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Little is known about the benefit-risk profile of second-generation androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. We aimed to examine the efficacy and safety of second-generation androgen receptor inhibitors in men aged 80 years or older with non-metastatic castration-resistant prostate cancer.We searched for all randomised controlled clinical trials evaluating second-generation androgen receptor inhibitors in patients with non-metastatic castration-resistant prostate cancer submitted to the US Food and Drug Administration before Aug 15, 2020, and pooled data from three trials that met the selection criteria. All three trials enrolled patients who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, castration-resistant prostate cancer, prostate-specific antigen (PSA) 2·0 μg/L or greater, PSA doubling time of 10 months or less, and no evidence of distant metastatic disease on conventional imaging per the investigator's assessment at the time of screening. All patients had histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell features. All patients who were randomly assigned to androgen receptor inhibitor or placebo groups in these trials were considered assessable and were included in this pooled analysis. We evaluated the effect of age on metastasis-free survival and overall survival across age groups (80 years vs ≥80 years) in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study treatment.Between Oct 14, 2013, and March 9, 2018, 4117 patients were assigned to androgen receptor inhibitor (apalutamide, enzalutamide, or daralutamide; n=2694) or placebo (n=1423) across three randomised trials. The median follow-up duration for metastasis-free survival was 18 months (IQR 11-26) and for overall survival was 44 months (32-55). In patients aged 80 years or older (n=1023), the estimated median metastasis-free survival was 40 months (95% CI 36-41) in the androgen receptor inhibitor groups and 22 months (18-29) in the placebo groups (adjusted hazard ratio [HR] 0·37 [95% CI 0·28-0·47]), and the median overall survival was 54 months (50-61) versus 49 months (43-58), respectively (adjusted HR 0·79 [0·64-0·98]). In patients younger than 80 years of age (n=3094), the estimated median metastasis-free survival was 41 months (95% CI 36-not estimable [NE]) in the androgen receptor inhibitor groups and 16 months (15-18) in the placebo groups (adjusted HR 0·31 [95% CI 0·27-0·35]), and the median overall survival was 74 months (74-NE) versus 61 months (56-NE), respectively (adjusted HR 0·69 [0·60-0·80]). In patients aged 80 years or older, grade 3 or worse adverse events were reported in 371 (55%) of 672 patients in the androgen receptor inhibitor groups and 140 (41%) of 344 patients in the placebo groups, compared with 878 (44%) of 2015 patients in the androgen receptor inhibitor groups and 321 (30%) of 1073 patients in the placebo groups among patients younger than 80 years. The most common grade 3-4 adverse events were hypertension (168 [8%] of 2015 patients aged80 years and 51 [8%] of 672 patients aged ≥80 years in the androgen receptor inhibitor groups vs 53 [5%] of 1073 patients aged80 years and 22 [6%] of 344 patients aged ≥80 years in the placebo groups) and fracture (61 [3%] and 36 [5%] in the androgen receptor inhibitor groups vs 15 [1%] and 11 [3%] in the placebo groups).The findings of this pooled analysis support the use of androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. Incorporating geriatric assessment tools in the care of older adults with non-metastatic castration-resistant prostate cancer might help clinicians to offer individualised treatment to each patient.None.

Risks of handheld electrical weapons include head impact trauma associated with uncontrolled falls, ocular probe penetration injuries, thermal injuries from the ignition of volatile fumes, and weapon confusion police-involved shooting. There is also an uncommon but critical risk of a shooting after a subject gained control of an officer’s electrical weapons. The authors searched for police shooting incidents involving loss of control of TASER® weapons via open-source media reports, crowd-sourced internet sites, litigation filings, and a survey of Axon law-enforcement master instructors. The authors report 131 incidents of subjects attempting to or gaining control of an officer’s electrical weapon from 2004 to 2020, 53 of which resulting in a shooting. These incidents demonstrated a risk of 11.8 shootings per million electrical weapon discharges (95% confidence limits of 9.0 to 15.1 per million by Wilson score interval). The use of electrical weapons presents a rare but real risk of injury and death from a shooting following a subject’s attempts to gain control of the weapon.

The US Food and Drug Administration (FDA) has approved multiple systemic vascular endothelial growth factor (VEGF) inhibitors since 2004 to treat various malignancies. Inhibition of the VEGF signaling pathway can result in impairment of vascular wall integrity through medial degeneration and endothelial dysfunction, potentially resulting in arterial (including aortic) aneurysm/dissection. We performed a postmarketing review to evaluate arterial aneurysm/dissection as a potential safety risk for patients with cancer treated with VEGF inhibitors. We searched the FDA Adverse Event Reporting System (FAERS) database and literature for reports of arterial (including aortic) aneurysm/dissection with VEGF inhibitors currently approved by the FDA for a cancer indication. We identified 240 cases of arterial aneurysm/dissection associated with VEGF inhibitors. The median time to onset of an arterial aneurysm/dissection event from the initiation of a VEGF inhibitor was 94 days (range 1–1955 days). Notably, 22% (53/240) of cases reported fatal outcomes related to arterial aneurysm/dissection. We determined the drug–event association as probable in 15 cases that lacked relevant confounding factors for arterial aneurysm/dissection, which is supported by unremarkable computed tomography (CT) findings prior to starting VEGF inhibitor therapy, despite nondrug-associated background arterial aneurysm/dissection generally demonstrating preexisting arterial abnormalities. FAERS and literature case-level evidence suggests that VEGF inhibitors may have contributed to arterial aneurysm/dissection, as a class effect, based on short onset relative to natural history of disease and biologic plausibility. Cardiovascular and oncology healthcare professionals should be aware of this rare, but life-threatening safety risk associated with VEGF inhibitors.

