Vitamin D binding protein correlate with estrogen increase after administration of human chorionic gonadotropin but do not affect ovulation, embryo, or pregnancy outcomes.

Background: Vitamin D binding protein (DBP) might increase substantially after ovarian stimulation and hence could be associated with IVF/ICSI outcomes because it determines the fraction of free bioavailable 25(OH) vitamin D. In this study, we aim to determine whether DBP is associated with E2 level after ovarian stimulation and IVF/ICSI outcomes. Design: Post-hoc analysis of a prospective observational cohort. Setting: Single-center study. Participants: 2569 women receiving embryo transfer. Intervention: None. Main outcome measures: The main outcomes were oocyte and embryo quality as well as pregnancy outcomes. Results: DBP concentration correlates with E2 on hCG day (=day of inducing ovulation with hCG; correlation coefficient r = 0.118, P<0.001) and E2 x-fold change to baseline level (r = 0.108, P<0.001). DBP is also positively correlated with total 25(OH)D (r = 0.689, R2 = 0.475, P<0.001) and inversely with free 25(OH)D (r=-0.424, R2=0.179, P<0.001), meaning that E2-stimulated DBP synthesis results in a decrease of free 25(OH)D during ovarian stimulation. However, such alteration does not affect IVF/ICSI outcomes when considering confounding factors, such as the number and quality of oocytes nor embryo quality as well as pregnancy outcomes. Conclusion: DBP concentration correlates with the degree of E2 increase after ovarian stimulation. DBP is also positively correlated with total 25(OH)D and inversely with free 25(OH)D, suggesting that the proportion of free 25(OH)D decreases during ovarian stimulation caused by E2-stimulated DBP synthesis. However, such alteration does not affect clinical IVF/ICSI outcomes.

Predictors of acute kidney injury after percutaneous nephrolithotomy in adult patients: prospective observational study.

PURPOSE: To assess the frequency and the predictive factors of Acute Kidney injury (AKI) in patients undergoing percutaneous nephrolithotomy (PNL). METHODS: A prospective observational work. Demographic, preoperative laboratory data, stone characteristics, and intraoperative and postoperative data were gathered. Perioperative AKI had been defined as an elevation in serum creatinine by ≥ 0.3 mg/dl within 48 h, or ≥ 1.5 times baseline, or urine volume less than 0.5 ml/ kg/hour for 6 hours. A multivariate logistic regression analysis was performed to determine the predictive factors of AKI. ROC curves were utilized to determine the cutoff values of the risk variables. P-values were deemed statistically significant when they were less than 0.05. RESULTS: A total of 418 participants had been involved. The frequency of AKI was 13.9, and 17.2% of patients with AKI developed CKD. The risk factors were age > 46.5 years, smoking, BMI > 28.5 kg/m2, hypertension, diabetes, utilization of angiotensin-converting enzyme inhibitors (ACEI), haemoglobin < 10.8 gm/dl, baseline creatinine > 1.41 mg/dl, eGFR < 65.2 ml/min./1.73 m2, serum uric acid > 5.2 mg/dl, stone volume > 1748 mm3, large tract size, long operative time, and intra-operative bleeding. Patients with AKI had a notably extended duration of hospitalization (3.2 days ± 0.45 vs 2.1 ± 0.42, p < 0.001). CONCLUSIONS: Perioperative AKI occurred in 13.9% of individuals undergoing PNL. Identification and optimization of the risk factors and meticulous technique during PNL procedures should be attempted to decrease the risk of AKI.

Impact of vitamin D in children with chronic tonsillitis (immunohistochemical study of CD68 polarisation and proinflammatory cytokines estimation).

Inflammatory processes are increasingly attributed to macrophage polarization. Proinflammatory macrophages promote T helper (Th) 1 response, tissue repair, and Th2 responses. Detection of macrophages in tissue sections is facilitated by CD68. Our study is focused on the expression of CD68 and the estimation of proinflammatory cytokines in children's patients with chronic tonsillitis secondary to vitamin D supplementation. This hospital-based Randomized prospective case-control study was conducted on 80 children with chronic tonsillitis associated with vitamin D deficiency where (40 received vitamin D 50,000 IU weekly for 3-6 months and 40 received 5 ml distilled water as placebo). The serum 25-hydroxyvitamin D [25(OH)D] was measured using an Enzyme-linked immunosorbent assay on all included children. Different histological and immunohistochemical studies for the detection of CD68 were done. There was a significantly lower serum level of 25(OH)D in the placebo group versus the vitamin D group (P < 0.001). The levels of pro-inflammatory cytokines, TNFα, and IL-2 significantly increased in the placebo group as compared to the vitamin D group (P < 0.001). The increased level of IL-4 and IL-10 in the placebo group as compared to the vitamin D group was insignificant (P = 0.32, 0.82) respectively. Vitamin D supplementation alleviated the deleterious effect of chronic tonsillitis on the histological structure of the tonsil. Tonsillar tissues of the children in the control and vitamin D groups demonstrated a highly statistically significantly lower number of CD68 immunoexpressing cells compared with those in the placebo group (P < 0.001). Low vitamin D may play a role in chronic tonsillitis. Vitamin D supplementation could help reduce the occurrence of chronic tonsillitis in susceptible children.

