studies describing gene expression profiles for CSFV, and found twelve novel candidate proteins. One of these proteins, MERTK, significantly reduced CSFV protein expression by RNA interference screening using a recombinant CSFV that contains a luciferase reporter to measure CSFV protein expression. Furthermore, our results demonstrated that either anti-MERTK antibodies or soluble MERTK ectodomain could reduce CSFV infection in PK-15 cells in a dose-dependent manner. Mechanistically, MERTK interacted with the E2 protein of CSFV and facilitated virus entry. After virus entry, MERTK downregulates of mRNA expression of IFN-β and promotes CSFV infection. Interestingly, the soluble MERTK ectodomain could also reduce the infection of bovine viral diarrhea virus (BVDV), another pestivirus. Taken together, our results suggested that MERTK is a CSFV entry factor that synergistically dampens innate immune responses in PK-15 cells and is also involved in BVDV infection.

To measure health state preferences and estimate utility values for tardive dyskinesia (TD) from the perspective of the US general population, accounting for factors affecting quality of life (QOL). Participants from the general population were recruited and asked to watch and assess videos of professional actors simulating nine health states, including psychiatric disorders with/without TD and moderate-to-severe TD without any underlying disease. Time tradeoff (TTO) methods were used to elicit utility values, which ranged from ���1 (worse than death) to +1 (perfect health) and represented individual preferences for avoiding specific health states associated with TD. Lower TTO utility values indicated individuals��� willingness to give up more years of life to avoid living in each health state. Based on TTO responses (n = 157), mean �� standard deviation utility for TD alone was 0.59 �� 0.38. Mean utilities for schizophrenia with negative symptoms (without TD: 0.43; with TD: 0.29) and positive symptoms (without TD: 0.44; with TD: 0.30) were generally lower than those for bipolar disorder (without TD: 0.59; with TD: 0.46) and major depressive disorder (without TD: 0.60; with TD: 0.44). According to utility decrements associated with TD (0.13���0.16), respondents were willing to give up 1.3 to 1.6 years during a 10-year lifespan to avoid living with TD. Utility decrements for TD in this study were slightly larger than previously reported values, potentially due to incorporation of QOL and social consequences in TD health state descriptions. An important limitation of this analysis is that participants��� willingness to trade future years of healthy life may not indicate actual willingness to accept the life decrement. These findings can be leveraged to improve cost-effectiveness analyses used to assess the value of treatments for TD.

Poor child feeding and childhood malnutrition are major public health problems in rural central and western China, with little evidence about their environmental determinants. This study aimed to investigate whether household water access is associated with dietary diversity and nutritional outcomes. We analyzed the cross-sectional data of 3727 children aged 6 to 59 months in rural central and western China, applying multivariate linear and logistic models to estimate the effect of water access on children’s anthropometric indices, hemoglobin, and dietary diversity. We found that unimproved water access was linked to a lower likelihood of achieving dietary diversity (OR = 0.65, 95% CI 0.44 to 0.98, p = 0.039); lower height-for-age z-score (β = −0.34, 95% CI −0.49 to −0.19, p < 0.001) and hemoglobin concentration (β = −2.78, 95% CI −5.16 to −0.41, p = 0.022); higher odds of stunting (OR = 1.50, 95% CI 1.01 to 2.25, p = 0.047) and anemia (OR = 1.34, 95% CI 1.02 to 1.77, p = 0.037). The associations between water access and nutritional outcomes were not explained by dietary diversity and were stronger in children who did not receive iron supplementation. These findings provide evidence for designing water-based nutritional interventions in China.

IntroductionHeart failure with preserved ejection fraction (HFpEF) affects more than half of the patients with heart failure. HFpEF and sarcopenia can interact with each other and contribute to reduced physiological function and increased mortality in elderly patients. Resistance training (RT) or resistance exercise rehabilitation (RER) may have benefits for elderly HFpEF patients with sarcopenia. Whey protein supplementation (WPS) may increase the effects of exercise on strength and muscle mass, in addition to promoting heart function and quality of life (QoL). However, studies are needed to evaluate effects of RER and WPS in patients with HFpEF with sarcopenia.Methods and analysisThis is a prospective, randomised, controlled clinical trial in which patients with HFpEF with sarcopenia will be randomly allocated to three groups, control, RT and RT+WP. Participants in all groups will receive basic intervention including standard medicine treatment, home-based aerobic exercise and basic nutritional intervention. The RT group will undergo resistance exercise programmes, and the RT+WP group will receive daily WPS apart from resistance exercise. The study variables will be evaluated at baseline and 12 weeks. Primary outcome measure is the change of 6 min walking distance. Secondary outcomes include parameters of muscle status, cardiac function, nutritional status, QoL and major adverse cardiovascular events. The primary efficacy analysis will follow the intention-to-treat principle.Ethics and disseminationThis study was approved by Ethics Committee of China-Japan Friendship Hospital for Clinical Research (No. 2022-KY-003). The results of this study will be disseminated via peer-reviewed publications and presentations at conferences.Trial registration numberChiCTR2200061069.

Chorea is characterized by sudden, involuntary movements that interfere with quality of life (QOL). Utility values measure preferences for different health states and reflect societal perceived disease severity. To date, no studies have reported utility values specifically for Huntington's disease (HD) chorea. We estimated impact on QOL of HD chorea severity using utility values from the general population.Participants were enrolled using computer-assisted telephone interviews. Participants read vignettes describing four health states for varying levels of chorea severity, with the same underlying HD severity. Time trade-off (TTO) methods were used to estimate utility values, which range from -1 (worse than death) to +1 (perfect health) and represent the number of years in an imperfect health state an individual is willing to give up to live in full health. TTO utilities were augmented with visual analog scale (VAS) participant responses. The primary outcome was HD chorea utility estimated by TTO.Mean ± SD TTO-derived utility values were 0.07 ± 0.52, 0.26 ± 0.50, 0.48 ± 0.47, and 0.64 ± 0.41 for severe, moderate/severe, moderate/mild, and mild chorea severity, respectively. Differences between each health state and its adjacent less severe health state were statistically significant (all P 0.0001). Respondents were willing to give up 3.6, 5.2, 7.4, and 9.3 years during a 10-year life span to avoid living with mild, mild/moderate, moderate/severe, and severe chorea, respectively. VAS and TTO results were consistent.Significant decreases in utility values were seen as HD chorea severity increased. These data can be leveraged for cost-effectiveness modeling to better understand the value of treatments for chorea.

Intimate partner violence (IPV) against women is a major public health problem and is widespread in sub-Saharan Africa (SSA). However, little is known about its environmental determinants. This study aimed to investigate whether inadequate living conditions are associated with IPV victimization in women in SSA. We analyzed cross-sectional data for 102,714 women in 25 SSA countries obtained from the Demographic and Health Surveys Program. Logistic regression was used to estimate the country-specific effects of inadequate living conditions (housing with at least one of four characteristics of unimproved water, unimproved sanitation, insufficient space, and unfinished materials) on multiple forms of IPV. Random effects meta-analysis was used to combined the country-specific estimates. We found an association between inadequate living conditions and a higher likelihood of experiencing any (OR = 1.12, 95% CI 1.03 to 1.23, p = 0.012), sexual (OR = 1.18, 95% CI 1.05 to 1.34, p = 0.008), emotional (OR = 1.12, 95% CI 1.02 to 1.23, p = 0.023), and physical (OR = 1.15, 95% CI 1.03 to 1.28, p = 0.010) IPV. The associations were stronger for rural and less-educated women. These findings suggest that future research to establish a causal link between living conditions and IPV and to elucidate the underlying pathways is crucial to design IPV interventions in SSA.

