Successful management of camrelizumab-induced immune-checkpoint-inhibitors-related myocarditis.

INTRODUCTION: Immune checkpoint inhibitors can cause immune-related toxicity in various systems, with myocarditis being the most severe and life-threatening manifestation. This report presents a case in which myocarditis developed following administration of programmed cell death protein-1 (PD-1) inhibitors therapy. We describe the diagnosis and treatment of this patient in detail. CASE REPORT: We present the case of a 59-year-old female diagnosed with post-operative esophageal cancer and hepatic metastases. The patient underwent second-line treatment with domestically-made PD-1 inhibitor, camrelizumab, in combination with paclitaxel (albumin-bound) and carboplatin for two cycles. During the course of treatment, an electrocardiogram (ECG) revealed ST segment elevation in leads II, III, aVF, V2, V3, and V4, along with T wave changes in leads I and aVL. Laboratory examinations showed abnormal levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT). Despite the absence of clinical symptoms, the patient was routinely hospitalized three weeks later. Based on the findings from the ECG, cardiac biomarkers, echocardiography, echocardiogram, cardiac magnetic resonance, and angiography, she was diagnosed with immune-checkpoint-inhibitors-related myocarditis. MANAGEMENT AND OUTCOME: The patient received immunoglobulin (0.5 g/kg/day) and was initially given methylprednisolone (1000 mg/day). Methylprednisolone was gradually reduced to 40 mg/day in 2 weeks. During this time, the levels of biomarkers indicative of myocardial injury also exhibited a simultaneous decline. DISCUSSION: This case highlights the importance of early detection and prompt intervention, including initiating appropriate steroid therapy and discontinuing of immune checkpoint inhibitors. Such measures can effectively prevent morbidity and mortality, ultimately leading to an improved prognosis.

Construction and validation of a predictive model for postoperative urinary retention after lumbar interbody fusion surgery.

BACKGROUND: Postoperative urine retention (POUR) after lumbar interbody fusion surgery may lead to recatheterization and prolonged hospitalization. In this study, a predictive model was constructed and validated. The objective was to provide a nomogram for estimating the risk of POUR and then reducing the incidence. METHODS: A total of 423 cases of lumbar fusion surgery were included; 65 of these cases developed POUR, an incidence of 15.4%. The dataset is divided into a training set and a validation set according to time. 18 candidate variables were selected. The candidate variables were screened through LASSO regression. The stepwise regression and random forest analysis were then conducted to construct the predictive model and draw a nomogram. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve and the calibration curve were used to evaluate the predictive effect of the model. RESULTS: The best lambda value in LASSO was 0.025082; according to this, five significant variables were screened, including age, smoking history, surgical method, operative time, and visual analog scale (VAS) score of postoperative low back pain. A predictive model containing four variables was constructed by stepwise regression. The variables included age (ß = 0.047, OR = 1.048), smoking history (ß = 1.950, OR = 7.031), operative time (ß = 0.022, OR = 1.022), and postoperative VAS score of low back pain (ß = 2.554, OR = 12.858). A nomogram was drawn based on the results. The AUC of the ROC curve of the training set was 0.891, the validation set was 0.854 in the stepwise regression model. The calibration curves of the training set and validation set are in good agreement with the actual curves, showing that the stepwise regression model has good prediction ability. The AUC of the training set was 0.996, and that of the verification set was 0.856 in the random forest model. CONCLUSION: This study developed and internally validated a new nomogram and a random forest model for predicting the risk of POUR after lumbar interbody fusion surgery. Both of the nomogram and the random forest model have high accuracy in this study.

Effects of elevated carbon dioxide (CO2)and ozone (O3)concentrations on ectoenzyme activities in rice rhizospheric soil.