Genetic-Guided Oral P2Y12 Inhibitor Selection and Cumulative Ischemic Events After Percutaneous Coronary Intervention.

BACKGROUND: Genetic-guided P2Y12 inhibitor selection has been proposed to reduce ischemic events by identifying CYP2C19 loss-of-function (LOF) carriers at increased risk with clopidogrel treatment after percutaneous coronary intervention (PCI). A prespecified analysis of TAILOR-PCI (Tailored Antiplatelet Therapy Following PCI) evaluated the effect of genetic-guided P2Y12 inhibitor therapy on cumulative ischemic and bleeding events. OBJECTIVES: Here, the authors detail a prespecified analysis of cumulative endpoints. The primary endpoint was cumulative incidence rate of ischemic events at 12 months. Cumulative incidence of major and minor bleeding was a secondary endpoint. Cox proportional hazards models as adapted by Wei, Lin, and Weissfeld were used to estimate the effect of this strategy on all observed events. METHODS: The TAILOR-PCI trial was a prospective trial including 5,302 post-PCI patients with acute and stable coronary artery disease (CAD) who were randomized to genetic-guided P2Y12 inhibitor or conventional clopidogrel therapy. In the genetic-guided group, LOF carriers were prescribed ticagrelor, whereas noncarriers received clopidogrel. TAILOR-PCI's primary analysis was time to first event in LOF carriers. RESULTS: Among 5,276 patients (median age 62 years; 25% women; 82% acute CAD; 18% stable CAD), 1,849 were LOF carriers (903 genetic-guided; 946 conventional therapy). The cumulative primary endpoint was significantly reduced in the genetic-guided group compared with the conventional therapy (HR: 0.61; 95% CI: 0.41-0.89; P = 0.011) with no significant difference in cumulative incidence of major or minor bleeding (HR: 1.36; 95% CI: 0.67-2.76; P = 0.39). CONCLUSIONS: Among CYP2C19 LOF carriers undergoing PCI, a genetic-guided strategy resulted in a statistically significant reduction in cumulative ischemic events without a significant difference in bleeding. (Tailored Antiplatelet Therapy Following PCI [TAILOR-PCI]; NCT01742117).

Renoprotective effects of empagliflozin are linked to activation of the tubuloglomerular feedback mechanism and blunting of the complement system.

The mechanisms of nephroprotection in nondiabetic chronic kidney disease (CKD) models by sodium-glucose cotransporter 2 (SGLT2) inhibitors are not well defined. Five groups were established: sham-operated rats, placebo-treated rats with 5/6 nephrectomy (5/6Nx), 5/6Nx + telmisartan (5 mg/kg/day), 5/6Nx + empagliflozin (3 mg/kg/day), and 5/6Nx + empagliflozin (15 mg/kg/day). Treatment duration was 95 days. Empagliflozin showed a dose-dependent beneficial effect on the change from baseline of creatinine clearance (Ccr). The urinary albumin-to-creatinine ratio likewise improved in a dose-dependent manner. Both dosages of empagliflozin improved morphological kidney damage parameters such as renal interstitial fibrosis and glomerulosclerosis. 5/6 nephrectomy led to a substantial reduction of urinary adenosine excretion, a surrogate parameter of the tubuloglomerular feedback (TGF) mechanism. Empagliflozin caused a dose-dependent increase in urinary adenosine excretion. The urinary adenosine excretion was negatively correlated with renal interstitial fibrosis and positively correlated with Ccr. Immunofluorescence analysis revealed that empagliflozin had no effect on CD8+ and CD4+ T cells as well as on CD68+ cells (macrophages). To further explore potential mechanisms, a nonhypothesis-driven approach was used. RNA sequencing followed by quantitative real-time polymerase chain reaction revealed that complement component 1Q subcomponent A chain (C1QA) as well as complement component 1Q subcomponent C chain (C1QC) gene expression were upregulated in the placebo-treated 5/6Nx rats and this upregulation was blunted by treatment with empagliflozin. In conclusion, empagliflozin-mediated nephroprotection in nondiabetic CKD is due to a dose-dependent activation of the TGF as well as empagliflozin-mediated effects on the complement system.