Background Occupational class is an integral part of socioeconomic status. The studies focused on the occupational difference in ischemic stroke outcome in a Chinese population are limited. We aimed to investigate the associations between occupational class and the prognosis of patients with ischemic stroke in China. Methods We included 1484 ischemic stroke participants (mean age: 63.42 ± 11.26 years) from the prospective cohort study: Infectious Factors, Inflammatory Markers and Prognosis of Acute Ischemic Stroke (IIPAIS). Occupational class was categorized into white-collar workers, blue-collar workers and farmers in our study. Study outcomes were cardiovascular events and all-cause mortality within 12 months after ischemic stroke onset. We applied Cox proportional hazard model to evaluate the associations between the occupational class and study outcomes after ischemic stroke. Results Within 12 months after ischemic stroke, there were 106 (7.5%) cardiovascular events and 69 (4.9%) all-cause deaths. The Kaplan–Meier plots showed that white-collar workers had highest risk of cardiovascular events after 12-month follow-up (Log-rank P = 0.02). Multivariate adjusted hazard ratio and 95% confidence intervals (CIs) of farmers versus white-collar workers was 0.43(0.20–0.91) for cardiovascular events. No significant difference showed in blue-collar workers versus white-collar workers, with fully adjusted hazard ratio 0.62(95% CIs, 0.23–1.67). Conclusions Compared with white-collar workers, farmers are associated with less risk of cardiovascular events at 12 months after ischemic stroke, while there are no significant differences in blue-collar workers.

Objective This study was performed to investigate the process of ectopic tooth formation. Methods A patient with an ectopic tooth was followed for 6 years. The tooth size and mineralization were evaluated by paranasal sinus computed tomography every 3 years. Results The ectopic tooth was present in the nasal crest of the maxilla and did not change significantly during the 6-year follow-up period. However, the patient developed a new ectopic tooth in the maxillary sinus (ETm). This tooth, located in the posterior wall of the left maxillary sinus, initially appeared as a small region of soft tissue on computed tomography. After 3 years, the area of mixed density had significantly increased, and some of it had significantly mineralized to form an ETm. After 6 years, the ETm had further mineralized and enlarged in situ. The width between the left and right sides of the ETm in 2018 (9.08 ± 2.09 mm) was significantly larger than that in 2015 (7.51 ± 2.18 mm), indicating that ETm formation is a gradual process of mineralization. Conclusion Ectopic teeth can gradually form by in situ mineralization after adolescence, suggesting that ectopic teeth are genetically regulated and result from a programmed formation process occurring at a specific time point.

Background Identifying individuals who are unlikely to adhere to a physical exercise regime has potential to improve physical activity interventions. The aim of this paper is to develop and test adherence prediction models using objectively measured physical activity data in the Mobile Phone-Based Physical Activity Education program (mPED) trial. To the best of our knowledge, this is the first to apply Machine Learning methods to predict exercise relapse using accelerometer-recorded physical activity data. Methods We use logistic regression and support vector machine methods to design two versions of a Discontinuation Prediction Score (DiPS), which uses objectively measured past data (e.g., steps and goal achievement) to provide a numerical quantity indicating the likelihood of exercise relapse in the upcoming week. The respective prediction accuracy of these two versions of DiPS are compared, and then numerical simulation is performed to explore the potential of using DiPS to selectively allocate financial incentives to participants to encourage them to increase physical activity. Results we had access to a physical activity trial data that were continuously collected every 60 sec every day for 9 months in 210 participants. By using the first 15 weeks of data as training and test on weeks 16–30, we show that both versions of DiPS have a test AUC of 0.9 with high sensitivity and specificity in predicting the probability of exercise adherence. Simulation results assuming different intervention regimes suggest the potential benefit of using DiPS as a score to allocate resources in physical activity intervention programs in reducing costs over other allocation schemes. Conclusions DiPS is capable of making accurate and robust predictions for future weeks. The most predictive features are steps and physical activity intensity. Furthermore, the use of DiPS scores can be a promising approach to determine when or if to provide just-in-time messages and step goal adjustments to improve compliance. Further studies on the use of DiPS in the design of physical activity promotion programs are warranted. Trial registration ClinicalTrials.gov NCT01280812 Registered on January 21, 2011.

Background There was a lack of studies on the association between Human Cytomegalovirus (HCMV) infection and prognosis of ischemic stroke, although it was indicated that human cytomegalovirus DNA has played a role in several cardiovascular disorders. Objective To examine the association between HCMV IgM levels in the acute phase and death and major disability after 2 weeks of acute ischemic stroke. Methods Serum HCMV IgM levels were measured in 1150 participants in China. Study outcome data on major disability and combined outcome of death and major disability were collected at 2 weeks after stroke onset or hospital discharge. Results After 2 weeks of follow-up, 351 participants (30.52%) suffered from a major disability or died. Serum HCMV IgM was correlated with the combined outcome of death and major disability significantly after adjustment confounding factors. For example, the highest quartile of HCMV IgM was related to an odds ratio (95% confidence interval) of 1.84 (1.12-3.11) for the combined outcome. Risk prediction of the combined outcome was improved by the addition of serum HCMV IgM to conventional risk factors (net reclassification index 25.41%, p＝0.0002; integrated discrimination improvement 0.70%, p＝0.04377). Conclusions Elevated serum HCMV IgM levels in the acute phase of ischemic stroke were correlated with increased risk of combined outcome of death and major disability, indicating that serum HCMV IgM could be an important predictive factor for poor prognosis of ischemic stroke.

HIV‐1 latency is a major obstacle to achieving a functional cure for AIDS. Reactivation of HIV‐1‐infected cells followed by their elimination via immune surveillance is one proposed strategy for eradicating the viral reservoir. However, current latency‐reversing agents (LRAs) show high toxicity and low efficiency, and new targets are needed to develop more promising LRAs. Here, we found that the histone chaperone CAF‐1 (chromatin assembly factor 1) is enriched on the HIV‐1 long terminal repeat (LTR) and forms nuclear bodies with liquid–liquid phase separation (LLPS) properties. CAF‐1 recruits epigenetic modifiers and histone chaperones to the nuclear bodies to establish and maintain HIV‐1 latency in different latency models and primary CD4(+) T cells. Three disordered regions of the CHAF1A subunit are important for phase‐separated CAF‐1 nuclear body formation and play a key role in maintaining HIV‐1 latency. Disruption of phase‐separated CAF‐1 bodies could be a potential strategy to reactivate latent HIV‐1.