Rising atmospheric carbon dioxide (CO2) and ozone (O3) concentrations are the main global change drivers. Soil ectoenzymes play an important role in maintaining soil ecosystem services. Exploring the responses of soil ectoenzymes to elevated CO2 and O3 concentrations is important for combating global climate change. In this study, we simulated elevated CO2 concentrations (+200 µmol·mol-1, eCO2), elevated O3 concentrations (0.04 µmol·mol-1, eO3), and their combination (eCO2+eO3) in open-top chambers (OTCs), and investigated the responses of rhizospheric soil ectoenzyme activities. The results showed that eCO2 significantly increased the ß-D-Glucosidase (ßG) activity by 73.0%, and decreased that of polyphenol oxidase (PHO), peroxidase (PEO), and acid phosphatase (AP) by 48.9%, 46.6% and 72.9% respectively, but did not affect that of cellulose hydrolase (CBH) and ß-N-Acetylglucosaminidase (NAG). eO3 significantly reduced the activities of CBH and AP by 34.2% and 30.4%, respectively. The activities of PHO and AP were reduced by 87.3% and 32.3% under the eCO2+eO3 compared with the control, respectively. Results of the principal coordinate analysis, permutation multivariate analysis of variance and redundancy analysis showed that both elevated CO2 and O3 significantly affected soil ectoenzyme activities, with stronger effects of elevated CO2 than elevated O3. Root nitrogen content, root carbon to nitrogen ratio, soil microbial biomass carbon and nitrate nitrogen were the main drivers of soil ectoenzyme activities under elevated CO2 and O3. Elevated O3 could partially neutralize the effects of elevated CO2 on soil ectoenzyme activities. In conclusion, elevated CO2 and O3 restrained the activities of most soil ectoenzyme, suggesting that climate change would threat soil ecosystem services and functions in the agroecosystem.

DNA methylation loci identification for pan-cancer early-stage diagnosis and prognosis using a new distributed parallel partial least squares method.

Aberrant methylation is one of the early detectable events in many tumors, which is very promising for pan-cancer early-stage diagnosis and prognosis. To efficiently analyze the big pan-cancer methylation data and to overcome the co-methylation phenomenon, a MapReduce-based distributed and parallel-designed partial least squares approach was proposed. The large-scale high-dimensional methylation data were first decomposed into distributed blocks according to their genome locations. A distributed and parallel data processing strategy was proposed based on the framework of MapReduce, and then latent variables were further extracted for each distributed block. A set of pan-cancer signatures through a differential co-expression network followed by statistical tests was further identified based on their gene expression profiles. In total, 15 TCGA and 3 GEO datasets were used as the training and testing data, respectively, to verify our method. As a result, 22,000 potential methylation loci were selected as highly related loci with early-stage pan-cancer diagnosis. Of these, 67 methylation loci were further identified as pan-cancer signatures considering their gene expression as well. The survival analysis as well as pathway enrichment analysis on them shows that not only these loci may serve as potential drug targets, but also the proposed method may serve as a uniform framework for signature identification with big data.

Dulaglutide, a long-acting GLP-1 receptor agonist, can improve hyperandrogenemia and ovarian function in DHEA-induced PCOS rats.