Evaluation and Assessment of Community Awareness About Coronary Artery Disease in the Aseer Region.

Background Coronary artery disease (CAD), a severe cardiovascular disorder, still remains the major reason for death among adults. In Saudi Arabia, the most common risk factors noticed were hypertension, diabetes, smoking, and dyslipidemia. To date, various therapies have been used for managing CAD, but primary prevention remains the cornerstone to reducing the incidence of CAD-linked mortality and morbidity. The present research aimed to evaluate public awareness levels about CAD in the Aseer region of Saudi Arabia. Materials and methods A structured questionnaire was used to assess the demographic variables, information regarding risk factors, and knowledge and awareness about CAD. To analyze the knowledge and awareness of the general population regarding CAD, 26 well-constructed questions were framed and asked. General characteristics like knowledge, awareness, risk factors, signs and symptoms, complications, effects, treatment, and prevention of CAD were recorded by asking questions with different options. The data obtained were then subjected to statistical analysis using SPSS version 20.0 software (IBM Corp., Armonk, NY). Results Out of 651 participants, 66.51% were males and 33.48% were females, and 36.40% were aged between 26 and 35 years. Of the participants, 14.13% had a positive family history of CAD, 66.05% had inactive lifestyle habits, and 59.60% did not report any stress. A total of 61.29% were unaware of CAD, but many of them were aware of the risk factors, symptoms, and complications of the disease. A total of 5.529% were suffering from CAD, with a time period of less than one year. Only 1.84% of participants were taking medicines for CAD. Conclusion Our study suggested that the community of the Aseer region of Saudi Arabia has meager knowledge and awareness about CAD. Westernized lifestyles and urbanization have caused poor physical well-being in people, leading to increased risk factors for CAD. Thus, we suggest that different educational public health awareness programs should be implemented by the Ministry of Health, Saudi Arabia to decrease the prevalence of these life-threatening diseases.

Identifying distracted-driving events from on-road observations using a moving vehicle: A case study in New Jersey.

Distracted driving is a major traffic safety concern in the USA. To observe and detect distracted-driving events, various methods (e.g., surveys, videos, and simulations) involving the collection of cross-sectional data from individual subjects have been used in the transportation field. In this study, we employed an unconventional approach of on-road observations using a moving vehicle to collect data on distracted-driving events for multiple subjects in New Jersey. A data-collection crew member continuously navigated selected corridors to record driver-distraction events. A GPS (Global Positioning System) tracker was used to timestamp and record the location of each incident. Two non-parametric tests (Mann-Whitney U test and Kruskal-Wallis test) were performed to identify the significance of the variations in distracted-driving behaviors due to changes in temporal variables (e.g., day of the week, season), the type of roadway, and the geometric properties of the roadway. The results indicated that cellphone use was the leading type of distraction. Additionally, "handheld phone use (phone to ear)," "fidgeting/grooming," "drinking/eating/smoking," and "talking to passengers" events were significantly affected by the time of day and the geometric properties of the roadway. The results of this study are expected to assist state and local agencies in promoting awareness of distracted driving with the aim of reducing the frequency and severity of distracted driving-related crashes.

Antifibrotic effects of low dose SGLT2 Inhibition with empagliflozin in comparison to Ang II receptor blockade with telmisartan in 5/6 nephrectomised rats on high salt diet.

To date, the lowest protective SGLT2 inhibitor dose is unknown. We initially performed a dose-response pilot study in normal rats. Based on the results of this pilot study we compared the cardio-renal effects of the SGLT-2 inhibitor empagliflozin, with placebo or telmisartan in rats with 5/6 nephrectomy (5/6 Nx) on a high salt diet (HSD). The experimental set up was as follows: Sham operation (Sham) with normal diet and placebo; 5/6 Nx with 2% HSD and placebo; 5/6 Nx with HSD and empagliflozin (0.6 mg/kg/day, bid); 5/6 Nx with HSD and telmisartan (5 mg/kg/day, qd). Empagliflozin treatment increased urinary glucose excretion, in parallel to empagliflozin plasma levels, in a dose-dependent manner starting at doses of 1 mg/kg in the pilot study. 5/6Nx rats on HSD treated with this low empagliflozin dose showed significantly reduced cardiac (-34.85%; P < 0.05) and renal (-33.68%; P < 0.05) fibrosis in comparison to 5/6Nx rats on HSD treated with placebo. These effects were comparable to the effects observed when implementing the standard dose (5 mg/kg/day) of telmisartan (cardiac fibrosis: -36.37%; P < 0.01; renal fibrosis; -43.96%; P < 0.01). RNA-sequencing followed by confirmatory qRT-PCR revealed that both telmisartan and empagliflozin exert their cardiac effects on genes involved in vascular cell stability and cardiac iron homeostasis, whereas in the kidneys expression of genes involved in endothelial function and oxidative stress were differentially expressed. Urinary adenosine excretion, a surrogate marker of the tubuloglomerular feedback (TGF) mechanism, was not affected. In conclusion, the antifibrotic properties of low dose empagliflozin were comparable to a standard dose of telmisartan. The underlying pathways appear to be TGF independent.