Respiratory and pulmonary diseases are among the leading causes of death globally. Despite tremendous advancements, there are no effective pharmacological therapies capable of curing diseases such as COPD (chronic obstructive pulmonary disease), ARDS (acute respiratory distress syndrome), and COVID-19. Novel and innovative therapies such as advanced therapy medicinal products (ATMPs) are still in early development. However, they have exhibited significant potential preclinically and clinically. There are several longitudinal studies published, primarily focusing on the use of cell therapies for respiratory diseases due to their anti-inflammatory and reparative properties, thereby hinting that they have the capability of reducing mortality and improving the quality of life for patients. The primary objective of this paper is to set out a state of the art review on the use of aerosolized MSCs and their potential to treat these incurable diseases. This review will examine selected respiratory and pulmonary diseases, present an overview of the therapeutic potential of cell therapy and finally provide insight into potential routes of administration, with a focus on aerosol-mediated ATMP delivery.

Purpose While generally reducing morbidity and mortality, TASER® electrical weapons have risks associated with their usage, including burn injuries and head and cervical trauma associated with uncontrolled falls. The primary non-fatal complications appear to be significant eye injury but no analysis of the mechanisms or suggested treatments has been published. Methods We used a biomechanical model to predict the risk of eye injury as a function of distance from the weapon muzzle to the eye. We compared our model results to recently published epidemiological findings. We also describe the typical presentation and suggest treatment options. Results The globe rupture model predicted that a globe rupture can be expected (50% risk) when the eye is within 6 m of the muzzle and decreases rapidly beyond that. This critical distance is 9 m for lens and retinal damage which is approximately the range of the most common probe cartridges. Beyond 9 m, hyphema is expected along with a perforation by the dart portion of the probe. Our prediction of globe rupture out to 6 m (out of a typical range of 9 m) is consistent with the published risk of enucleation or unilateral blindness being 69 ± 18%, with an eye penetration. Conclusions Significant eye injury is expected from a penetration by an electrical weapon probe at close range. The risk decreases rapidly at extended distances from the muzzle. Not all penetrating globe injuries from electrical weapon probes will result in blindness.

OBJECTIVES Sudden cardiac arrest is a leading cause of death in athletes. Although athletes wear various athletic chest protectors (ACPs) to prevent commotio cordis (CC), cardiac arrest cases still occur. Although it is established that cardiopulmonary resuscitation (CPR) quality affects outcome, little research has evaluated the effect of ACPs on CPR compressions quality. This study aimed to observe whether: (1) ACPs impact depth, rate, and hand positioning of both bystander and LUCAS CPR. (2) LUCAS devices affect CPR performance compared with traditional compressions. METHODS An observational, prospective, convenient sample of 26 emergency medicine residents performed CPR on a high-fidelity Laerdal mannequin, which recorded real-time performance data. Baseline CPR for 1- and 2-minute cycles, CPR on a mannequin wearing the ACP, and ACP removal time was recorded. LUCAS CPR performance was measured at baseline and over the ACP. RESULTS Bystander CPR had a statistically significant difference in both hand placement and compression rate for baseline versus ACP compressions (85% vs 57%, P < 0.05; 138 vs 142, P < 0.05, respectively), but not in compression depth (51.08 vs 50.05 mm, P = 0.39). LUCAS CPR had no significant difference in CPR performance. Bystander versus LUCAS CPR had a significant difference in compression rate (138 vs 101, P < 0.01), but not in depth or hand placement. CONCLUSIONS Athletic chest protectors significantly impacted hand placement during bystander CPR, which may diminish CPR quality. Considering ACP removal required only 5.4 seconds, removing the ACP before standard CPR may improve quality.

Background Acquired thrombophilia is a potential sequela of malignancy, chronic inflammation, and conditions characterized by severe protein deficiency (for example, nephrotic syndrome, protein-losing enteropathy). As such, venous thrombosis is often a feature, and occasionally a presenting sign, of systemic disease. Ménétrier’s disease is a rare hyperplastic gastropathy that may lead to gastrointestinal protein loss and hypoalbuminemia. To date, reports of venous thrombosis associated with Ménétrier’s disease are exceedingly scarce. Case presentation We report the case of a 40-year-old white man who presented with unprovoked deep venous thrombosis, pulmonary embolism, and renal vein thrombosis. Upon receiving therapeutic anticoagulation, he developed severe gastrointestinal bleeding, and endoscopic evaluation led to a diagnosis of Ménétrier’s disease. A laboratory workup revealed deficiency of protein C, protein S, and antithrombin III, as well as markedly elevated levels of factor VIII. He was determined to have an acquired thrombophilia as a direct result of Ménétrier’s disease. Conclusions This case describes an acquired thrombophilic state in a patient with Ménétrier’s disease and profound hypoalbuminemia. Although this association is rarely described, we discuss the probable mechanisms leading to our patient’s thrombosis. Specifically, we posit that his gastrointestinal protein loss led to a deficiency of several anticoagulant proteins and a compensatory elevation in factor VIII, as occurs in nephrotic syndrome and inflammatory bowel disease. Of note, this patient’s recurrent venous thrombosis was the initial clinical sign of his gastrointestinal pathology.

Anterior crown fractures are a common form of traumatic dental injuries that mainly affect the maxillary incisors especially in children and adolescents. Complicated crown fractures although less common can be a challenging task to the clinician. Since the development of adhesive dentistry, the patient's own broken tooth fragment can be used to restore the fractured tooth. Reattachment of fractured tooth fragments with fiber postreinforcement offers a viable restorative alternative. Such procedure is economical and needs less chair-side time as compared to many traditional methods. In addition, the procedure provides good and long-lasting esthetics, as the original morphology, color, and surface texture are preserved. The main objective while treating such cases is successful pain management and immediate restoration of function, esthetics and phonetics. This paper presents a report of two cases of coronal tooth fracture that is successfully managed using tooth fragment reattachment.