OBJECTIVE: The purpose of this study was to explore the effect of dulaglutide on DHEA induced PCOS rats and its mechanism, to provide new drugs and research directions for clinical treatment of PCOS. METHODS: In this study, the PCOS model was established by giving female SD rats subcutaneous injection of DHEA for 21 consecutive days. After modeling, the treatment group was injected subcutaneously with three doses of dulaglutide for 3 weeks. The model group was injected with sterile ultrapure water, and the normal group did not get any intervention. The body weight changes of rats in each group were recorded from the first day when rats received the administration of dulaglutide. Three weeks later, the rats were fasted the night after the last treatment, determined fasting insulin and fasting glucose the next day. After the rats were anesthetized by chloral hydrate, more blood was collected from the heart of the rat. The serum insulin, testosterone and sex hormone binding globulin (SHBG) levels were detected by the enzyme-linked immunoassay method. After removing the adipose tissue, the obtained rat ovary tissue was used for subsequent experimental detection, using HE staining for morphology and follicular development analysis; qRT-PCR for the detection of 3ßHSD, CYP17α1, CYP19α1, and StAR gene expression in ovarian tissue; and western blotting analysis of CYP17α1, CYP19α1, StAR protein expression and insulin level to verify whether dulaglutide has a therapeutic effect on PCOS in rats. RESULTS: After treated with different concentrations of dulaglutide, we found that the body weight of rats in the treatment groups were reduced. Compared with the rats in PCOS group, the serum androgen level of rats in the treatment groups was significantly decreased, and the serum sex hormone binding protein content was significantly increased, and there was statistically significant difference between these groups and PCOS group. In terms of protein expression and gene regulation, the expression of 3ßHSD, CYP19α1 and StAR in the ovarian tissue of rats in treatment groups were decreased significantly after received the treatment of dulaglutide, and there was statistically significant difference between these groups and PCOS group. In addition, dulaglutide reduced the insulin content in the ovarian tissue of PCOS rats. CONCLUSION: Dulaglutide may reduce the hyperandrogenemia of PCOS rats by regulating the content of serum SHBG and the expression of 3ßHSD, CYP19α1, and StAR related genes and proteins, thereby inhibiting the excessive development of small follicles and the formation of cystic follicles in the ovaries of PCOS rats, thereby improving polycystic ovary in PCOS rats. In addition, dulaglutide may reduce the weight of PCOS rats, further reducing the level of high androgen in PCOS rats, and improving the morphology of their polycystic ovaries.

Cost-Effectiveness Analysis of Michigan's School-Wide Sexually Transmitted Disease Screening Program in Four Detroit High Schools.

PURPOSE: The Michigan Department of Health and Human Services, in collaboration with St. John Providence Health System, initiated voluntary school-wide sexually transmitted disease (STD) screenings in four Detroit public high schools. We sought to assess the cost-effectiveness of the STD screening program from 2010 to 2015, with a focus on chlamydia. METHODS: The costs and effectiveness of the school-based screening were compared with those of a "no school screening" scenario using a healthcare system perspective. A decision tree model was constructed to project cases of chlamydia, epididymitis, and pelvic inflammatory disease (PID) in each of the two scenarios among students tested positive and their partners. Health effects were measured as cases of PID prevented, and quality-adjusted life-years (QALYs) gained. Cost estimates included program costs, chlamydia testing/treatment costs in the absence of school screening, and treatment costs for epididymitis, PID, and PID sequelae. The incremental cost-effectiveness ratio (ICER) was measured as cost/QALY gained. Multivariate sensitivity analyses were conducted on key parameter estimates and assumptions used. RESULTS: Under base-case assumptions, at a total program cost of $333,848 over 5 years, the program prevented an estimated 1.9 cases of epididymitis and 17.3 cases of PID, resulting in an ICER of $38,235/QALY gained (yearly ICER ranging from $27,417 to $50,945/QALY). Of 10,000 Monte Carlo simulation runs, the yearly ICER remained ≤$50,000/QALY in 64%-98% of the simulation runs. CONCLUSIONS: We found favorable cost-effectiveness ratios for Michigan's school-wide STD screening program in Detroit. School-based STD screening programs of this type warrant careful considerations by policy makers and program planners.

Bioactive peptide apelin rescues acute kidney injury by protecting the function of renal tubular mitochondria.