Lichen sclerosis-induced long segment anterior urethral stricture: The early outcome of one-stage repair using dorsolateral onlay buccal mucosa graft.

BACKGROUND: Substitution urethroplasty using buccal mucosal grafts can be performed by several approaches including ventral onlay graft, dorsal onlay graft, or ventral urethrotomy with dorsal inlay graft. Our study aims to evaluate the surgical outcome of dorsolateral buccal mucosal graft for long segment anterior urethral stricture >6 cm in patients with Lichen sclerosus (LS). METHODS: A retrospective study included patients who underwent repair for long segment anterior urethral stricture >6 cm due to LS between January 2013 and April 2019. All patients were followed-up at 3, 6, 9, and 12 months postoperatively and then yearly by clinical symptoms, uroflowmetry, and calculation of post-void residual urine volume. Retrograde urethrogram was requested for patients with voiding symptoms or decreased maximum flow rate. Stricture recurrence that required subsequent urethrotomy or urethroplasty was considered failure. The success rate and surgical complications were collected and analyzed. RESULTS: Thirty patients were identified. The median age (range) was 39 (25-61) years and a median (range) stricture length was 8 (6-14) cm. Most of postoperative complications were of minor degree. The success rate at median follow-up of 15 (12-24) months was 86.5%. The median maximum flow rate increased significantly from 6 (2-11) ml/s preoperatively to 18 (range: 6-23) ml/s at the 6th month (p value < 0.001). CONCLUSION: Dorsolateral buccal mucosal grafts urethroplasty for long anterior urethral stricture caused by LS has a high success rate and low risk of complications including stricture recurrence.

Angiopoietin-2 predicts all-cause mortality in male but not female end-stage kidney disease patients on hemodialysis.

BACKGROUND: Angiopoietin-2 (Ang-2) plays a pivotal role in pathological vascular remodeling and angiogenesis. Both vascular mechanisms are active in patients with end-stage renal disease (ESRD) and may contribute to the high mortality in these patients. The aim of this multicenter prospective cohort study was to investigate baseline serum Ang-2 concentrations in ESRD patients on hemodialysis (HD) for their ability to predict all-cause mortality. METHODS: We conducted a prospective cohort study in 340 stable HD patients from different chronic dialysis centers in Berlin, Germany. The primary endpoint was all-cause mortality during a 5-year follow-up period. Blood samples and clinical data were collected at baseline. Serum Ang-2 was measured with a validated enzyme-linked immunosorbent assay (Biomedica, Vienna, Austria). RESULTS: A total of 313 HD patients (206 men and 107 women) were finally included in the study. Receiver operating characteristic (ROC) analysis of Ang-2 concentrations yielded an area under the curve (AUC) of 0.65 (P < 0.0001) for predicting all-cause mortality in the entire study population and was used to determine the optimal cut-off (111.0 pmol/L) for all-cause mortality. Kaplan-Meier survival analysis indicated that male but not female end-stage kidney disease patients on HD with higher Ang-2 concentrations had a significantly lower survival (log-rank test, P < 0.0001 and P = 0.380 for male and female patients, respectively). Multivariable Cox regression analyses adjusted for age, comorbidity, smoking, dialysis vintage, serum creatinine, hemoglobin, C-reactive protein, serum albumin, intact parathyroid hormone (iPTH), low-density lipoprotein (LDL) and Kt/V likewise indicated that elevated Ang-2 concentrations are associated with all-cause mortality in male {hazard ratio [HR] 3.294 [95% confidence interval (CI) 1.768-6.138]; P = 0.0002} but not in female end-stage kidney disease patients on HD [HR 1.084 (95% CI 0.476-2.467); P = 0.847]. CONCLUSION: Ang-2 at baseline is independently associated with all-cause mortality in male ESRD patients on HD.

Synchronous transurethral cystolitholapaxy and TURP reveals better results than transurethral cystolitholapaxy plus medical therapy for BPH: a randomized prospective study on 100 patients with concomitant urinary bladder stone(s) and BPH.

