Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in the Treatment of Recurrent High-Grade Glioma.

Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the treatment of patients with recurrent high-grade glioma (NCT01817751). Clinical toxicities were grade 1 and grade 2, with one grade 3 toxicity for maculopapular rash (6.4%). For all evaluable patients, the median progression-free survival was 3.65 months and overall survival (OS) 10.0 months. There was promising evidence showing clinical activity and benefit. In the 33 evaluable patients, low protein levels of the chaperone GRP78 (HSPA5) was significantly associated with a better OS (p < 0.0026). A correlation between the expression of PDGFRα and OS approached significance (p < 0.0728). Five patients presently have a mean OS of 73.6 months and remain alive. This is the first therapeutic intervention glioblastoma trial to significantly associate GRP78 expression to OS. Our data suggest that the combination of sorafenib tosylate, valproic acid, and sildenafil requires additional clinical development in the recurrent glioma population.

A phase 1 study of regorafenib and sildenafil in adults with advanced solid tumors.

The purpose of this study is to establish the recommended phase 2 dose for regorafenib in combination with sildenafil for patients with advanced solid tumors. Secondary outcomes included identification of antitumor effects of regorafenib and sildenafil, toxicity of the combination, determination of PDE5 expression in tumor samples, and the impact of sildenafil on the pharmacokinetics of regorafenib. This study was a phase 1, open-label single-arm dose-escalation trial using a 3 + 3 design. Additional patients were enrolled at the maximum tolerated dose (MTD) until a total of 12 patients were treated at the MTD. A total of 29 patients were treated in this study. The median duration of treatment was 8 weeks. The recommended phase 2 doses determined in this study are regorafenib 160 mg daily with sildenafil 100 mg daily. The most common toxicities included palmar-plantar erythrodysesthesia syndrome (20 patients, 69%) and hypophosphatemia (18 patients, 62%). Two patients (7%) experienced grade 4 lipase increase. Objective responses were not observed; however, 14 patients (48%) had a period of stable disease during the study. Stable disease for up to 12 months was observed in patients with ovarian cancer as well as up to 20 months for a patient with cervical cancer. The combination of regorafenib and sildenafil at the recommended phase 2 dose is safe and generally well tolerated. Disease control in patients with gynecologic malignancies was especially encouraging. Further evaluation of the combination of regorafenib and sildenafil in gynecologic malignancies is warranted. Clinical Trial Registration Number: NCT02466802.

Clinical Characteristics and Outcomes of SARS-CoV-2 Positive Neonates Born to Persons With SARS-CoV-2 Infection in Pregnancy in Los Angeles County, California, May 22, 2020-February 22, 2021.

BACKGROUND: It is well established that pregnant persons with SARS-CoV-2 are at an increased risk for preterm birth, however, less is known about perinatal outcomes for neonates with intrauterine exposure to SARS-CoV-2. METHODS: Characteristics of 50 SARS-CoV-2 positive neonates born to SARS-CoV-2 pregnant persons positive between May 22, 2020, and February 22, 2021, in Los Angeles County, CA, were assessed. Pattern of neonate SARS-CoV-2 test results and time to positive test was analyzed. Objective clinical severity criteria were applied to assess neonatal disease severity. RESULTS: Median gestational age was 39 weeks with 8 (16%) neonates born preterm. Most (74%) were asymptomatic, while 13 (26%) were symptomatic from any cause. Four (8%) symptomatic neonates met criteria for severe disease, of which 2 (4%) were likely secondary to COVID-19. The other 2 with severe disease had more likely alternate diagnoses, and 1 of these neonates subsequently died at 7 months of life. Among 12 (24%) that were positive within 24 hours after birth, one was persistently positive and represented likely intrauterine transmission. Sixteen (32%) were admitted to the neonatal intensive care unit. CONCLUSION: In this case series of 50 SARS-CoV-2 positive mother-neonate pairs, we found that most neonates were asymptomatic regardless of when they tested positive during the 14 days after birth, that there was relatively low risk of COVID-19 associated severe disease, and that intrauterine transmission can occur in rare cases. Although short-term outcomes are mostly promising, more research is needed to study long-term consequences of SARS-CoV-2 infection in neonates born to positive pregnant persons.

Multistate, Population-Based Distributions of Candidate Vaccine Targets, Clonal Complexes, and Resistance Features of Invasive Group B Streptococci Within the United States, 2015-2017.