Activation of the PI3K–AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, although necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations. Notably, cotargeting SGK1 and AKT resulted in significantly higher growth suppression than inhibiting either PI3K or AKT alone. Overall, these findings underscore the clinical relevance of AKT-independent pathways in tumors driven by genetic lesions targeting the PI3K cascade. Cancer Res; 77(24); 6914–26. ©2017 AACR.

Patient: Female, 24 Final Diagnosis: Mucinous ovarian adenocarcinoma Symptoms: Nonproductive cough • shortness of breath with exertion Medication: — Clinical Procedure: — Specialty: Oncology Objective: Rare co-existance of disease or pathology Background: Mucinous ovarian adenocarcinoma is one of the less common epithelial cancers of the ovaries, and typically does not occur in younger women. Nearly all mucinous ovarian adenocarcinomas present with early-stage disease without significant sequelae of cancer, such as clotting. Anchoring bias is a common problem in medicine that has been shown to significantly affect physician decision-making. Case Report: We present the case of a 24-year-old healthy female Chinese immigrant with no significant past medical history, who presented with a subacute history of nonproductive cough and shortness of breath with exertion. Initial workup was directed towards diagnosis of tuberculosis and other infectious etiologies due to anchoring to patient’s nationality and her positive family history for tuberculosis. She was eventually diagnosed with extensive bilateral pulmonary emboli and bilateral deep vein thromboses as well as a right ventricular thrombus. This extensive clot burden helped lead to the diagnosis of mucinous ovarian adenocarcinoma. Conclusions: This case is significant not only because the diagnosis of mucinous ovarian adenocarcinoma is uncommon in healthy young females under the age of 25, but, more importantly, because such extensive pulmonary emboli and deep vein thromboses in a young female with local/early-stage ovarian cancer is very rare. This case is also significant because it serves as an important reminder of the risks of anchoring bias in skewing perceptions and delaying the correct diagnosis by physicians.

The FDA has approved three androgen receptor inhibitors—enzalutamide, apalutamide, and darolutamide—for the treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). These approvals were all based on randomized, double blind, placebo-controlled trials demonstrating large improvements in metastasis-free survival (MFS) and internally consistent evidence of benefit seen across secondary endpoints. In this article, we summarize the FDA regulatory history of MFS and we describe the design, conduct, and results of the three pivotal trials supporting these important treatment options for patients with nmCRPC.

Objective A 12-lead electrocardiogram (ECG) is the standard of care for chest pain patients. However, 12-lead ECGs have difficulty detecting ischemia of the right ventricle or posterior wall of the heart. New technology exists to mathematically synthesize these leads from a 12-lead ECG; however, this technology has not been evaluated in the emergency department (ED). We assessed the level of agreement between synthesized 18-lead ECGs and actual 18-lead ECGs in identifying ST elevations, ST depressions, and T wave inversions in ED patients. Methods Actual 12- and 18-lead ECGs were acquired and synthesized 18-lead ECGs were produced based on waveforms from 12-lead ECGs. A blinded cardiologist interpreted the actual and synthesized 18-lead ECGs to identify the presence of abnormalities. Using actual 18-lead ECGs as the reference, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and kappa of synthesized 18-lead ECGs in identifying abnormalities were determined. Results Data from 295 patients were analyzed. There was 100% agreement between synthesized 18-lead ECGs and actual 18-lead ECGs in identifying ST elevations and ST depressions (sensitivity, specificity, PPV, and NPV of 100%, and kappa of 1.00). Synthesized 18-lead ECGs had 95% sensitivity, 80% specificity, 97% PPV, and 70% NPV in identifying T wave inversions, when compared with actual 18-lead ECGs (kappa: 0.70). Conclusion Synthesized 18-lead ECGs demonstrated 100% agreement with actual 18-lead ECGs in the identification of ST elevations and ST depressions and good agreement in the identification of T wave inversions in a sample of patients ED patients with complaints suspicious of cardiac origin.

4559 Background: The International Metastatic RCC Database Consortium (IMDC) risk model was developed for prognosis of patients with mRCC treated with vascular endothelial growth factor (VEGF)-targeted monotherapy in the first-line setting. Efficacy in trials of anti-VEGF therapy has been generally consistent across risk groups, including for overall survival (OS). For trials of immunotherapy combinations, the small numbers of OS events for the favorable risk group in each trial limited reliable conclusions; however, there was a suggestion of possible differential effects on OS between favorable risk and other risk groups. Methods: We pooled individual patient data (n=3447) from four phase III randomized trials of combinations of immunotherapy + immunotherapy (n=1) or immunotherapy + anti-VEGF therapy (n=3) submitted to the US Food and Drug Administration in support of marketing applications. All trials calculated IMDC risk group for each patient and used a control arm of sunitinib. We combined intermediate and poor prognostic groups (“intermediate/poor”) and compared their OS to that of the favorable risk group using Kaplan-Meier and Cox Proportional Hazards methods. Results: In this pooled analysis, treatment with combination immune checkpoint therapy did not demonstrate an improvement in OS compared to sunitinib in the favorable risk group (HR 0.953; 95% CI: 0.72, 1.27). An improvement in OS was observed in the intermediate/poor risk group (HR 0.696; 95% CI: 0.62, 0.78). Conclusions: Our analysis of OS in patients treated with immunotherapy combinations compared to sunitinib suggests possible differential benefit in the favorable risk compared to the intermediate/poor risk group. These results are not conclusive and considered exploratory due to the relative immaturity of OS in the favorable risk group. Follow-up for survival continues in each study to allow for more definitive results.[Table: see text]