Using national representative data, we found the prevalence of and risk factors associated with low BMD differed by race and ethnicity. Race/ethnicity is an important determinant of osteoporosis risk. The study aims were to (1) estimate the racial and ethnic differences in the prevalence of low BMD, (2) identify factors associated with low BMD by race and ethnic group, and (3) evaluate if the association between sleep duration and low BMD is modified by age, sex, gender, and/or race/ethnicity. Using data from the National Health and Nutrition Examination Survey (NHANES) database from 2005 to 2014, totally, 7992 participants aged ≥ 50 years were included as the primary cohort. Three race/ethnic groups were included: non-Hispanic Whites, Hispanics, and non-Hispanic Blacks. Low BMD was defined by femoral neck BMD T-scores less than − 1, as measured by DXA scan. Univariate and multivariate analyses were performed to determine associations between participants’ demographics, comorbidities, lifestyle characteristics, and prevalent low BMD. Prevalence of low BMD was 50.8% among non-Hispanic Whites, 23.7% among non-Hispanic Blacks, and 44.0% among Hispanics. After adjusting for confounders, advanced age, female gender, and fracture history were significantly associated with increased odds of low BMD in all three race/ethnic groups. Family history of osteoporosis, ever used glucocorticoids daily, and vitamin D deficiency or insufficiency were associated with increased odds of low BMD only among non-Hispanic Whites. Cardiovascular disease (CVD) history and diabetes were associated with low BMD only among non-Hispanic Blacks. Short sleep duration was not associated with low BMD in all ethnic groups, but was significantly associated with low BMD in older adults (> 65 years) and females. Prevalence of low BMD among three race/ethnic groups in the USA is determined, with race/ethnic disparities in several risk factors associated with low BMD identified. By contrast, advanced age, female gender, and fracture history are associated with increased odds of low BMD across all race/ethnic groups. The association between sleep duration and low BMD is modified by age and sex. Together, these findings may help clinicians and healthcare providers formulate better care for individual’s bone health.

The extent to which recurrences of pericarditis episodes impact patients’ health-related quality of life (HRQOL) remains poorly understood. This study aimed to evaluate HRQOL and work productivity in patients with recurrent pericarditis (RP). Adult patients from a centralized recruitment database for the rilonacept Phase 2/3 clinical trials were invited to participate in a survey. Inclusion criteria were confirmed RP diagnosis and ≥1 recurrence within the previous 12 months. The 11-Point Pain Numeric Rating Scale, Patient Global Impression of Pericarditis Severity, Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health v1.2, PROMIS Short Form Sleep Disturbance 8b, Work Productivity and Activity Impairment v2.0, and customized questions about fear and economic impact were used. In total, 83 patients (55% female, average age = 49.3 years) completed the survey. The median time since pericarditis diagnosis was 3.0 years at the time of survey completion; 49% experienced ≥3 recurrences in the previous 12 months. Forty percent had an emergency room visit, and 25% were hospitalized for their most recent recurrence. Sixty-six percent of participants rated the symptoms of their last recurrence as severe. The mean value for worst pericarditis pain (0 to 10 scale) during the most recent recurrence was 6.1. The average T-scores for PROMIS physical and mental health were 37.6 and 42.8, respectively, compared with 50 in the general population. Participants reported 50% of overall work impairment and 62% of activity impairment due to RP. In conclusion, patients with RP experienced a high number of recurrences with severe symptoms that substantially reduced their HRQOL and work productivity.

The prevalence of unilateral hearing loss(UHL) is higher, and the clinical attention to the hearing rehabilitation of UHL is not enough, resulting in many UHL patients cannot get rehabilitation timely and effectively. Severe to profound UHL(also known as single-sided deafness) patients lack binaural hearing superiority, especially the inadequate ability of sound localization, which will seriously affect their daily life and academic performance. At present, the main rehabilitation methods of UHL include various kinds of bone conduction hearing aids, vibrant soundbridge and cochlear implantation, etc. However, the rehabilitation effect of UHL patients' ability to locate the sound source is affected by the occurrence age, the type, the degree and the duration of the hearing loss. The results of rehabilitation in different literature vary greatly. This paper reviews the effects of different rehabilitation strategies on the ability of sound location and analyzes its possible causes and mechanisms.

Interaural time difference and interaural level difference signals are insufficient in patients with single-sided deafness (SSD). This insufficiency leads to an absence of sound localization abilities and a decrease in speech intelligibility in noisy environments. SSD occurring in children further affects their language learning and cognitive abilities and their academic performance because they lack spatial abilities and binaural hearing. The early stages of central auditory system development are critical for auditory function development and morphological refinement. SSD occurring in the critical period can cause significant lateralization in the bilateral auditory pathway. This may increase the risk that affected individuals cannot re-establish binaural benefits after rehabilitation of hearing loss in the post-sensitive period. For otorhinolaryngologists, there is the concern that children with congenital SSD cannot benefit from cochlear implantation. Only a few studies have investigated auditory rehabilitation in children with congenital SSD with cochlear implantation and their results were inconsistent. The present review aims to clarify the main problems and challenges of clinical rehabilitation of congenital SSD, particularly focusing on the effect of CI on sound localization ability in children with congenital SSD.

Chitosan is a product of the deacetylation of chitin, which is widely found in nature. Chitosan is insoluble in water and most organic solvents, which seriously limits both its application scope and applicable fields. However, chitosan contains active functional groups that are liable to chemical reactions; thus, chitosan derivatives can be obtained through the chemical modification of chitosan. The modification of chitosan has been an important aspect of chitosan research, showing a better solubility, pH-sensitive targeting, an increased number of delivery systems, etc. This review summarizes the modification of chitosan by acylation, carboxylation, alkylation, and quaternization in order to improve the water solubility, pH sensitivity, and the targeting of chitosan derivatives. The applications of chitosan derivatives in the antibacterial, sustained slowly release, targeting, and delivery system fields are also described. Chitosan derivatives will have a large impact and show potential in biomedicine for the development of drugs in future.

BACKGROUND: Overuse of health care resources has been identified as the leading contributor to waste in the US health care system. OBJECTIVE: To explore health care system factors associated with regional variation in systemic overuse of health care resources as measured by the Johns Hopkins Overuse Index (JHOI) which aggregates systemic overuse of 20 health care services. DESIGN: Using Medicare fee-for-service claims data from beneficiaries age 65 or over in 2008, we calculated the JHOI for the 306 hospital referral regions in the United States. We used ordinary least squares regression and multilevel models to estimate the association of JHOI scores and characteristics of regional health care delivery systems listed in the Area Health Resource File and Dartmouth Atlas. KEY RESULTS: Regions with a higher density of primary care physicians had lower JHOI scores, indicating less systemic overuse (P

Study objective We analyzed the effect of insurance expansion on emergency department (ED) utilization among the uninsured in Maryland, which expanded Medicaid eligibility and created health insurance exchanges in 2014. Methods This was a retrospective analysis of statewide administrative claims for July 2012 to December 2015. We used coarsened exact matching to pair uninsured and insured (Medicaid, Medicare, commercial, and other) adult Maryland residents who visited an ED or were hospitalized at baseline (July 2012 to December 2013). We compared ED utilization between these groups after insurance expansion (January 2014 to December 2015), using a difference-in-differences quasi-experimental design. Nonreturning patients from the baseline period were included in the post–insurance expansion rates as having zero visits. Results Matching yielded 178,381 pairs. In the 12 months before insurance expansion, the baseline uninsured group visited the ED at a rate of 26.1 per 100 patient-quarters versus 28.2 among the insured group (relative rate=0.93). In the 24 months after insurance expansion, 45% of the baseline uninsured returned to an ED, of whom 33% returned uninsured, 40% returned with Medicaid, and 21% returned with commercial insurance. After insurance expansion, with 55% of patients in each group not returning, the ED visit rate for both the baseline uninsured and insured groups was 15.9 per 100 patient-quarters (relative rate=1.00). This 8% relative increase from baseline in ED visits among the uninsured group was driven primarily by increases in higher-acuity visits. Uninsured patients from high-poverty zip codes (N=34,964 pairs) increased their ED utilization by 15% after insurance expansion, whereas baseline uninsured patients with no comorbidities (N=94,330 pairs) showed a 3% decrease. Conclusion Insurance expansion in Maryland was associated with a modest relative increase in ED visits among the uninsured, driven by increases in higher-acuity visits. It remains unclear whether insurance coverage helped the uninsured address their unmet medical needs.