Mitochondrial dysfunction in proximal tubular epithelial cells is a key event in acute kidney injury (AKI), which is a risk factor for the development of chronic kidney disease (CKD). Apelin is a bioactive peptide that protects against AKI by alleviating inflammation, inhibiting apoptosis, and preventing lipid oxidation, but its role in protecting against mitochondrial damage remains unknown. Herein, we examined the protective effects of apelin on mitochondria in cisplatin-stimulated human renal proximal tubular epithelial cells and evaluated its therapeutic efficacy in cisplatin-induced AKI mice. In vitro, apelin inhibited the cisplatin-induced mitochondrial fission factor (MFF) upregulation and the fusion-promoting protein optic atrophy 1 (OPA1) downregulation. Apelin co-treatment reversed the decreased levels of the deacetylase, Sirt3, and the increased levels of protein acetylation in mitochondria of cisplatin-stimulated cells. Overall, apelin improved the mitochondrial morphology and membrane potential in vitro. In the AKI model, apelin administration significantly attenuated mitochondrial damage, as evidenced by longer mitochondrial profiles and increased ATP levels in the renal cortex. Suppression of MFF expression, and maintenance of Sirt3 and OPA1 expression in apelin-treated AKI mice was also observed. Finally, exogenous administration of apelin normalized the serum level of creatinine and urea nitrogen and the urine levels of NGAL and Kim-1. We also confirmed a regulatory pathway that drives mitochondrial homeostasis including PGC-1α, ERRα and Sirt3. In conclusion, we demonstrated that apelin ameliorates renal functions by protecting tubular mitochondria through Sirt3 upregulation, which is a novel protective mechanism of apelin in AKI. These results suggest that apelin has potential renoprotective effects and may be an effective agent for AKI treatment to significantly retard CKD progression.

Effects of Condom Use on Human Immunodeficiency Virus Transmission Among Adolescent Sexual Minority Males in the United States: A Mixed Epidemiology and Epidemic Modeling Study.

BACKGROUND: We examined condom use patterns and potential population-level effects of a hypothetical condom intervention on human immunodeficiency virus (HIV) transmission among adolescent sexual minority males (ASMM). METHODS: Using 3 data sets: national Youth Risk Behavior Survey 2015 to 2017 (YRBS-National), local YRBS data from 8 jurisdictions with sex of partner questions from 2011 to 2017 (YRBS-Trends), and American Men's Internet Survey (AMIS) 2014 to 2017, we assessed associations of condom use with year, age, and race/ethnicity among sexually active ASMM. Using a stochastic agent-based network epidemic model, structured and parameterized based on the above analyses, we calculated the percent of HIV infections averted over 10 years among ASMM ages 13 to 18 years by an intervention that increased condom use by 37% for 5 years and was delivered to 62% of ASMM at age 14 years. RESULTS: In YRBS, 51.8% (95% confidence interval [CI], 41.3-62.3%) and 37.9% (95% CI, 32.7-42.3%) reported condom use at last sexual intercourse in national and trend data sets, respectively. In AMIS, 47.3% (95% CI, 44.6-49.9%) reported condom use at last anal sex with a male partner. Temporal trends were not observed in any data set (P > 0.1). Condom use varied significantly by age in YRBS-National (P < 0.0001) and YRBS-Trends (P = 0.032) with 13- to 15-year-olds reporting the lowest use in both; age differences were not significant in AMIS (P = 0.919). Our hypothetical intervention averted a mean of 9.0% (95% simulation interval, -5.4% to 21.2%) of infections among ASMM. CONCLUSIONS: Condom use among ASMM is low and appears to have remained stable during 2011 to 2017. Modeling suggests that condom use increases, consistent with previous interventions, have potential to avert 1 in 11 new HIV infections among ASMM.

Circular RNA CircCDYL Regulates Proliferation and Apoptosis in Non-Small Cell Lung Cancer Cells by Sponging miR-185-5p and Upregulating TNRC6A.

AIM: A series of research reveal that circular RNA (circRNA) plays a vital role in regulating the development of tumor cells. In this research, we would explore the role and mechanism of circCDYL in non-small cell lung cancer (NSCLC). METHODS: RT-PCR was performed to detect the expression of circCDYL in NSCLC tissues, plasma, and cell lines. The tumor cell proliferation ability was evaluated by clone formation assay, and cell cycle determination. Flow cytometry was used to detect apoptosis in NSCLC cell lines. Western blot and RT-PCR were used to assess the expression of proteins and genes. Luciferase assay was performed to confirm the relationship of circRNA-miRNA-mRNA. RESULTS: The decreased level of circCDYL was observed in NSCLC patients' tissues and plasma, which was also downregulated in NSCLC cell lines. Forced expression of circCDYL inhibited cell viability, proliferation and induced apoptosis in A549 cells. Luciferase assay verified that circCDYL could bind with miR-185-5p and confirmed that TNRC6A was a downstream target of miR-185-5p. Overexpression of miR-185-5p or silencing of TNRC6A could inhibit the anti-tumor effect of circCDYL in A549 cells via regulating the ERK1/2 signal. CONCLUSION: Here, we revealed that circCDYL inhibited proliferation and induced apoptosis in NSCLC cell lines via regulating ERK1/2 signal, and the mechanism of this progression may target miR-185-5p/TNRC6A, which provided a theoretical basis for clinical therapy.