12038 Background: The FDA has approved three androgen receptor (AR) inhibitors for nonmetastatic castration-resistant prostate cancer (nmCRPC) based on improvements in metastasis-free survival (MFS). MFS is an earlier endpoint, defined as the time from randomization to either imaging-detectable distant disease or death. This pooled analysis examines MFS, time to initiation of cytotoxic chemotherapy (TTCyto), and safety outcomes in men over 80 treated with AR inhibitors. Methods: Data was pooled from three randomized controlled studies (n=4117) of AR inhibitors for nmCRPC. The treatment effect of AR inhibitors on MFS and TTCyto across age groups was evaluated using Kaplan-Meier estimates and a Cox proportional hazards regression model. Hazard Ratios for MFS and TTCyto were adjusted for baseline ECOG, total Gleason score, PSA doubling time, and prior bone-targeting therapy. Results: For patients age 80 years or older (n=675) who were treated with AR inhibitors, the hazard ratio was 0.38 (95% CI 0.29, 0.49) with an estimated median MFS of 40 months (95% CI 36, 41) versus 22 months (95% CI 18, 29) for those treated with placebo (n=348). For patients

Background: The quality of antenatal care (ANC) a woman receives during pregnancy is crucial to both the child and the mother’s life. It has been established that providing high-quality ANC can save lives and has a positive impact on postnatal health care services. However, the quality of ANC in Zambia requires attention as maternal and neonatal mortality rates are still unacceptably high with Lusaka district not being left out of the problem. Methods: Using a cross-sectional study design, the main aim of this study was to determine the demand side factors associated with high-quality antenatal care among pregnant women in Lusaka. It also estimated the proportion of women who received high-quality ANC during their last antenatal visit. Multifactorial logistic regression model was fitted in STATA version 13 to predict the demographic, socio and economic factors that influence the quality of ANC. Results: It was established that only 47.1% of pregnant women received high-quality ANC while 52.9% received low quality. Six key ANC interventions were considered, among which urine (36.7%) and blood (46.8%) testing were the least received basic components of ANC. After adjusting for the effect of other factors, women with secondary education had higher odds of receiving high-quality ANC than women with primary level of education (OR = 1.98; 95% CI: 1.24 to 3.14). Women staying with their husband/partners had lesser odds of receiving high quality ANC compared to those that were not staying with their partners (OR = 0.47; 95% CI: 0.28 to 0.79). Conclusion: The quality of antenatal care received by pregnant women in Lusaka is low. Continued efforts to improve the delivery of basic ANC services such as blood and urine testing is required to improve the quality of healthcare services provided by medical personnel at all levels.

The U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). At the prespecified interim analysis, a statistically significant improvement in overall survival was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm. The overall benefit-risk profile supports the expanded indication for enzalutamide. On September 10, 2014, the U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Enzalutamide was initially approved in 2012 for use in patients with mCRPC who had previously received docetaxel. The current approval was based on the results of a randomized, placebo-controlled, double-blind trial conducted in 1,717 asymptomatic or minimally symptomatic patients with chemotherapy-naïve mCRPC. Patients were assigned to receive either enzalutamide 160 mg or placebo orally once daily. The coprimary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS), which was assessed by independent central radiology review. At the prespecified interim analysis, a statistically significant improvement in OS was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.60–0.84). The median OS was 32.4 and 30.2 months in the enzalutamide and placebo arms, respectively. A statistically significant prolongation of rPFS was observed in patients in the enzalutamide arm (HR, 0.17; 95% CI, 0.14–0.21). In addition, the time to initiation of cytotoxic chemotherapy was prolonged in the enzalutamide arm (HR, 0.35; 95% CI, 0.30–0.40), with median times of 28.0 and 10.8 months in the enzalutamide and placebo arms, respectively. The safety profile was similar to that previously reported for enzalutamide. Adverse reactions of interest included seizure, hypertension, and falls. Enzalutamide should be discontinued if a seizure occurs during treatment. The overall benefit-risk profile supports the expanded indication for enzalutamide. Implications for Practice: This new approval expands the enzalutamide indication, allowing health care providers and patients to use enzalutamide for the treatment of metastatic castration-resistant prostate cancer either before or after cytotoxic chemotherapy.

Purpose While generally reducing morbidity and mortality, electrical weapons have risks associated with their usage, including burn injuries and trauma associated with uncontrolled fall impacts. However, the prevalence of significant eye injury has not been investigated. Methods We searched for incidents of penetrating eye injury from TASER® conducted electrical weapon (CEW) probes via open source media, litigation filings, and a survey of CEW law-enforcement master instructors. Results We report 20 previously-unpublished cases of penetrating eye injury from electrical weapon probes in law-enforcement field uses. Together with the 8 previously published cases, there are a total of 28 cases out of 3.44 million field uses, giving a demonstrated CEW field-use risk of penetrating eye injury of approximately 1:123 000. Confidence limits [85 000, 178 000] by Wilson score interval. There have been 18 cases of total unilateral blindness or enucleation. We also present legal decisions on this topic. Conclusions The use of electrical weapons presents a rare but real risk of total or partial unilateral blindness from electrical weapon probes. Catastrophic eye injuries appear to be the dominant non-fatal complication of electronic control.

Introduction—We have previously published on the ventricular fibrillation (VF) risk with TASER® X26 conducted electrical weapon (CEW). Our risk model accounted for realistic body mass index distributions, modeled the effects of partial or oblique dart penetration, and used epidemiological CEW statistics. As new CEWs have become available to law enforcement, their cardiac safety profile was not quantified. Therefore, we applied our VF probability model to evaluate their cardiac risk.

Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy for patients with ST-segment elevation myocardial infarction (STEMI). Effective and safe adjunct antithrombotic therapy is a major determinant for short- and long-term outcomes after primary PCI. Two separate studies have shown significant benefits vs conventional therapy for 2 recently approved drugs. In the Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, bivalirudin after pretreatment with clopidogrel resulted in improved net clinical outcome compared with heparin plus glycoprotein IIb/IIIa inhibitors. However, during the first 24 hours after PCI, there was an increase in stent thrombosis rates with bivalirudin. In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis In Myocardial Infarction (TRITON-TIMI) 38 trial, prasugrel was superior to clopidogrel in patients with acute coronary syndrome with and without ST-segment elevation. The synergic actions of prasugrel and bivalirudin may maximize the benefit of antithrombotic therapy for STEMI patients undergoing primary PCI. However, no specifically designed studies have so far compared the combination of prasugrel plus bivalirudin with that of clopidogrel plus unfractionated heparin in these patients. The Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 study is a randomized, open-label, multicenter trial aimed to test the hypothesis that a strategy based on prasugrel plus bivalirudin is superior to a strategy based on clopidogrel plus unfractionated heparin in terms of net clinical outcome in STEMI patients with planned primary PCI.

Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation. Mol Cancer Ther; 12(9); 1715–27. ©2013 AACR.

On April 25, 2016, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior antiangiogenic therapy. The approval was based on data from one randomized, open-label, multicenter study in which patients with RCC who had received prior antiangiogenic therapy were treated with either cabozantinib 60 mg orally once daily (n = 330) or everolimus 10 mg orally once daily (n = 328). The major efficacy outcome measure was progression-free survival (PFS) as assessed by a blinded independent radiology review committee in the first 375 randomized patients. A statistically significant improvement in PFS was seen, with a median PFS of 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45–0.74; P < 0.0001]. At a second interim analysis, a statistically significant improvement in overall survival (OS) in the intent-to-treat population was also demonstrated, with a median OS of 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003). The most common (greater than or equal to 25%) adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar–plantar erythrodysesthesia syndrome, hypertension, vomiting, weight loss, and constipation. Clin Cancer Res; 23(2); 330–5. ©2016 AACR.

Aim To study the prevalence and correlation of Enamel Hypoplasia and Dental caries among school children aged 6-15 years in Bagalkot, Karnataka. Materials and Methods 5500 school children aged 6-15 years from different schools in Bagalkot were examined with mouth mirror and probe under natural light. The findings were entered into standard examination forms. Results Out of 5500 school children between the age of 6 - 15 years, 507 (9%) had carious teeth with hypoplasia with a mean of 3.1 carious teeth per child. In 5500 children 1987 (41%) had carious teeth without enamel hypoplasia with a mean of 1.39 decayed teeth per child and this shows that the prevalence of caries in hypoplastic teeth was evident and was statistically significant.

Background: The PD-1 inhibitors release T cells from PD-L1 and PD-L2 mediated blockade, resulting in enhancement of immune responses. These immune responses include not only antitumor activity but also autoimmune reactions. The most serious toxicities of PD-1 inhibitors are immune-mediated, consistent with their mechanism of action. The purpose of this retrospective analysis was to characterize the immune-related adverse reactions (IMARs) of PD-1 inhibitor therapy in patients with cHL. Methods: Data were pooled from three single-arm trials in adults with multiply-relapsed or refractory cHL treated with nivolumab or pembrolizumab at their approved doses. The pool included 243 patients from Study CA209-205 (NCT02181738), 23 patients from Study CA209-039 (NCT01592370), and 210 patients from Study MK-3475-087 (NCT02453594). IMARs were ascertained using grouped MedDRA terms for the following categories: adrenal insufficiency, cardiac disorder, diabetes, diarrhea, encephalitis, hepatitis, hypophysitis, infusion reaction, kidney injury, myositis, pancreatitis, pneumonitis, rash, thyroid disorder, and uveitis. The pooled data set was queried for the incidence, timing, and outcome of IMARs in the population overall. Key patient characteristics assessed as risk factors for IMARs included age, sex, race, ethnicity, weight, body mass index (BMI), B symptoms, bulky disease, prior irradiation, prior autologous stem cell transplantation (aHSCT), prior brentuximab use, and prior lines of therapy. To identify risk factors, multivariable models were developed using a backward-stepping elimination procedure after the initial selection using p-value < 0.2 in the univariable analysis. In the multivariable analysis, p-values < 0.05 were considered statistically significant. Results: The study cohort included 476 patients of median age 34 years (range, 18-76 years); 56% were male, and 87% were Caucasian. Treatment consisted of a median of 13 doses over a median of 9.3 months. An IMAR was reported in 301 (63.2%) patients, and the IMAR was grade 3-4 in 52 (10.9%) patients. No fatal IMARs were reported. There were 51 (11%) patients treated with corticosteroids, and 48 (10%) had study drug interrupted or withdrawn. The most common (>10%) IMARs were rash (28.6%), diarrhea (26.5%), thyroid disorder (14.3%), infusion reaction (13.2%), and hepatitis (11.1%). The most common (>1%) grade 3-4 IMARs were pancreatitis (3.6%), hepatitis (2.9%), and diarrhea (2.3%). The table below shows the IMARs listed in order of time to onset. Risk factors for the occurrence of any IMAR were prior aHSCT (p=0.004) and elevated BMI (p=0.049). When assessed by individual IMAR, the risk factors identified were age for cardiac disorder; prior aHSCT for diarrhea; race for hepatitis; race and weight for infusion reaction; number of prior lines of therapy and BMI for kidney injury; weight and B symptoms for pneumonitis; prior aHSCT and BMI for rash; and sex and prior radiation for thyroid disorders. No risk factors were identified for adrenal insufficiency, diabetes, hypophysitis, myositis, pancreatitis, or uveitis. Conclusions: The majority of patients with cHL treated with a PD-1 inhibitor experienced an adverse event consistent with an IMAR, although few events were grade 3-4. Most of these events started after 2-3 months of treatment, but overall, they occurred at any time during treatment. Prior aHSCT was identified as a significant risk factor for IMAR, although this was driven largely by the categories rash and diarrhea. Acknowledgment: Data were provided for nivolumab by Bristol-Myers Squibb Company and for pembrolizumab by Merck Sharp & Dohme Corp. Table. Table. Disclosures No relevant conflicts of interest to declare.