OBJECTIVE: This report presents the results of a randomized prospective study comparing synchronous transurethral cystolitholapaxy and transurethral resection of the prostate (TURP) with transurethral cystolitholapaxy plus medical treatment for benign prostatic hyperplasia (BPH) in patients with concomitant vesical stone(s) and BPH. PATIENTS AND METHODS: The study included 100 patients with bladder stone(s) < 2.5 cm associated with BPH. Eligible patients were divided randomly into two groups: group I (n = 50 patients) underwent simultaneous transurethral cystolitholapaxy and TURP, and group II (n = 50 patients) underwent transurethral cystolitholapaxy and received postoperative tamsulosin plus finasteride. RESULTS: The mean follow-up was 20.1 ± 5.3 months. No statistically significant differences were found between the 2 groups regarding the preoperative parameters (age, prostatic volume, bladder stone characteristics, prostate-specific antigen level, International Prostate Symptom Score, peak urinary flow rate, and post-void residual urine volume). Both groups experienced statistically significant postoperative improvement in IPSS, post-void residual (PVR) urine volume, and peak flow rate compared with the preoperative parameters (P < 0.001 for all parameters). However, patients in group 1 had a more pronounced improvement (P < 0.001 for all parameters). Thus, 15 patients in group 2 underwent TURP during follow-up. PVR urine and prostate volume predicted the failure of medical therapy and the need for TURP. CONCLUSION: Synchronous transurethral cystolitholapaxy and TURP revealed better results than transurethral cytolitholapaxy plus medical therapy. Cystolitholapaxy without TURP should not be indicated especially in patients with significant PVR urine volumes and larger prostates.

Synergistic Anti-inflammatory and Neuroprotective Effects of Cinnamomum cassia and Zingiber officinale Alleviate Diabetes-Induced Hippocampal Changes in Male Albino Rats: Structural and Molecular Evidence.

Background: Depression has been reported as a common comorbidity in diabetes mellitus although the underlying mechanism responsible for this is not well known. Although both ginger and cinnamon has anti-diabetic, antioxidant, and neuroprotective properties, their efficacy in inhibiting neuroinflammation, when simultaneously administrated, has not been investigated yet. Objectives: The study was designed to assess the synergistic effect of Cinnamomum cassia and Zingiber officinale on regulating blood glucose, improve hippocampal structural changes and depressive-like alternations in diabetic rats, and try to identify the mechanism behind this effect. Materials and Methods: Thirty male Sprague-Dawley rats were divided into five equal groups (n = 6): the normal control, untreated streptozotocin (STZ)-diabetic, cinnamon-treated diabetic [100 mg/kg of body weight (BW)/day for 6 weeks], ginger-treated diabetic (0.5 g/kg BW/day for 6 weeks), and ginger plus cinnamon-treated diabetic groups. Forced swim test and elevated plus maze behavioral tests were performed at the end of the experiment. HOMA-IR, HOMA ß-cells, blood glucose, insulin, corticosterone, pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and IL-6), and total anti-oxidant capacity (TAC) were assessed in the serum. BDNF mRNA level was assessed in hippocampus using qRT-PCR. Hippocampal histopathological changes were also assessed, and immunoexpression of glial fibrillary acidic protein (GFAP), caspase-3, and Ki-67 was measured. Results: Diabetes-induced depressive-like changes in the STZ group were biochemically confirmed by assessing serum corticosterone level, as well as behaviorally using FST and EPM tests. Diabetes also induced degenerative changes in the hippocampus. Treatment of diabetic rats with ginger, cinnamon, or the combination of these alleviated the degenerative structural changes and significantly up-regulated serum insulin, TAC, hippocampal BDNF mRNA, and hippocampal immunoexpression of ki67, while they significantly reduced serum blood glucose, IL-6, TNF-α, IL1ß, as well as hippocampal immunoexpression of GFAP and Caspase-3 compared to the untreated diabetic group. Improvement induced by the combination of ginger and cinnamon was superior to the single administration of either of these. Conclusion: Cinnamomum cassia and Zingiber officinale have synergistic anti-diabetic, antioxidant, anti-inflammatory, antidepressant-like, and neuroprotective effects. The use of a combination of these plants could be beneficial as alternative or complementary supplements in managing DM and decreasing its neuronal and psychiatric complications.

Osteoprotegerin is an independent risk factor predicting death in stable renal transplant recipients.