Background: Human papillomavirus (HPV) vaccination could prevent most HPV-associated cancers, but few U.S. adolescents are vaccinated according to guidelines. To inform efforts to counsel parents more effectively, we sought to quantify their views on the best and worst reasons for guideline-consistent HPV vaccination. We hypothesized that parents' views would differ according to their vaccination confidence. Methods: We developed a best–worst scaling experiment to evaluate 11 reasons healthcare providers commonly give for HPV vaccination. The instrument was administered in 2016 via a national online survey to 1,177 parents of adolescents. Parents completed 11 choice tasks of 5 reasons each, indicating the best and worst reason in each task. We used conditional logistic regression to rank reasons for the sample overall and by vaccination confidence (low/high). Results: Parents viewed cancer prevention as the best reason for HPV vaccination (P < 0.001). Other commonly endorsed reasons were preventing a common infection, having lasting benefits, or being a safe vaccine (all P < 0.001). Reasons viewed as worst were: It is a scientific breakthrough; I got it for my own child; and your child is due (all P < 0.001). Stratified analyses indicated small differences in how often parents with low versus high vaccination confidence endorsed messages (P < 0.001), but the two groups ranked reasons similarly overall. Conclusions: Parents prioritized cancer prevention as the best reason for guideline-consistent HPV vaccination. Several other common reasons, including having vaccinated one's own child, may warrant additional testing. Impact: Providers should emphasize cancer prevention when discussing HPV vaccination, as recommended by the Centers for Disease Control and Prevention, the President's Cancer Panel, and others. Cancer Epidemiol Biomarkers Prev; 27(7); 762–7. ©2018 AACR.

Latent class analysis (LCA) has been increasingly used to explore preference heterogeneity, but the literature has not been systematically explored and hence best practices are not understood. We sought to document all applications of LCA in the stated-preference literature in health and to inform future studies by identifying current norms in published applications. We conducted a systematic review of the MEDLINE, EMBASE, EconLit, Web of Science, and PsycINFO databases. We included stated-preference studies that used LCA to explore preference heterogeneity in healthcare or public health. Two co-authors independently evaluated titles, abstracts, and full-text articles. Abstracted key outcomes included segmentation methods, preference elicitation methods, number of attributes and levels, sample size, model selection criteria, number of classes reported, and hypotheses tests. Study data quality and validity were assessed with the Purpose, Respondents, Explanation, Findings, and Significance (PREFS) quality checklist. We identified 2560 titles, 99 of which met the inclusion criteria for the review. Two-thirds of the studies focused on the preferences of patients and the general population. In total, 80% of the studies used discrete choice experiments. Studies used between three and 20 attributes, most commonly four to six. Sample size in LCAs ranged from 47 to 2068, with one-third between 100 and 300. Over 90% of the studies used latent class logit models for segmentation. Bayesian information criterion (BIC), Akaike information criterion (AIC), and log-likelihood (LL) were commonly used for model selection, and class size and interpretability were also considered in some studies. About 80% of studies reported two to three classes. The number of classes reported was not correlated with any study characteristics or study population characteristics (p > 0.05). Only 30% of the studies reported using statistical tests to detect significant variations in preferences between classes. Less than half of the studies reported that individual characteristics were included in the segmentation models, and 30% reported that post-estimation analyses were conducted to examine class characteristics. While a higher percentage of studies discussed clinical implications of the segmentation results, an increasing number of studies proposed policy recommendations based on segmentation results since 2010. LCA is increasingly used to study preference heterogeneity in health and support decision-making. However, there is little consensus on best practices as its application in health is relatively new. With an increasing demand to study preference heterogeneity, guidance is needed to improve the quality of applications of segmentation methods in health to support policy development and clinical practice.

The antiviral activity of host factor apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G, A3G) and its degradation mediated by human immunodeficiency virus type 1 (HIV-1) Vif protein are important topics. Although accumulating evidence indicates the importance of deubiquitination enzymes (DUBs) in innate immunity, it is unknown if they participate in A3G stability. Here, we found that USP49 directly interacts with A3G and efficiently removes ubiquitin, consequently increasing A3G protein expression and significantly enhancing its anti-HIV-1 activity. Unexpectedly, A3G degradation was also mediated by a Vif- and cullin-ring-independent pathway, which was effectively counteracted by USP49. Furthermore, clinical data suggested that USP49 is correlated with A3G protein expression and hypermutations in Vif-positive proviruses, and inversely with the intact provirus ratio in the HIV-1 latent reservoir. Our studies demonstrated a mechanism to effectively stabilize A3G expression, which could comprise a target to control HIV-1 infection and eradicate the latent reservoir.

Mutated N-Ras causes leukemia and melanoma when properly delivered to cellular membranes. Here, VPS35, a component of the retromer, is shown to carry N-Ras from one membrane compartment to another. Thus, VPS35 may be a target for anticancer drug discovery., Ras guanosine triphosphatases (GTPases) regulate signaling pathways only when associated with cellular membranes through their C-terminal prenylated regions. Ras proteins move between membrane compartments in part via diffusion-limited, fluid phase transfer through the cytosol, suggesting that chaperones sequester the polyisoprene lipid from the aqueous environment. In this study, we analyze the nature of the pool of endogenous Ras proteins found in the cytosol. The majority of the pool consists of farnesylated, but not palmitoylated, N-Ras that is associated with a high molecular weight (HMW) complex. Affinity purification and mass spectrographic identification revealed that among the proteins found in the HMW fraction is VPS35, a latent cytosolic component of the retromer coat. VPS35 bound to N-Ras in a farnesyl-dependent, but neither palmitoyl- nor guanosine triphosphate (GTP)–dependent, fashion. Silencing VPS35 increased N-Ras’s association with cytoplasmic vesicles, diminished GTP loading of Ras, and inhibited mitogen-activated protein kinase signaling and growth of N-Ras–dependent melanoma cells.

The three human RAS genes encode four proteins that play central roles in oncogenesis by acting as binary molecular switches that regulate signaling pathways for growth and differentiation. Each is subject to a set of post-translational modifications (PTMs) that modify their activity or are required for membrane targeting. The enzymes that catalyze the various PTMs are potential targets for anti-RAS drug discovery. The PTMs of RAS proteins are the focus of this review.

The most frequently mutated oncogene in cancer is KRAS, which uses alternative fourth exons to generate two gene products (KRAS4A and KRAS4B) that differ only in their C-terminal membrane-targeting region1. Because oncogenic mutations occur in exons 2 or 3, two constitutively active KRAS proteins-each capable of transforming cells-are encoded when KRAS is activated by mutation2. No functional distinctions among the splice variants have so far been established. Oncogenic KRAS alters the metabolism of tumour cells3 in several ways, including increased glucose uptake and glycolysis even in the presence of abundant oxygen4 (the Warburg effect). Whereas these metabolic effects of oncogenic KRAS have been explained by transcriptional upregulation of glucose transporters and glycolytic enzymes3-5, it is not known whether there is direct regulation of metabolic enzymes. Here we report a direct, GTP-dependent interaction between KRAS4A and hexokinase 1 (HK1) that alters the activity of the kinase, and thereby establish that HK1 is an effector of KRAS4A. This interaction is unique to KRAS4A because the palmitoylation-depalmitoylation cycle of this RAS isoform enables colocalization with HK1 on the outer mitochondrial membrane. The expression of KRAS4A in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically.