Unicystic ameloblastoma, a variant of solid or multicystic ameloblastoma is commonly reported to occur in third decade and encountered in the posterior mandible with a biologically low-grade course and with limited recurrence potential. Clinically, it frequently manifests as a painless swelling, which can be accompanied by facial deformity, malocclusion and paresthesia of the affected area.Histologically, the minimum criterion for diagnosing a lesion as unicystic ameloblastoma is the demonstration of a single cystic sac lined by odontogenic(ameloblastomatous) epithelium often seen only in focal areas whereas radiographically they represent a unilocular radiolucency. This report presents a case of 28 year old male patient with bilateral occurrence of unicystic ameloblastoma.

Background: Spanish-speaking individuals comprise a growing percentage of the United States population. They have greater difficulty than most in accessing and remaining in psychiatric treatments, including psychotherapy, their stated preference. The literature on cultural competence in treating Hispanic patients provides few details of psychotherapeutic adaptations. Objective: This article, based on interpersonal psychotherapy (IPT) supervision for a low-socioeconomic sample of monolingual Spanish-speaking New York City patients, describes culturally specific psychotherapy. Method: In conducting IPT for Spanish-speaking patients with DSM-IV major depressive disorder, we reviewed cases in weekly supervision over 3 years (January 2005 to January 2008) to explore treatment themes and evaluate the congruence of IPT in addressing them. Important themes are illustrated by case example. Results: Key themes include (1) the centrality of family, (2) conflicts due to migration and acculturation, (3) gender roles, (4) need to avoid humiliating or irrevocable social confrontation, and (5) equanimity in facing an unpredictable environment. Conclusions: IPT appears a compatible intervention, focusing on and adaptable to these important issues for Hispanic patients.

Importance Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by restricted venous outflow from the brain and spinal cord. Whether this condition is associated with multiple sclerosis (MS) and whether venous percutaneous transluminal angioplasty (PTA) is beneficial in persons with MS and CCSVI is controversial. Objective To determine the efficacy and safety of venous PTA in patients with MS and CCSVI. Design, Setting, and Participants We analyzed 177 patients with relapsing-remitting MS; 62 were ineligible, including 47 (26.6%) who did not have CCSVI on color Doppler ultrasonography screening. A total of 115 patients were recruited in the study timeframe. All patients underwent a randomized, double-blind, sham-controlled, parallel-group trial in 6 MS centers in Italy. The trial began in August 2012 and concluded in March 2016; data were analyzed from April 2016 to September 2016. The analysis was intention to treat. Interventions Patients were randomly allocated (2:1) to either venous PTA or catheter venography without venous angioplasty (sham). Main Outcomes and Measures Two primary end points were assessed at 12 months: (1) a composite functional measure (ie, walking control, balance, manual dexterity, postvoid residual urine volume, and visual acuity) and (2) a measure of new combined brain lesions on magnetic resonance imaging, including the proportion of lesion-free patients. Combined lesions included T1 gadolinium-enhancing lesions plus new or enlarged T2 lesions. Results Of the included 115 patients with relapsing-remitting MS, 76 were allocated to the PTA group (45 female [59%]; mean [SD] age, 40.0 [10.3] years) and 39 to the sham group (29 female [74%]; mean [SD] age, 37.5 [10.6] years); 112 (97.4%) completed follow-up. No serious adverse events occurred. Flow restoration was achieved in 38 of 71 patients (54%) in the PTA group. The functional composite measure did not differ between the PTA and sham groups (41.7% vs 48.7%; odds ratio, 0.75; 95% CI, 0.34-1.68;P = .49). The mean (SD) number of combined lesions on magnetic resonance imaging at 6 to 12 months were 0.47 (1.19) in the PTA group vs 1.27 (2.65) in the sham group (mean ratio, 0.37; 95% CI, 0.15-0.91;P = .03: adjustedP = .09) and were 1.40 (4.21) in the PTA group vs 1.95 (3.73) in the sham group at 0 to 12 months (mean ratio, 0.72; 95% CI, 0.32-1.63;P = .45; adjustedP = .45). At follow-up after 6 to 12 months, 58 of 70 patients (83%) in the PTA group and 22 of 33 (67%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 2.64; 95% CI, 1.11-6.28;P = .03; adjustedP = .09). At 0 to 12 months, 46 of 73 patients (63.0%) in the PTA group and 18 of 37 (49%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 1.80; 95% CI, 0.81-4.01;P = .15; adjustedP = .30). Conclusion and Relevance Venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS. Trial Registration clinicaltrials.gov Identifier:NCT01371760