Efficient, green, and rapid strategy for separating actinomycin D and X2 using supercritical fluid chromatography.

Actinomycin D has long been used as a first-line antitumor drug in clinical practice. Actinomycin X2, a new drug lead, is often isolated along with actinomycin D. The minor differences between the two actinomycin analogs pose a daunting challenge in separation. In this study, supercritical fluid chromatography (SFC) was successfully utilized for the purification of actinomycin X2 and actinomycin D from a marine derived Streptomyces sp. DQS-5. After one-step SFC purification, the purities of these two compounds were determined to be 97.3 % and 97.8 %, respectively. This method provides a green alternative for the separation of these pharmacologically important actinomycin antibiotics. This study also demonstrated the development of a simple and rapid method for the separation of natural products based on SFC.

Cost-Effectiveness of a School-Based Chlamydia Screening Program, Duval County, FL.

During the 2015-2016 school year, the Florida Department of Health in Duval County hosted Teen Health Centers (TeenHC) at five high schools of Jacksonville providing HIV/STD screening and pregnancy testing. The purpose of this study was to assess the cost-effectiveness of the TeenHC chlamydia screening program and determine at what student participation level, the program can be cost-effective. We assessed the costs and effectiveness of the chlamydia screening program compared with "no TeenHC". Cost-effectiveness was measured as cost per quality-adjusted life years (QALY) gained. At a program cost of US$61,001 and 3% participation rate, the cost/QALY gained was $124,328 in the base-case analysis and $81,014-$264,271 in 95% of the simulation trials, all greater than the frequently citied $50,000/QALY benchmark. The cost/QALY gained could be <$50,000/QALY if student participation rate was >7%. The TeenHC chlamydia screening has the potential to be cost-effective. Future program efforts should focus on improving student participation.

Mathematical modeling study of school-based chlamydia screening: potential impact on chlamydia prevalence in intervention schools and surrounding communities.

BACKGROUND: Chlamydia screening in high schools offers a way to reach adolescents outside of a traditional clinic setting. Using transmission dynamic modeling, we examined the potential impact of high-school-based chlamydia screening programs on the burden of infection within intervention schools and surrounding communities, under varying epidemiological and programmatic conditions. METHODS: A chlamydia transmission model was calibrated to epidemiological data from three different settings. Philadelphia and Chicago are two high-burden cities with existing school-based screening programs. Rural Iowa does not have an existing program but represents a low-burden setting. We modeled the effects of the two existing programs to analyze the potential influence of program coverage and student participation. All three settings were used to examine a broader set of hypothetical programs with varying coverage levels and time trends in participation. RESULTS: In the modeled Philadelphia program, prevalence among the intervention schools' sexually active 15-18 years old population was 4.34% (95% credible interval 3.75-4.71%)after 12 program years compared to 5.03% (4.39-5.43%) in absence of the program. In the modeled Chicago program, prevalence was estimated as 5.97% (2.60-7.88%) after 4 program years compared to 7.00% (3.08-9.29%) without the program. In the broader hypothetical scenarios including both high-burden and low-burden settings, impact of school-based screening programs was greater in absolute terms in the higher-prevalence settings, and benefits in the community were approximately proportional to population coverage of intervention schools. Most benefits were garnered if the student participation did not decline over time. CONCLUSIONS: Sustained high student participation in school-based screening programs and broad coverage of schools within a target community are likely needed to maximize program benefits in terms of reduced burden of chlamydia in the adolescent population.

lncRNA Signature for Predicting Cerebral Vasospasm in Patients with SAH: Implications for Precision Neurosurgery.