BACKGROUND: Vascular calcification is common in chronic kidney disease and is associated with significant cardiovascular morbidity and mortality. One of the important factors regulating vascular calcification is osteoprotegerin (OPG). There are, however, limited data on the impact of OPG on all-cause mortality and graft loss in kidney transplant recipients so far. Given its impact on vascular calcification, the aim of our study is to analyze whether OPG was a risk factor of all-cause mortality and graft loss in 600 stable kidney transplant recipients. MATERIALS AND METHODS: 600 stable renal transplant recipients (367 women, 233 men) were followed for all-cause mortality and graft loss for 3 years. Blood and urine samples for analysis and clinical data were collected at study entry. We performed Kaplan-Meier survival analysis and Cox regression models considering confounding factors such as age, estimated glomerular filtration rate (eGFR), cold ischemia time, HbA1c, phosphorus, calcium, and albumin. RESULTS: 65 patients died, and 38 patients had graft loss during the observation period. The OPG baseline concentrations had no effect on graft loss, whereas Kaplan-Meier survival curve showed that baseline plasma OPG concentrations were associated with all-cause mortality in stable kidney transplant recipients (p < 0.0001, log-rank test). After multiple Cox regression analysis adjusting for age, eGFR, cold ischemia time, HbA1c, phosphorus, calcium, and albumin, plasma levels of OPG remained an independent predictor of all-cause mortality (HR, 1.181; 95%CI 1.035 - 1.347; p = 0.014). CONCLUSION: Baseline plasma OPG is an independent risk factor for all-cause mortality but not graft loss in patients after kidney transplantation.

Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection vs Conventional Clopidogrel Therapy on Ischemic Outcomes After Percutaneous Coronary Intervention: The TAILOR-PCI Randomized Clinical Trial.

Importance: After percutaneous coronary intervention (PCI), patients with CYP2C19*2 or *3 loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown. Objective: To determine the effect of a genotype-guided oral P2Y12 inhibitor strategy on ischemic outcomes in CYP2C19 LOF carriers after PCI. Design, Setting, and Participants: Open-label randomized clinical trial of 5302 patients undergoing PCI for acute coronary syndromes (ACS) or stable coronary artery disease (CAD). Patients were enrolled at 40 centers in the US, Canada, South Korea, and Mexico from May 2013 through October 2018; final date of follow-up was October 2019. Interventions: Patients randomized to the genotype-guided group (n = 2652) underwent point-of-care genotyping. CYP2C19 LOF carriers were prescribed ticagrelor and noncarriers clopidogrel. Patients randomized to the conventional group (n = 2650) were prescribed clopidogrel and underwent genotyping after 12 months. Main Outcomes and Measures: The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months. A secondary end point was major or minor bleeding at 12 months. The primary analysis was in patients with CYP2C19 LOF variants, and secondary analysis included all randomized patients. The trial had 85% power to detect a minimum hazard ratio of 0.50. Results: Among 5302 patients randomized (median age, 62 years; 25% women), 82% had ACS and 18% had stable CAD; 94% completed the trial. Of 1849 with CYP2C19 LOF variants, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point occurred in 35 of 903 CYP2C19 LOF carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (hazard ratio [HR], 0.66 [95% CI, 0.43-1.02]; P = .06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding in CYP2C19 LOF carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR, 1.22 [95% CI, 0.60-2.51]; P = .58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR, 0.84 [95% CI, 0.65-1.07]; P = .16). Conclusions and Relevance: Among CYP2C19 LOF carriers with ACS and stable CAD undergoing PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy without point-of-care genotyping, resulted in no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia based on the prespecified analysis plan and the treatment effect that the study was powered to detect at 12 months. Trial Registration: ClinicalTrials.gov Identifier: NCT01742117.

Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the Cardiovascular Inflammation Reduction Trial.

AIMS: In epidemiologic cohorts initiated >30 years ago, inflammatory biomarkers, such as interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were shown to independently predict future cardiovascular events with a magnitude of effect comparable to that of low-density lipoprotein cholesterol (LDLC). Whether aggressive contemporary therapy for atherosclerosis has altered these relationships is unknown yet has major implications for future drug development. METHODS AND RESULTS: Interleukin-6, hsCRP, and LDLC were measured at baseline in up to 4168 North American patients enrolled in the contemporary Cardiovascular Inflammation Reduction Trial with prior myocardial infarction or multivessel coronary disease who additionally had diabetes or metabolic syndrome and were followed for a period of up to 5 years for incident major recurrent cardiovascular events and all-cause mortality. Three-quarters of the cohort were previously revascularized and the great majority was taking statins, angiotensin blocking agents, beta-blockers, and antithrombotic agents. Participants were randomly allocated to low-dose methotrexate 15 mg weekly or to placebo. Randomized use of methotrexate had no effect on event rates nor plasma levels of IL-6, hsCRP, or LDL over time. Yet, baseline levels of IL-6, hsCRP, and LDLC were all predictors of major recurrent cardiovascular events; adjusted hazard ratios [HR; 95% confidence interval (CI)] for the lowest to highest baseline quartiles of IL-6 were 1.0 (referent), 1.66 (1.18-2.35), 1.92 (1.36-2.70), and 2.11 (1.49-2.99; P < 0.0001), while adjusted HRs for increasing quartiles of hsCRP were 1.0 (referent), 1.28 (0.92-1.79), 1.73 (1.25-2.38), and 1.79 (1.28-2.50; P < 0.0001) and adjusted HRs for increasing quartiles of LDLC were 1.0 (referent), 1.12 (0.78-1.62), 1.25 (0.87-1.79), and 2.38 (1.72-3.30; P < 0.0001). Effect estimates were not statistically different in these analyses for comparisons between IL-6, hsCRP, or LDLC, although IL-6 was the strongest predictor of all-cause mortality. The highest absolute risks were observed among those with elevated levels of both cholesterol and inflammation [HR 6.4 (95% CI 2.9-14.1) for those in the top quartiles of baseline IL-6 and LDLC, HR 4.9 (95% CI 2.6-9.4) for those in the top quartiles of baseline hsCRP and LDLC, both P < 0.0001]. CONCLUSION: Despite aggressive contemporary secondary prevention efforts, the relationships between inflammation, cholesterol, and cardiovascular risk are largely unchanged from those described two decades ago. These data are consistent with the hypothesis that future treatments for atherosclerosis may require a combination of inflammation inhibition and additional cholesterol reduction. CLINICAL TRIAL: ClinicalTrials.gov NCT01594333.