Introduction - The TASER(®) conducted electrical weapon (CEW) delivers electrical pulses that can temporarily incapacitate subjects. We analyzed the distribution of TASER CEW currents in tissues posterior to the sternum to understand the likelihood of triggering cardiac arrhythmias. We also assessed the electrical 'shielding' effects of the sternum. METHODS and Results - Finite element modeling (FEM) was used to approximate the current density and electric field strength in tissues around the sternum. We analyzed 2 CEW dart deployment scenarios: (a) both darts over the anterior aspect of the sternum; and (b) a CEW dart anterior to the sternum and the other over the abdomen. In both scenarios, the sternum provided significant attenuation of CEW currents. Particularly, both FEMs predicted that the residual electrical current or charge from CEWs would be insufficient to cause either cardiac capture or induction of ventricular fibrillation at locations where cardiac tissue would reside relative to the posterior aspect of the sternum. CONCLUSION - The sternum offers significant 'shielding' effect and protects the tissues posterior to it against effects of electrical current flow from anteriorly-placed CEW electrodes. Language: en

Introduction Human electrical safety standards are based almost exclusively on animal studies and there is an unjustified assumption that ventricular fibrillation (VF) thresholds in animals are the same as those in humans. Methods and results We analyzed differences between animals and humans in cardiac stimulation. A broad literature survey revealed that swine are a fragile electrophysiologic research species and have a dense intramural Purkinje fiber network, which is not found in some other species, including humans. Anesthesia agents have to be chosen carefully as swine are prone to malignant hyperthermia. Cardiac stimulation thresholds depend on weight and capture rates. Thus, the animal weight has to be representative of the weight of human subjects. Studies have shown significant ECG differences between humans and other species, including swine and canine. At least one study suggested that rabbit hearts tend to develop VF in a manner more similar to that seen in humans. Conclusion Animal studies can play a role in conservatively evaluating cardiac safety. However, while still abiding by the precautionary principle, animal study design has to take into account the significant anatomical and electrophysiological differences between humans and other mammals. Data from multiple animal models may offer broader perspectives. If attempts are made to extrapolate animal results to humans then appropriate numerical correction factors should be applied, such as some of those discussed in this article.

INTRODUCTION The most common cause of death due to electric shock is ventricular fibrillation (VF). This work reviews applicable results from the literature and provides an estimation model for the risk of VF with short-duration pulses. METHODS AND RESULTS For 1 ms pulses, the predicted current and charge thresholds required for successful transthoracic cardiac stimulation were 1.12 A and 1.12 mC, respectively. For pulses of 0.1 ms durations, the transthoracic current and charge thresholds predicted by the model are 10.9 A and 1.09 mC, respectively. CONCLUSION In humans, the charge required for single-response cardiac capture using transthoracic electrodes and 0.1 ms pulses is at least 0.5 mC. The transthoracic charge required to trigger repetitive ventricular responses in humans is at least several times higher than that for single responses. Hence, in adult humans, the transthoracic charge threshold required to induce repetitive ventricular responses, tachycardia, or fibrillation, with 0.1 ms pulses is expected to be significantly greater than 1 mC.

The historical trauma response is a constellation of characteristics associated with massive cumulative group trauma across generations, similar to those found among Jewish Holocaust survivors and descendants. Trauma response features include elevated mortality rates and health problems emanating from heart disease, hypertension, alcohol abuse, and suicidal behavior. This article explores gender differences in the historical trauma response among the Lakota (Teton Sioux) and the correlation with health and mental health statistics. The theory of a Lakota historical trauma response is first explained. Traditional gender roles are described in combination with modifications engendered by traumatic Lakota history. Then, data from a study on Lakota historical trauma are presented, including gender differences in response to an experimental intervention aimed at facilitating a trauma resolution process. The data revealed significant gender differences. The sample of women presented initially with a greater degree of conscious affective experience of historical trauma. In contrast, the men reported more lifespan trauma associated with boarding school attendance and appeared to be at an earlier stage of grief. However, at the end of the intervention, women's experience of survivor guilt--a significant trauma response feature-decreased while men's consciousness of historical trauma and unresolved grief increased. Degree of traditional presentation-of-self, including phenotype, appeared to interact with gender to place male participants at greater risk for being traumatized over the lifespan and perhaps subsequently utilizing more rigid defenses against the conscious experience of the trauma with the exception of survivor guilt. The article concludes with a discussion of health and mental health implications for prevention and treatment of the trauma response which could positively impact the health status of the Lakota. Recommendations for future research are suggested.

SUMMARY This article presents evidence to suggest that historical trauma has affected Lakota parents and children by changing parenting behavior and placing children at risk for alcohol and other substance abuse. The theoretical explanation of the Lakota historical trauma response is described and used as a framework for the design of a parenting skills curriculum. This intervention focuses on (1) facilitating parental awareness of life span and communal trauma across generations and (2) a re-cathexis or re-attachment to traditional Lakota values. The experimental curriculum intervention was delivered to a group of ten Lakota parents and two Lakota parent facilitators on a Lakota reservation. Qualitative study results revealed that parents experienced the curriculum as effective, particularly the focus on both historical trauma and the reconnection with traditional Lakota mores. The curriculum's emphasis on traditional protective factors for alcohol and other substance abuse prevention for Lakota children...

Purpose: On December 15, 2008, the US Food and Drug Administration approved plerixafor (Mozobil®; Genzyme Corp.), a new small-molecule inhibitor of the CXCR4 chemokine receptor, for use in combination with granulocyte colony-stimulating factor (G-CSF) to mobilize hematopoietic stem cells (HSC) to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). This summary reviews the database supporting this approval. Experimental Design: The safety and efficacy of plerixafor were demonstrated by 2 multicenter, randomized, placebo-controlled studies in patients with NHL and MM who were eligible for autologous HSC transplantation. The primary efficacy end points were the collection of ≧5 × 106 CD34+ cells/kg from the peripheral blood in 4 or fewer apheresis sessions in patients with NHL or ≧6 × 106 CD34+ cells/kg from the peripheral blood in 2 or fewer apheresis sessions in patients with MM. Results: The 2 randomized studies combined enrolled 600 patients (298 with NHL and 302 with MM). Fifty-nine percent of patients with NHL who were mobilized with G-CSF and plerixafor had peripheral blood HSC collections of ≧5 × 106 CD34+ cells/kg in 4 or fewer apheresis sessions, compared with 20% of patients with NHL who were mobilized with G-CSF and placebo (p < 0.001). Seventy-two percent of patients with MM who were mobilized with Mozobil and G-CSF had peripheral blood HSC collections of ≧6 × 106 CD34+ cells/kg in 2 or fewer apheresis sessions, compared with 34% of patients with MM who were mobilized with placebo and G-CSF (p < 0.001). Common adverse reactions included diarrhea, nausea, vomiting, flatulence, injection site reactions, fatigue, arthralgia, headache, dizziness, and insomnia. Conclusions: This report describes the Food and Drug Administration review supporting the approval of plerixafor.