Subarachnoid hemorrhage (SAH) patients' surgery is performed to prevent extravasation of blood into the subarachnoid space. Cerebral vasospasm (CVS; narrowing of cerebral arteries) occurs following SAH and represents a major cause of associated mortality and morbidity. To improve postsurgery care of SAH patients and their prognosis, the ability to predict CVS onset is critical. We report a long noncoding RNA (lncRNA) signature to distinguish SAH patients with CVS from SAH patients without CVS. Cerebrospinal fluid (CSF) was obtained from SAH patients without CVS (n = 10) and SAH patients with CVS (n = 10). lncRNAs ZFAS1 and MALAT1 were significantly upregulated (p < 0.05), whereas lncRNAs LINC00261 and LINC01619 were significantly downregulated in SAH patients with CVS (p < 0.05) compared to SAH patients without CVS. We applied this lncRNA signature to retrospectively predict CVS in SAH patients (n = 38 for SAH patients without CVS, and n = 27 for SAH patients with CVS). The 4-lncRNA signature was found to be predictive in >40% of samples and the 2-lncRNA comprising MALAT1 and LINC01619 accurately predicted CVS in ∼90% cases. These results are initial steps toward personalized management of SAH patients in clinics and provide novel CSF biomarkers that can substantially improve the clinical management of SAH patients.

Mechanisms of resveratrol in the prevention and treatment of gastrointestinal cancer.

Gastrointestinal (GI) cancer is one of the leading causes of cancer-related deaths worldwide. According to the Global Cancer Statistics, colorectal cancer is the second leading cause of cancer-related mortality, closely followed by gastric cancer (GC). Environmental, dietary, and lifestyle factors including cigarette smoking, alcohol intake, and genetics are the most important risk factors for GI cancer. Furthermore, infections caused by Helicobacter pylori are a major cause of GC initiation. Despite improvements in conventional therapies, including surgery, chemotherapy, and radiotherapy, the length or quality of life of patients with advanced GI cancer is still poor because of delayed diagnosis, recurrence and side effect. Resveratrol (3, 4, 5-trihydroxy-trans-stilbene; Res), a natural polyphenolic compound, reportedly has various pharmacologic functions including anti-oxidant, anti-inflammatory, anti-cancer, and cardioprotective functions. Many studies have demonstrated that Res also exerts a chemopreventive effect on GI cancer. Research investigating the anti-cancer mechanism of Res for the prevention and treatment of GI cancer has implicated multiple pathways including oxidative stress, cell proliferation, and apoptosis. Therefore, this paper provides a review of the function and molecular mechanisms of Res in the prevention and treatment of GI cancer.

Acute Kidney Injury in Oncology Patients.

With rapid progress in cancer diagnosis and treatment in the last two decades, outcomes in oncological patients have improved significantly. However, the incidence of acute kidney injury (AKI) in this population has also increased significantly. AKI complicates many aspects of patients' care and adversely affects their prognoses; thus, accurately diagnosing the risk factors for AKI ensures appropriate management. AKI may be caused by pre-renal, intrinsic renal, and post-renal reasons, as well as for combined reasons. This review summarizes the potential etiologies of AKI according to the three classifications. For each underlying cause of AKI, the cancer itself and/or cancer treatment may contribute to a patient developing AKI. Therefore, we present disease- and treatment-related factors for each cause category, with special focus on immune checkpoint inhibitors, which are being used increasingly more often. It is important for nephrology services to be knowledgeable to provide the best level of care.

Different iron deposition patterns in hemodialysis patients with and without restless legs syndrome: a quantitative susceptibility mapping study.