Clopidogrel Pharmacogenetics.

Common genetic variation in CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) *2 and *3 alleles leads to a loss of functional protein, and carriers of these loss-of-function alleles when treated with clopidogrel have significantly reduced clopidogrel active metabolite levels and high on-treatment platelet reactivity resulting in increased risk of major adverse cardiovascular events, especially after percutaneous coronary intervention. The Food and Drug Administration has issued a black box warning advising practitioners to consider alternative treatment in CYP2C19 poor metabolizers who might receive clopidogrel and to identify such patients by genotyping. However, routine clinical use of genotyping for CYP2C19 loss-of-function alleles in patients undergoing percutaneous coronary intervention is not recommended by clinical guidelines because of lack of prospective evidence. To address this critical gap, TAILOR-PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to Decreased Clopidogrel Response After Percutaneous Coronary Intervention) is a large, pragmatic, randomized trial comparing point-of-care genotype-guided antiplatelet therapy with routine care to determine whether identifying CYP2C19 loss-of-function allele patients prospectively and prescribing alternative antiplatelet therapy is beneficial.

Mechanisms of GLP-1 receptor-independent renoprotective effects of the dipeptidyl peptidase type 4 inhibitor linagliptin in GLP-1 receptor knockout mice with 5/6 nephrectomy.

Dipeptidyl peptidase type 4 (DPP-4) inhibitors were reported to have beneficial effects in experimental models of chronic kidney disease. The underlying mechanisms are not completely understood. However, these effects could be mediated via the glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP1R) pathway. Here we investigated the renal effects of the DPP-4 inhibitor linagliptin in Glp1r-/- knock out and wild-type mice with 5/6 nephrectomy (5/6Nx). Mice were allocated to groups: sham+wild type+placebo; 5/6Nx+ wild type+placebo; 5/6Nx+wild type+linagliptin; sham+knock out+placebo; 5/6Nx+knock out+ placebo; 5/6Nx+knock out+linagliptin. 5/6Nx caused the development of renal interstitial fibrosis, significantly increased plasma cystatin C and creatinine levels and suppressed renal gelatinase/collagenase, matrix metalloproteinase-1 and -13 activities; effects counteracted by linagliptin treatment in wildtype and Glp1r-/- mice. Two hundred ninety-eight proteomics signals were differentially regulated in kidneys among the groups, with 150 signals specific to linagliptin treatment as shown by mass spectrometry. Treatment significantly upregulated three peptides derived from collagen alpha-1(I), thymosin ß4 and heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) and significantly downregulated one peptide derived from Y box binding protein-1 (YB-1). The proteomics results were further confirmed using western blot and immunofluorescence microscopy. Also, 5/6Nx led to significant up-regulation of renal transforming growth factor-ß1 and pSMAD3 expression in wild type mice and linagliptin significantly counteracted this up-regulation in wild type and Glp1r-/- mice. Thus, the renoprotective effects of linagliptin cannot solely be attributed to the GLP-1/GLP1R pathway, highlighting the importance of other signaling pathways (collagen I homeostasis, HNRNPA1, YB-1, thymosin ß4 and TGF-ß1) influenced by DPP-4 inhibition.

The Sagittal Thoracic Modifier Component of the Lenke Classification System in Moderate and Severe Adolescent Idiopathic Scoliosis: Reliability and Reproducibility of Measurements Among 5 Observers.