Single-vehicle (SV) crashes are of major concerns because of their high fatality rates. To understand the proneness of high injury severity for vehicle operators brought about by SV crashes without the confounding influence of other road users, this study focuses on those SV crashes without colliding with pedestrians, which are defined as out-of-control SV crashes given the general consequence of involved vehicles. Moreover, to compare the influence of contributory factors (including driver-vehicle/rider-vehicle, roadway, and environmental characteristics) by vehicle types, the injury severity for riders of motorized two-wheelers and drivers of other motorized vehicles are investigated separately using two disaggregated ordered probit models. The results show that for both riders and drivers, variables such as age (65 and above), drink driving, error type of failing to have proper control, driving maneuvers of left and right turns as well as driving after midnight are associated with more severe injuries whereas factors such as wet, oily or sandy surfaces are related to less severe injury. Four other variables, i.e., foreign vehicle registration, probation or expired license, high speed-limit roads, and type of median lane, have different influences on riders and drivers on injury severity. Additionally, factors such as road traffic type and nationality are only found to significantly influence only riders and drivers respectively. The results shed light on both the similar and different causes of high injury severity for riders and drivers involved in out-of-control SV crashes. Based on the findings, targeted countermeasures may be introduced from multiple perspectives such as driver education and policy development to improve non-traffic-interactive safety.

Background: Research on the changes to knee structures in asymptomatic amateur ice hockey players (AAIHPs) has been limited. We aimed to assess the performance of the knees in AAIHPs using 3.0-T magnetic resonance imaging (MRI). Methods: A total of 71 asymptomatic knees (32 AAIHPs and 39 age- and sex-matched controls) were imaged using a 3.0-T MRI scanner at the Affiliated Zhongshan Hospital of Dalian University in April 2017. Two experienced musculoskeletal radiologists were blinded to assess all MRI findings, including bursae around the knee, bone marrow edema (BME), meniscal signal changes, and articular cartilage and ligament damage. Any disagreements were resolved by a third professor of musculoskeletal radiology. Categorical variables were compared using the Chi-square test and continuous variables using the Student’s t-test or Mann-Whitney U-test. Results: The most common finding was fluid-filled bursae surrounding the knee. In the AAIHP group, which totaled 32 knees and 416 bursae, 155 (37%) fluid-filled bursae were present. In the control group, there were a total of 39 knees and 507 bursae, and 91 (18%) fluid-filled bursae were present. There was a significant difference in the number of fluid-filled bursae between the two groups (P < 0.05). However, in AAIHPs, the prevalence of meniscal signal changes (16 knees, 50%) was higher than in the control group (2 knees, 5%; P < 0.001). Importantly, 15 of the 19 were grade II signals. Other changes were only found in AAIHPs. Articular cartilage lesions were detected in 47% of their knees, predominantly at the patellofemoral joint, and BME was found in 34% of their knees. Conclusion: The MRI findings of knees in AAIHPs mainly manifested as self-protection reaction, and proper ice hockey exercise could be advocated. Key words: Articular; Cartilage; Hockey; Knee; Magnetic Resonance Imaging; Meniscus

The accumulation characteristics and potential risk posed by polycyclic aromatic hydrocarbons (PAHs) in soils and vegetables grown in the home garden and agricultural field were investigated in this research. The average concentrations of 16 PAHs in soils and vegetables in the home garden were 508.9 ng/g and 197.3 ng/g, respectively, and in agricultural fields were 589.9 ng/g and 171.3 ng/g, respectively. The 16 PAHs concentrations of vegetables in the home garden were a little higher than in agricultural field. The most abundant PAHs in soils and vegetables was Phe, followed by Fla and Pyr in our study area. The concentrations of low-molecular-weight PAHs (L-PAHs) were higher in vegetables as compared to higher molecular weight 4–6 ring PAHs (H-PAHs). The results of plant concentration factor (PCF) indicated that L-PAHs have greater mobility in our research. Based on the results of PAH ratios, the main sources of the PAHs in soils were determined to be the combustion of biomass, coal, and petroleum. The total values of incremental lifetime cancer risk (ILCR) for males and females induced by soils and vegetables in home garden and agricultural field were all about 10−7 and 10−10. All the ILCRs value were lower than the baseline value, indicated that the carcinogenic risk for the soils and vegetables contaminated with PAHs in our study area for the residents was negligible.

Background Routine childhood immunization coverage has been low in northern Nigeria. While local authorities and international partners have been working hard to improve coverage, population preferences for interventions have not been documented. This study aimed to understand parents’ preferences and identify possible interventions to improve uptake of childhood immunization. Methods Preferences for immunization interventions were elicited using a best-worst scaling (BWS) instrument among parents with children under five. We explored the value of six program attributes (each varying across three levels) identified through a literature review and engagement with local stakeholders. In each of 18 hypothetical programs identified through a main effect orthogonal design, respondents selected the best and worst attributes that may facilitate vaccination of children. Assuming sequential best-worst responses, we used conditional logit to estimate preferences. We employed latent class analysis (LCA) to categorize and examine respondents’ preferences across interventions. Results 97 men and 101 women in 198 households were surveyed. The most preferred level for each attribute included door-to-door vaccinations, free food supplements, bundling with nutritional support programs, involvement of religious leaders, information dissemination through media campaigns, and strengthening of health services by the government. Three types of preferences were recognized in the LCA. The value-driven group (14%) characterized by youngest age, predominantly female, and lower education perceived bundled services with food and nutritional programs as the most important feature of an intervention. Convenience and information seekers (28%) characterized by oldest age and the lowest employment preferred door-to-door vaccinations and media campaigns. The remaining complacent group (58%), characterized by highest education and highest employment, did not show strong preferences to any intervention compared to the other two groups. Conclusions Routine immunization programs should consider joining forces with food and nutritional programs to improve vaccination uptake. Incorporating door-to-door visits and media campaigns to target older and unemployed populations may increase childhood immunization uptake in northern Nigeria.

The concentration, composition, sources and incremental lifetime cancer risk of farmland soil polycyclic aromatic hydrocarbons (PAHs) of the Yinma River Basin were analyzed. In 2016, the total concentration of 16 PAHs ranged from 491.65 to 1007.73 ng/g in May, from 427.31 to 781.38 ng/g in August and from 580.40 to 999.40 ng/g in November, respectively. Levels of seven potentially carcinogenic PAHs generally accounted for 33–36.7% of total 16 PAHs in three seasons, and the PAHs contained two to six rings, mainly Fla, Pyr, and Chr. The correlation analysis suggested that the soil organic matter (SOM) was no correlation with PAHs except for August, and there were no significant relationship between the pH and total PAHs. Isomer ratios indicated that the soil PAHs in the farmland of the Yinma River Basin was determined to be the combustion of coal, biomass, and petroleum. The toxic equivalent (BaPeq) concentrations ranged from 15.2 to 133 ng BaPeq g−1 in three seasons. The 95th percentiles of incremental lifetime cancer risk (ILCR) due to human exposure to farmland soil PAHs of the Yinma River Basin was (1.36 × 10−6) in May, (1.00 × 10−6) in August, and (1.18 × 10−6) in November for children, (1.10 × 10−6) in May, (8.15 × 10−7) in August, and (9.58 × 10−7) in November for adolescence and (1.61 × 10−6) in May, (4.22 × 10−6) in August and (1.40 × 10−6) in November for adulthood. The result indicated a moderate carcinogenic risk and the risk of exposure to farmland soil PAHs was pervasive for residents. This investigation might provide useful information on human exposure to PAHs in soil of the Yinma River Basin, and is valuable for policy makers and scientists.