OBJECTIVE: Brain iron deposition in hemodialysis (HD) patients increases over time. Iron deficiency in gray matter nuclei has been reported to lead to idiopathic restless legs syndrome (RLS) symptoms. Regardless of unpleasant RLS sensations, the patterns of iron deposition between hemodialysis patients with RLS (HD-RLS) and hemodialysis patients without RLS (HD-nRLS) are still unclear. To evaluate the differences in iron deposition patterns between HD-RLS and HD-nRLS patients, we utilized quantitative susceptibility mapping (QSM). METHODS: In sum, 24 HD-RLS patients, 25 HD-nRLS patients and 30 age- and sex-matched healthy controls (HCs) were enrolled. The QSM was used to assess susceptibility values of the regions of interest (ROIs), including the caudate nucleus (CN), putamen (PUT), globus pallidus (GP), thalamus (THA), substantia nigra (SN), red nucleus (RN) and dentate nucleus (DN). RESULTS: HD duration was significantly longer in HD-RLS patients than in HD-nRLS patients (P < 0.05). The susceptibility of HD-RLS and HD-nRLS patients in PUT was higher than that in HCs (P < 0.05), illustrating elevated iron content in the nucleus. Compared with HD-nRLS patients, HD-RLS patients demonstrated reduced susceptibility in CN and PUT (both P < 0.05). Compared with HCs, HD-RLS patients displayed decreased susceptibility in DN (P < 0.05). CONCLUSIONS: Different iron deposition patterns between HD-RLS and HD-nRLS patients in PUT and DN, which further support disturbed sensory processing in RLS, may be involved in RLS pathogenesis in HD patients.

Human Immunodeficiency Virus, Chlamydia, and Gonorrhea Testing in New York Medicaid-Enrolled Adolescents.

BACKGROUND: Although growing public health efforts have been expended on increasing adolescents' access to human immunodeficiency virus (HIV) and sexually transmitted infection (STI) testing, little is known about the current utilization of those services in clinical settings. METHODS: Using 2010 to 2012 New York State Center for Medicare and Medicaid Services Medicaid Analytic eXtract data, we estimated the annual percentage of 13- to 19-year-olds who were tested for HIV, chlamydia (CT), and gonorrhea (GC). A regression analysis was performed to identify factors independently associated with testing utilization. We further examined testing utilization in all adolescent females with 1 or more health care encounter, pregnant females, and adolescents at increased risk for HIV/STI. RESULTS: From 2010 to 2012, HIV, CT, and GC testing rates increased in the overall study population and in most demographic subgroups. Female adolescents, black and Hispanic adolescents, at-risk adolescents, and adolescents with 6 months or longer of enrollment were significantly more likely to be tested. Among adolescent females with 1 or more health care encounter, 19.2% were tested for CT and 16.9% tested for GC in 2012. Among pregnant females, 35.2%, 53.9%, and 46.1% were tested for HIV, CT, and GC, respectively. Among at-risk adolescents, 39.9%, 63.7%, and 54.4% were tested for HIV, CT, and GC, respectively. CONCLUSIONS: Although progress had been made by New York State providers to adhere to recommended testing for adolescents, there was a clear gap between the recommended level of testing and the actual level of utilization among sexually active females, pregnant females, and at-risk adolescents. Opportunities exist for community provider and public health collaboration to increase adolescent HIV and STI testing.

3EZ, 20Ac-ingenol induces cell-specific apoptosis in cyclin D1 over-expression through the activation of ATR and downregulation of p-Akt.

Acute lymphoblastic leukemia (ALL) samples exhibit an activated PI3K/Akt pathway, which suggests a general role of Akt in the development of leukemia. We have previously used western blot analysis to show that the catalytic topoisomerase (topo) inhibitor, 3EZ, 20Ac-ingenol, induced DNA damage response (DDR), which activated ATR, downregulated p-Akt through upregulation of PTEN level, and led to cell cycle arrest or apoptosis. In this study, we used ATR or PTEN siRNA and observed that the specific cell arrest and apoptosis of BALL-1 cells in DDR caused by 3EZ, 20Ac-ingenol was dependant on activation of ATR and downregulation of nuclear p-Akt through upregulation of PTEN. Moreover, some B cell lymphomas among ALLs overexpress cyclin D1. The DDR induced during the S-phase with 3EZ, 20Ac-ingenol treatment was increased by the intra S-phase checkpoint response that was triggered by the loss of nuclear cyclin D1 regulation in BALL-1 cells overexpressing cyclin D1. Although topo 1 catalytic inhibitors induce a decatenation checkpoint and subsequent G2/M phase arrest, the decatenation checkpoint caused by 3EZ, 20Ac-ingenol induced apoptosis only in the BALL-1 cells that accumulated cyclin D1.