Purpose: On June 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy including imatinib. This summary reviews the database supporting this approval. Experimental Design: Four single-arm multicenter studies supported the efficacy and safety of dasatinib. The primary efficacy end point in chronic phase CML was major cytogenetic response. The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph+ ALL was major hematologic response. Results: The four studies combined enrolled 445 patients. In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%. Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph+ ALL were 59%, 32%, 31%, and 42%, respectively. Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph+ ALL. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention. Conclusions: This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph+ ALL based on the rates and durability of cytogenetic and hematologic responses.

Background The ability of primary percutaneous coronary intervention (PCI) to salvage myocardium in patients with acute ST-segment elevation myocardial infarction (STEMI) presenting >12 hours after symptom onset is questionable. The aim of this study was to assess the ability of primary PCI to salvage myocardium in patients with STEMI presenting between 12 and 48 hours after the symptom onset. Methods In the BRAVE-2 trial, 365 patients with acute STEMI presenting between 12 and 48 hours from the symptom onset were randomized to an invasive (PCI) or a conservative treatment strategy. Two-hundred sixty-one patients enrolled in 2 centers had scintigraphy before randomization and 5 to 10 days later and constitute the cohort of the present study. Salvage index (proportion of initial perfusion defect salvaged) was the primary end point of this study. Results There were 131 patients randomly assigned to the invasive treatment and 130 patients assigned to the conservative treatment. Initial perfusion defect (median [25th-75th percentiles]) did not differ between groups (17.0% [9.0-28.5] vs 16.0% [9.0-37.5] of the left ventricle; P = .99). The final infarct size, measured in the follow-up scintigraphy, was significantly smaller in patients assigned to the invasive treatment than in those assigned to the conservative treatment (8.0% [2.0-16.0] vs 12.0% [3.2-25.0] of the left ventricle; P = .004). Salvage index was 0.44 (0.13-0.80) in the invasive group versus 0.23 (0.0-0.50) in the conservative group ( P Conclusion Primary PCI leads to significant myocardial salvage in patients with STEMI presenting between 12 and 48 hours after symptom onset.

Historical trauma (HT) is cumulative emotional and psychological wounding over the lifespan and across generations, emanating from massive group trauma experiences; the historical trauma response (HTR) is the constellation of features in reaction to this trauma. The HTR often includes depression, self-destructive behavior, suicidal thoughts and gestures, anxiety, low self-esteem, anger, and difficulty recognizing and expressing emotions. It may include substance abuse, often an attempt to avoid painful feelings through self-medication. Historical unresolved grief is the associated affect that accompanies HTR; this grief may be considered fixated, impaired, delayed, and/or disenfranchised. This article will explain HT theory and the HTR, delineate the features of the HTR and its grounding in the literature, offer specific Native examples of HT and HTR, and will suggest ways to incorporate HT theory in treatment, research and evaluation. The article will conclude with implications for all massively traumatized populations.

To the Editor, We read with interest the case report ‘Frequent use of stun gun may be associated with vibration-induced Raynaud’s phenomenon: A case series’ in which the authors report four cases of Raynaud’s syndrome which they postulated may be related to repeated use of a ‘stun gun’ [1]. Unfortunately, this case report suffers from too many flaws to even propose such a link. They did not report the type of ‘stun gun’ used by the four patients, however, since they reference literature on TASER ® conducted electrical weapons (CEW), we will assume, for the purpose of this letter, that they are implicating these weapons.

The androgen receptor (AR), an important molecular target in the aetiology and progression of prostate cancer, has been found recently to drive key signalling responses in castration resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed. Here we describe the biological characterisation of a novel and selective small molecule AR downregulator and propose this mechanism as a potential new approach for the treatment of CRPC. The compound is a derivative of a novel AR binding core with selectivity over other nuclear hormone receptors, and causes a reduction of AR protein in human LNCaP prostate cancer cells in vitro. The reduction in AR protein is observed in steroid depleted serum (CSS) conditions and demonstrates a differential mode of action from a classical AR antagonist (bicalutamide) which has no effect on AR protein expression. This AR downregulation translates into functional activity in vitro and in vivo. In cell viability assays in vitro the compound has activity in cells expressing wild-type (VCaP) and mutated (T877A) AR, but is inactive in AR-negative PC3 and DU145 prostate cancer cells, indicating a dependency on AR for efficacy. We have also observed a reduction in PSA synthesis in vitro, consistent with the inhibition of AR signalling. The compound also reduced AR protein expression, PSA synthesis and cell viability in LNCaP-Casodex™-Resistant and LNCaP-Androgen-Independent cells in vitro. We investigated in vivo activity using the Hershberger castrated rat assay where oral dosing (100mg/kg twice-daily for 7 days) resulted in a significant inhibition of testosterone-induced growth of sexual accessory organs. In summary we describe data supporting our hypothesis that a selective AR downregulator offers a novel approach for delivering therapeutic benefit in CRPC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B107.