The two products of the KRAS locus, K-Ras4A and K-Ras4B, are encoded by alternative fourth exons and therefore, possess distinct membrane-targeting sequences. The common activating mutations occur in exons 1 or 2 and therefore, render both splice variants oncogenic. K-Ras4A has been understudied, because it has been considered a minor splice variant. By priming off of the splice junction, we developed a quantitative RT-PCR assay for K-Ras4A and K-Ras4B message capable of measuring absolute amounts of the two transcripts. We found that K-Ras4A was widely expressed in 30 of 30 human cancer cell lines and amounts equal to K-Ras4B in 17 human colorectal tumors. Using splice variant-specific antibodies, we detected K-Ras4A protein in several tumor cell lines at a level equal to or greater than that of K-Ras4B. In addition to the CAAX motif, the C terminus of K-Ras4A contains a site of palmitoylation as well as a bipartite polybasic region. Although both were required for maximal efficiency, each of these could independently deliver K-Ras4A to the plasma membrane. Thus, among four Ras proteins, K-Ras4A is unique in possessing a dual membrane-targeting motif. We also found that, unlike K-Ras4B, K-Ras4A does not bind to the cytosolic chaperone δ-subunit of cGMP phosphodiesterase type 6 (PDE6δ). We conclude that efforts to develop anti-K-Ras drugs that interfere with membrane trafficking will have to take into account the distinct modes of targeting of the two K-Ras splice variants.

A number of studies on motor vehicle crashes have suggested that older drivers are more likely to be at-fault compared to younger drivers. The objective of this paper is to identify factors that contribute to older drivers (aged 65 and above) being at fault in light vehicle crashes in Singapore. Based on 3 years of crash data, the calibrated binary logit model shows that older drivers are more likely to be at fault during peak periods and festive seasons between November to February, as well as at gore areas of expressways, intersections. Curb lanes of multi-lane roads and single-lane roads are also found to increase the odds of older drivers being at fault. Furthermore, older drivers appear to have more problems on roads with wet surfaces and speed limits of 60 km/h and 70 km/h. In the light of an aging population in Singapore, it is imperative that more targeted countermeasures be taken from multiple perspectives to lower such risks.

Study on the occurrence, sources and potential human health risk of polycyclic aromatic hydrocarbons in farmland soils around reservoirs is of great significance for the people drinking water security. In the present study, representative farmland soil samples around main reservoirs of Jilin Province, China, were investigated for 16 PAHs. The total concentrations of 16 priority PAHs in 32 farmland soil samples ranged from 602.12 to 1271.87 ng/g, with an arithmetic average of 877.23 ng/g, and the sum of seven carcinogenic PAH concentrations ranged from 30.07 to 710.02 ng/g, with a mean value of 229.04 ng/g. The 3-ring and 4-ring PAHs were major exist and account for 45.78 and 32.03%, respectively. Non-cancer and cancer risk of pollutants were calculated, and the results indicate that the complex PAHs in farmland soils were not considered to pose significant health effects. The isomer ratios Fla/(Fla + Pyr) and BaA/(BaA + Chr) show that the PAHs in soils were generally derived from biomass and coal combustion.

Ras is the best-studied member of the superfamily of small GTPases because of its role in cancer. Ras proteins transmit signals for proliferation, differentiation and survival. Three RAS genes encode 4 isoforms. All Ras isoforms have long been considered membrane bound, a localization required for function. Our recent study revealed that N-Ras differs from all other isoforms in being largely cytosolic even following modification with a prenyl lipid. Endogenous, cytosolic N-Ras chromatographed in both high and low molecular weight pools, a pattern that required prenylation, suggesting prenyl-dependent interaction with other proteins. VPS35, a coat protein of the retromer, was shown to interact with prenylated N-Ras in the cytosol. Silencing VPS35 results in partial N-Ras mislocalization on vesicular and tubulovesicular structures, reduced GTP-loading of Ras proteins, and inhibited proliferation and MAPK signaling in an oncogenic N-Ras-driven tumor cell line. Our data revealed a novel regulator of N-Ras trafficking and signaling.

Background Research and clinical applications have demonstrated that the effects of tendon allografts are comparable to those of autografts when reconstructing injured tendons or ligaments, but allograft safety remains problematic. Sterilisation could eliminate or decrease the possibility of disease transmission, but current methods seldom achieve satisfactory sterilisation without affecting the mechanical properties of the tendon. Hypothesis Peracetic acid-ethanol in combination with low-dose gamma irradiation (PE-R) would inactivate potential deleterious microorganisms without affecting mechanical and biocompatible properties of tendon allograft. Study design Controlled laboratory design. Methods HIV, PPV, PRV and BVDV inactivation was evaluated. After verifying viral inactivation, the treated tendon allografts were characterised by optical microscopy, scanning electron microscopy and tensile testing, and the cytocompatibility was assessed with an MTT assay and by subcutaneous implantation. Results Effective and efficient inactivation of HIV, PPV, PRV and BVDV was observed. Histological structure and ultrastructure were unchanged in the treated tendon allograft, which also exhibited comparable biomechanical properties and good biocompatibility. Conclusion The preliminary results confirmed our hypothesis and demonstrated that the PE-R tendon allograft has significant potential as an alternative to ligament/tendon reconstruction. Clinical relevance Tendon allografts have been extensively used in ligament reconstruction and tendon repair. However, current sterilisation methods have various shortcomings, so PE-R has been proposed. This study suggests that PE-R tendon allograft has great potential as an alternative for ligament/tendon reconstruction. What is known about this subject Sterilisation has been a great concern for tendon allografts. However, most sterilisation methods cannot inactivate viruses and bacteria without impairing the mechanical properties of the tendon allograft. What this study adds to existing knowledge Peracetic acid/ethanol with gamma irradiation can effectively inactivate viruses and bacteria. Meanwhile, tendon allografts sterilised by this method maintain their physiological tendon structure, biomechanical integrity and good compatibility.