The Optimal Age for Screening Adolescents and Young Adults Without Identified Risk Factors for HIV.

PURPOSE: To assess the optimal age at which a one-time HIV screen should begin for adolescents and young adults (AYA) in the U.S. without identified HIV risk factors, incorporating clinical impact, costs, and cost-effectiveness. METHODS: We simulated HIV-uninfected 12-year-olds in the U.S. without identified risk factors who faced age-specific risks of HIV infection (.6-71.3/100,000PY). We modeled a one-time screen ($36) at age 15, 18, 21, 25, or 30, each in addition to current U.S. screening practices (30% screened by age 24). Outcomes included retention in care, virologic suppression, life expectancy, lifetime costs, and incremental cost-effectiveness ratios in $/year-of-life saved (YLS) from the health-care system perspective. In sensitivity analyses, we varied HIV incidence, screening and linkage rates, and costs. RESULTS: All one-time screens detected a small proportion of lifetime infections (.1%-10.3%). Compared with current U.S. screening practices, a screen at age 25 led to the most favorable care continuum outcomes at age 25: proportion diagnosed (77% vs. 51%), linked to care (71% vs. 51%), retained in care (68% vs. 44%), and virologically suppressed (49% vs. 32%). Compared with the next most effective screen, a screen at age 25 provided the greatest clinical benefit, and was cost-effective ($96,000/YLS) by U.S. standards (<$100,000/YLS). CONCLUSIONS: For U.S. AYA without identified risk factors, a one-time routine HIV screen at age 25, after the peak of incidence, would optimize clinical outcomes and be cost-effective compared with current U.S. screening practices. Focusing screening on AYA ages 18 or younger is a less efficient use of a one-time screen among AYA than screening at a later age.

Apelin attenuates TGF-ß1-induced epithelial to mesenchymal transition via activation of PKC-ε in human renal tubular epithelial cells.

Epithelial to mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells transition to a mesenchymal phenotype, has been implicated in the pathogenesis of renal fibrosis. Apelin, a bioactive peptide, has recently been recognized to protect against renal profibrotic activity, but the underlying mechanism has not yet been elucidated. In this study, we investigated the regulation of EMT in the presence of apelin-13 in vitro. Expression of the mesenchymal marker alpha-smooth muscle actin (α-SMA) and the epithelial marker E-cadherin was examined by immunofluorescence and western blotting in transforming growth factor beta 1 (TGF-ß1)-stimulated human proximal tubular epithelial cells. Expression of extracellular matrix, fibronectin and collagen-I was examined by quantitative real-time PCR and ELISA. F13A, an antagonist of the apelin receptor APJ, and small interfering RNA targeting protein kinase C epsilon (PKC-ε) were used to explore the relevant signaling pathways. Apelin attenuated TGF-ß1-induced EMT, and inhibited the EMT-associated increase in α-SMA, loss of E-cadherin, and secretion of extracellular matrix. Moreover, apelin activated PKC-ε in tubular epithelial cells, which in turn decreased phospho-Smad2/3 levels and increased Smad-7 levels. APJ inhibition or PKC-ε deletion diminished apelin-induced modulation of Smad signaling and suppression of tubular EMT. Our findings identify a novel PKC-ε-dependent mechanism in which apelin suppresses TGF-ß1-mediated activation of Smad signaling pathways and thereby inhibits tubular EMT. These results suggest that apelin may be a new agent that can suppress renal fibrosis and retard chronic kidney disease progression.