STUDY DESIGN: A prospective radiographic study. SUMMARY OF BACKGROUND DATA: As the importance of the spinal sagittal profile becomes increasingly evident, there is a need to ensure that the measuring methods used to evaluate thoracic kyphosis (TK) are both accurate and reproducible. OBJECTIVE: The purpose of the following study was to determine the intraobserver and interobserver variability of measurements of the sagittal profile in moderate and severe thoracic scoliosis. METHODS: Five experienced Faculty Spine surgeons independently reviewed thirty standing long 30-inch cassette lateral radiographs of preoperative moderate and severe curves ≥50 degrees of adolescent idiopathic scoliosis (AIS) patients on 2 different occasions. The parameters measured were the vertebral endplate clarity and measurability of the sagittal angle from D5 to D12 and categories of thoracic sagittal modifier. κ statistics and Intraclass Correlation Coefficient (ICC) were used for analysis. RESULTS: The interobserver percentage of agreement for the Sagittal modifier was 58% in both trials. The mean κ coefficient value was only moderate 0.43 (range, 0.14-0.66) for both trials. The number of the vertebral endplates that were difficult to identify was 201 of 300 measurements (67%). There was a predominance of difficulty to identify vertebral endplate clarity in all curve types. CONCLUSIONS: The results of this study yielded poor to moderate interobserver reliability of the thoracic sagittal profile component of the Lenke classification system in moderate and severe AIS. This was attributed to the difficulty in identification of the vertebral endplates. The current standard lateral radiographs routinely used in AIS patients have inherent difficulties and limitations to visualize, identify, and analyze the thoracic endplates in moderate and severe curves.

Low-Dose Methotrexate for the Prevention of Atherosclerotic Events.

BACKGROUND: Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1ß, resulted in a lower rate of cardiovascular events than placebo in a previous randomized trial. We sought to determine whether an alternative approach to inflammation inhibition with low-dose methotrexate might provide similar benefit. METHODS: We conducted a randomized, double-blind trial of low-dose methotrexate (at a target dose of 15 to 20 mg weekly) or matching placebo in 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or the metabolic syndrome. All participants received 1 mg of folate daily. The primary end point at the onset of the trial was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Near the conclusion of the trial, but before unblinding, hospitalization for unstable angina that led to urgent revascularization was added to the primary end point. RESULTS: The trial was stopped after a median follow-up of 2.3 years. Methotrexate did not result in lower interleukin-1ß, interleukin-6, or C-reactive protein levels than placebo. The final primary end point occurred in 201 patients in the methotrexate group and in 207 in the placebo group (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 to 1.16). The original primary end point occurred in 170 patients in the methotrexate group and in 167 in the placebo group (incidence rate, 3.46 vs. 3.43 per 100 person-years; hazard ratio, 1.01; 95% CI, 0.82 to 1.25). Methotrexate was associated with elevations in liver-enzyme levels, reductions in leukocyte counts and hematocrit levels, and a higher incidence of non-basal-cell skin cancers than placebo. CONCLUSIONS: Among patients with stable atherosclerosis, low-dose methotrexate did not reduce levels of interleukin-1ß, interleukin-6, or C-reactive protein and did not result in fewer cardiovascular events than placebo. (Funded by the National Heart, Lung, and Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333.).

A Survey of the Knowledge and Attitudes of Oncology Nurses toward Pain in United Arab Emirates Oncology Settings.

BACKGROUND: Effective cancer pain management mandates precise attitude, assessment, skills, and knowledge. Health professionals' knowledge and attitudes concerning cancer pain management have often been referred to as insufficient. AIMS: This study explored pain knowledge and attitudes of nurses working in oncology settings. SETTING AND PARTICIPANTS: Population 115 oncology nurses working at 2 hospitals in the United Arab Emirates. METHODS: A descriptive, correlational, cross-sectional design was used to examine nurse knowledge and attitudes about pain using the Nurses' Attitude and Knowledge Survey Regarding Pain (NKASRP) survey. NKASRP score differences were examined among nurses with varying demographics, levels of pain education and experience. RESULTS: The mean KASRP was 45%, significantly below the passing score of 80%. Pain management education was not found to have a significant impact on KASRP thus suggesting the need for more effective educational approaches to developing appropriate knowledge and attitudes towards pain among the nurses. No significant differences between sex, educational level, nursing and oncology experience, and nationality or religion were found. INTERPRETATION AND CONCLUSIONS: The study highlights the need for new initiatives targeting nurses working with cancer patients who are likely to experience significant pain. An ongoing need exists for more effective evidence-based educational programs in cancer pain management. Interactive teaching strategies such as on the job training, improvisational learning, and case studies should be tested for their influence on pain knowledge and attitudes and patient outcomes.