Before 1986, the development of tissue banking in China has been slow and relatively uncoordinated. Under the support of International Atomic Energy Agency (IAEA), Tissue Banking in China experienced rapid development. In this period, China Institute for Radiation Protection tissue bank mastered systematic and modern tissue banking technique by IAEA training course and gradually developed the first regional tissue bank (Shanxi Provincial Tissue Bank, SPTB) to provide tissue allograft. Benefit from training course, SPTB promoted the development of tissue transplantation by ways of training, brochure, advertisement and meeting. Tissue allograft transplantation acquired recognition from clinic and supervision and administration from government. Quality system gradually is developing and perfecting. Tissue allograft transplantation and tissue bank are developing rapidly and healthy.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with complex genetic predisposing factors involved. ITGAM and FCγRIIIA are two kinds of immune complex clearance molecules. The variants in ITGAM and FCγRIIIA genes have been confirmed to be associated with SLE. The aim of this study is to investigate the association of mRNA expression levels of ITGAM and FCγRIIIA with SLE. Real-time transcription-polymerase chain reaction analysis (RT-PCR) was used to determine the expression levels of ITGAM and FCγRIIIA mRNA in peripheral blood mononuclear cells (PBMC) from 60 patients with SLE and 60 healthy controls. Flow cytometry was used to measure the expression level of ITGAM and FcγRIIIA from 30 SLE patients and 30 healthy controls. The expression levels of ITGAM mRNA was significantly decreased in SLE patients compared with healthy controls (P = 0.007). Patients with arthritis had higher ITGAM mRNA level than those without arthritis (P = 0.029). The expression level of FCγRIIIA mRNA in SLE patients was significantly lower than that of healthy controls (P = 0.001). Decreased expression level of FCγRIIIA mRNA was also found in patients with LN compared with those without LN (P = 0.015). The level of ITGAM mRNA in patients with anti-SSB positive, anti-RNP positive, complement reduction and increased IgG was significantly reduced. No significant correlation was found between ITGAM and FcγRIIIA mRNA expression level in SLE patients (r = -0.019, P = 0.882). Expression of ITGAM protein in T cells, neutrophil and monocyte of SLE patients was significantly lower than healthy controls (P0.05). For FcγRIIIA protein expression in monocyte and NK cells, there were no significant difference between SLE patients and healthy controls (P0.05). The altered expression levels of ITGAM and FCγRIIIA mRNA in SLE patients and their correlations with clinical data suggest that ITGAM and FCγRIIIA may play a role in this disease.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by excessive production of a variety of autoantibodies, accumulation of immune complexes, and multiple organ systems involvement. Interleukin-10 (IL-10) has an important role in the growth, survival, differentiation, and function of B cells. Abnormally increased IL-10 synthesis seems contributing to the spontaneous hyperactivity of the B cell compartment, so that it can directly result in autoantibody production by committed plasma cells, circulating immune complexes formation, and eventually in tissue and organ damage, suggesting it might associate with the development of SLE. A better understanding of the regulation of IL-10 and its receptors (IL-10R) can likely provide more valuable clues to the pathogenic mechanisms underlying specific forms of SLE, so as to pave the way toward more effective therapeutics.

Objective: The interleukin-10 (IL-10) gene polymorphism (–1082A/G) has been shown to be associated with systemic lupus erythematosus (SLE), but findings are not consistent across studies. The aim of our meta-analysis was to assess the association between the –1082A/G polymorphism in the IL-10 gene and SLE. Methods: We searched all publications on the association between the IL-10 (−1082A/G) polymorphism and SLE in PubMed, Elsevier Science Direct, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI) and Wanfang (Chinese). Meta-analysis was conducted using software Stata version 10.1. Meta-odds ratios (ORs) and 95% confidence intervals (CIs) based on fixed-/random-effects models depended on Cochran’s Q-statistic and I2 values. Results: A total of 17 studies with 2396 cases and 3653 controls were included in this meta-analysis. Meta-analysis was performed for genotypes GG versus AA, GG + AG versus AA, GG versus AG + AA, and G allele versus A allele. Significant differences were found in genotype distribution between SLE and normal controls in whole-population GG versus AA (OR = 1.428, 95% CI = 1.006–2.208). Similar results were detected in the dominant genetics effect of the G allele (OR = 1.202, 95% CI = 1.030–1.403). No significant association was found in allele distribution in whole-population G versus A (OR = 1.125, 95% CI = 0.998–1.269). In subgroup analysis by ethnicity, significant association was found when GG + AG versus AA was performed in a European population (OR = 1.240, 95% CI = 1.022–1.503) and GG versus AG + AA was performed in an Asian population (OR = 3.596, 95% CI = 1.389–9.311). Significant association was found between genotype distribution in Asians (OR = 4.491, 95% CI = 1.552–13.000). Publication year was detected as the source of heterogeneity. In the stratified analysis by publication year, the pooled OR was 1.049 (95% CI = 0.940–1.171; Pheterogeneity = 0.431; I2 = 0.4%) in subgroup 1 (publication years 1999–2004). No significant association was found between the IL-10 (−1082 G) allele and SLE in subgroup 1 ( Z = 0.85, p = 0.431). In subgroup 2 (publication years 2005–2011), the pooled OR was 1.327 (95% CI = 1.125–1.565; Pheterogeneity = 0.143; I2 = 35.8%). Significant association was found between the IL-10 (−1082 G) allele and SLE ( Z = 3.36, p = 0.001). Conclusions: This meta-analysis demonstrates the association between the IL-10 (−1082A/G) polymorphism and SLE. However, further studies are needed for a definitive conclusion.

The RANTES (regulated on activation normal T cell expressed and secreted) and MBL (mannose binding lectin) single-nucleotide polymorphisms have been repeatedly associated with systemic lupus erythematosus (SLE), but the findings are not consistent across studies. The aim of this study was to determine whether the functional RANTES-28, -403 and MBL2 A/O polymorphisms confer susceptibility to SLE in multiple ethnic populations. A meta-analysis was conducted (allelic contrast, the additive model, the dominant model and the recessive model) on RANTES with seven studies (four studies for RANTES-28: three Asian and one American studies; three studies for RANTES-403: two Asian and one European studies), MBL with eight studies (five European and three American studies). OR is used as a measure of the effect of the association in a fixed/random effects model. The meta-analysis indicated that none of the two polymorphisms in gene of the RANTES showed any significant association with SLE risk, respectively, except for the recessive model (OR = 1.24, 95 % CI: 1.01-1.52, P = 0.04) in all study subjects combined with the two polymorphisms. According to the MBL2 A/O polymorphism, the results indicated a significant association between the polymorphism and SLE in allelic contrast (OR = 0.83, 95 % CI: 0.73-0.93, P = 0.002). While stratified by ethnicity in European, no significant association was found. In summary, the present study suggests that the RANTES-28, -403 polymorphisms do not associate with SLE, but the MBL2 A/O polymorphism might associate with SLE.

The aim of this study was to evaluate whether two single-nucleotide polymorphisms (SNPs), AF4/FMR2 family, member 1 (AFF1) rs340630 and AF4/FMR2 family, member 3 (AFF3) rs10865035, show significant evidence for association with systemic lupus erythematosus (SLE) in a Chinese population. A total of 868 Chinese patients with SLE and 975 geographically and ethnically matched healthy control subjects were enrolled in the current study. The genotypes of these two SNPs were determined by Sequenom MassArray technology. Significant evidence for association of AFF3 rs10865035 with SLE was detected (for A versus G, P = 4.81 × 10(-4), odds ratio (OR) 1.26, 95% confidence interval (95% CI) 1.11-1.44). However, no association between AFF1 rs340630 and SLE was found in the Chinese population (for A versus G, P = 0.79, OR 0.98, 95% CI 0.86-1.12). No significant evidence for association of AFF3 rs10865035 polymorphism with any clinical features was detected. By targeting a variant with convincing evidence for association with rheumatoid arthritis, significant association of AFF3 rs10865035 with SLE was detected in the Chinese population, indicating that AFF3 might be a common autoimmunity gene. Further case-control studies based on larger sample sizes in diverse ethnic populations are required to clarify the role of AFF1 rs340630 in SLE.

// Ming Yang 1, * , Haiyong Wang 1, * , Mo Zhou 1, * , Weilin Liu 1 , Pengqun Kuang 1 , Hao Liang 1 , Qipeng Yuan 1 1 State Key Laboratory of Chemical Resource Engineering, Beijing Laboratory of Biomedical Materials, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China * These authors contributed equally to this work Correspondence to: Qipeng Yuan, email: yuanqp@mail.buct.edu.cn Keywords: sulforaphene, lung cancer, isothiocyanate, PI3K-AKT Received: December 03, 2015 Accepted: September 12, 2016 Published: September 28, 2016 ABSTRACT Lung cancer is one of the leading causes of cancer death worldwide. Isothiocyanates from cruciferous vegetables been shown to possess anticarcinogenic activities in lung malignances. We previously found sulforaphene (4-methylsufinyl-3-butenyl isothiocyanate, SFE), one new kind of isothiocyanates, existing in a relative high abundance in radish seeds. An efficient methodology based on macroporous resin and preparative high-performance liquid chromatography was developed to isolate SFE in reasonably large quantities, high purity and low cost. However, it is still largely unclear whether SFE could function as an antineoplastic compound, especially in lung cancer. In this study, we systematically investigated the anti-cancer effects of SFE in vitro as well as its possible underling molecular mechanisms in lung cancer. The acute toxicity tests and pharmacokinetics tests for SFE were performed to evaluate its drugability in mice. Also, we evaluated the in vivo anti-cancer effects of SFE using nude Balb/C mice with lung cancer xenograft. SFE can induce apoptosis of multiple lung cancer celllines and, thus, inhibited cancer cell proliferation. Lung cancer cells treated with SFE exhibit significant inhibition of the PI3K-AKT signaling pathway, including depressed PTEN expression and inhibition of AKT phosphoralation. At well-tolerated doses, administration of SFE to mice bearing lung cancer xenografts leads to significant inhibitions of tumor growth. In summary, our work identifies SFE as a novel natural broad-spectrum small molecule inhibitor for lung cancer.

In an attempt to improve the antitumor activity and reduce the side effects of irinotecan (2), novel prodrugs of SN-38 (3) were prepared by conjugating amino acids or dipeptides to the 10-hydroxyl group of SN-38 via a carbamate linkage. The synthesized compounds completely generated SN-38 in pH 7.4 buffer or in human plasma, while remaining stable under acidic conditions. All prodrug compounds demonstrated much greater in vitro antitumor activities against HeLa cells and SGC-7901 cells than irinotecan. The most active compounds, 5h, 7c, 7d, and 7f, exhibited IC50 values that were 1000 times lower against HeLa cells and 30 times lower against SGC-7901 cells than those of irinotecan, and the inhibitory activities of these prodrugs against acetylcholinesterase (AchE) were significantly reduced, with IC50 values more than 6.8 times greater than that of irinotecan. In addition, compound 5e exhibited the same level of tumor growth inhibitory activity as irinotecan (CPT-11) in a human colon xenograft model in vivo.

Published data on the associations between interleukin-4 receptor (IL-4R) gene polymorphisms (Q551R, I50V) and rheumatoid arthritis (RA) risk are controversial. To quantitatively evaluate the relationships, a meta-analysis was performed.Studies were identified from the databases of PubMed, MEDLINE, Chinese Biomedical Literature Database, and Chinese National Knowledge Infrastructure, with the last report up to June 2012. The effect summary odds ratio (OR) and 95% confidence interval (CI) were obtained.A total of six separate comparisons involving 2173 patients and 1892 controls were included to assess the association of IL-4R gene Q551R polymorphism and RA susceptibility. Overall, no significantly elevated RA risk was found in the meta-analysis. The pooled OR for the minor R allele was 0.942 (95% CI: 0.848-1.047, p=0.268) in patients with RA. After stratification by ethnicity, there was still no significant association detected in the European population (OR=0.979, 95% CI: 0.875-1.094). As for I50V polymorphism, there were four comparisons involving 1653 patients and 1584 controls in this meta-analysis. The pooled OR for the V allele was 1.104 (95% CI: 1.001-1.217) in RA, the V allele of the IL-4R gene I50V variant might be a risk factor for RA. However, the relationship between the V allele of IL-4R gene I50V polymorphism and rheumatoid factor positive in patients with RA was not identified through a minor meta-analysis, including four independent relevant comparisons.This meta-analysis indicates that the I50V polymorphism of IL-4R gene may confer susceptibility to RA; up to now, there is still not enough evidence to reveal the association of the IL-4R gene Q551R polymorphism with RA risk.

Several polymorphisms in the interleukin-18 (IL-18) and nterleukin-28B (IL-28B) genes have been reported to influence hepatitis B virus (HBV) infection. However, the published findings have been conflicting. We conducted meta-analyses of randomized, controlled trials to address the association of IL-18 or IL-28B polymorphisms and the outcomes of HBV infection. Weipu, Wanfang, CNKI, MEDLINE, PubMed, EMBASE, and Cochrane Library databases were employed to search for citations using the MeSH terms as “interleukin-18”/“interleukin-28B” AND “HBV” AND “gene” AND “polymorphism” without any restriction in language and publication year. Meta-analysis was conducted by RevMan 5.0 software. The results showed that the IL28B rs8099917 AA genotype (AA vs AC + CC: odds ratio (OR) = 0.63, 95 % confidence interval (CI) = 0.46–0.87) was associated with a decreased risk of hepatocellular carcinoma (HCC). Carriage of IL28B rs12979860 CC genotype was associated with an increased risk for developing liver cirrhosis among patients with HBV infection (CC vs CT + TT: OR = 1.39, 95 % CI = 1.04–1.85). Further well-designed large studies are warranted to confirm the mechanisms by which these are involved in these outcomes of HBV infection.

Interleukin-10 (IL-10) is a pleiotropic cytokine and plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Unlike IL-10 protein, few studies have focused on the potential association between IL-10 receptor (IL-10R) and SLE. The purpose of this study was to examine the association of a single nucleotide polymorphism, rs2834167 (A/G), in IL-10R2 gene (IL-10RB) with SLE in a Chinese Han population. A total of 667 patients with SLE and 676 healthy controls were enrolled in the present study. IL-10RB rs2834167 (A/G) polymorphism was specified from genomic DNA using TaqMan genotyping assay on a 7300 real-time reverse transcription polymerase chain reaction system. We found that the frequency of A allele for rs2834167 in patients (44.53 %) was significantly higher than in controls (40.16 %) (χ 2 = 5.24, P = 0.022). Allele A was associated with a 1.196-fold (95 % confidence interval (CI), 1.026–1.394) greater risk for the occurrence of SLE compared with the G allele. And both genotypes AG and AA were associated with the susceptibility to SLE as compared with the GG genotype (AG versus GG, odds ratio (OR) = 1.332; 95 %CI, 1.047–1.696; AA versus GG, OR = 1.373; 95 %CI, 1.004–1.878). We also found a statistical significance in the dominant model (AA + AG versus GG, OR = 1.343; 95 %CI, 1.070–1.687). However, no significant evidence for the association of IL-10RB rs2834167 (A/G) polymorphism with any clinical manifestations was detected. Our observations indicate that IL-10RB rs2834167 (A/G) polymorphism may be a potential biomarker for susceptibility to SLE.

The aim to this study was to investigate the association between the single-nucleotide polymorphisms (SNPs) of interleukin (IL)-23 receptor gene and systemic lupus erythematosus (SLE) in a Chinese population. A case–control study was performed to investigate the associations of SNPs in IL-23R gene (rs10889677 and rs1884444) with susceptibility to SLE in 521 Chinese SLE patients and 527 normal controls. The chi-square test and unconditional Logistic regression were used to analysis by SPSS 10.1 software. No significant differences were detected for the distribution of allele and genotype frequencies of these two SNPs between patients and controls as well as SLE patients with nephritis (LN) and those without nephritis. The findings suggest that the polymorphisms of IL-23R gene might not contribute to the susceptibility of SLE in the Chinese population.