BACKGROUND: Group B Streptococcus (GBS) is a leading cause of neonatal sepsis and meningitis and an important cause of invasive infections in pregnant and nonpregnant adults. Vaccines targeting capsule polysaccharides and common proteins are under development. METHODS: Using whole genome sequencing, a validated bioinformatics pipeline, and targeted antimicrobial susceptibility testing, we characterized 6340 invasive GBS isolates recovered during 2015-2017 through population-based Active Bacterial Core surveillance (ABCs) in 8 states. RESULTS: Six serotypes accounted for 98.4% of isolates (21.8% Ia, 17.6% V, 17.1% II, 15.6% III, 14.5% Ib, 11.8% IV). Most (94.2%) isolates were in 11 clonal complexes (CCs) comprised of multilocus sequence types identical or closely related to sequence types 1, 8, 12, 17, 19, 22, 23, 28, 88, 452, and 459. Fifty-four isolates (0.87%) had point mutations within pbp2x associated with nonsusceptibility to 1 or more ß-lactam antibiotics. Genes conferring resistance to macrolides and/or lincosamides were found in 56% of isolates; 85.2% of isolates had tetracycline resistance genes. Two isolates carrying vanG were vancomycin nonsusceptible (minimum inhibitory concentration = 2 µg/mL). Nearly all isolates possessed capsule genes, 1-2 of the 3 main pilus gene clusters, and 1 of 4 homologous alpha/Rib family determinants. Presence of the hvgA virulence gene was primarily restricted to serotype III/CC17 isolates (465 isolates), but 8 exceptions (7 IV/CC452 and 1 IV/CC17) were observed. CONCLUSIONS: This first comprehensive, population-based quantitation of strain features in the United States suggests that current vaccine candidates should have good coverage. The ß-lactams remain appropriate for first-line treatment and prophylaxis, but emergence of nonsusceptibility warrants ongoing monitoring.

Phase I trial of dimethyl fumarate, temozolomide, and radiation therapy in glioblastoma.

BACKGROUND: Dimethyl fumarate (DMF), an oral agent approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), has promising preclinical activity against glioblastoma (GBM). This phase I study sought to determine the recommended phase 2 dose (RP2D) of DMF and evaluate its safety and toxicity when combined with standard concurrent radiotherapy (RT) and temozolomide (TMZ) followed by maintenance TMZ in patients with newly diagnosed GBM. METHODS: Using a standard 3 + 3 dose-escalation design with 3 dose levels, patients received daily DMF with 60 Gy RT and concurrent TMZ 75 mg/m2 daily, followed by maintenance DMF (continuously) and TMZ 150-200 mg/m2 on days 1-5 of each 28-day cycle for up to 6 cycles. The maximum tolerated dose (MTD) was determined by evaluation of dose-limiting toxicity (DLT) during the first 6 weeks of therapy. RESULTS: Twelve patients were treated at the 3 dose levels, and no DLTs were observed. There were no unexpected toxicities. The most common grade 3/4 treatment related adverse events (AEs) were lymphopenia (58%), decreased CD4 count (17%), and thrombocytopenia (17%). Four patients completed all planned treatment; seven patients had progression on treatment. One patient chose to withdraw from the study during maintenance. The median progression-free survival (PFS) for all patients was 8.7 months with no difference in PFS between those with stable disease or a partial response; median overall survival was 13.8 months. CONCLUSIONS: DMF may be safely combined with RT and TMZ in patients with newly diagnosed GBM. The RP2D for DMF is 240 mg three times daily.

Phase I Study of Sorafenib and Vorinostat in Advanced Hepatocellular Carcinoma.

OBJECTIVES: Preclinical data suggest histone deacetylase inhibitors improve the therapeutic index of sorafenib. A phase I study was initiated to establish the recommended phase 2 dose of sorafenib combined with vorinostat in patients with unresectable hepatocellular carcinoma. MATERIALS AND METHODS: Patients received vorinostat (200 to 400 mg by mouth once daily, 5 of 7 d) and sorafenib at standard or reduced doses (400 mg [cohort A] or 200 mg [cohort B] by mouth twice daily). Patients who received 14 days of vorinostat in cycle 1 were evaluable for dose-limiting toxicity (DLT). RESULTS: Sixteen patients were treated. Thirteen patients were evaluable for response. Three patients experienced DLTs, 2 in cohort A (grade [gr] 3 hypokalemia; gr 3 maculopapular rash) and 1 in cohort B (gr 3 hepatic failure; gr 3 hypophosphatemia; gr 4 thrombocytopenia). Eleven patients required dose reductions or omissions for non-DLTtoxicity. Ten patients (77%) had stable disease (SD). The median treatment duration was 4.7 months for response-evaluable patients. One patient with SD was on treatment for 29.9 months, and another patient, also with SD, was on treatment for 18.7 months. Another patient electively stopped therapy after 15 months and remains without evidence of progression 3 years later. CONCLUSIONS: Although some patients had durable disease control, the addition of vorinostat to sorafenib led to toxicities in most patients, requiring dose modifications that prevented determination of the recommended phase 2 dose. The combination is not recommended for further exploration with this vorinostat schedule in this patient population.

Integrated versus nOn-integrated Peripheral inTravenous catheter. Which Is the most effective systeM for peripheral intravenoUs catheter Management? (The OPTIMUM study): a randomised controlled trial protocol.

INTRODUCTION: Peripheral intravenous catheters (PIVCs) are frequently used in hospitals. However, PIVC complications are common, with failures leading to treatment delays, additional procedures, patient pain and discomfort, increased clinician workload and substantially increased healthcare costs. Recent evidence suggests integrated PIVC systems may be more effective than traditional non-integrated PIVC systems in reducing phlebitis, infiltration and costs and increasing functional dwell time. The study aim is to determine the efficacy, cost-utility and acceptability to patients and professionals of an integrated PIVC system compared with a non-integrated PIVC system. METHODS AND ANALYSIS: Two-arm, multicentre, randomised controlled superiority trial of integrated versus non-integrated PIVC systems to compare effectiveness on clinical and economic outcomes. Recruitment of 1560 patients over 2 years, with randomisation by a centralised service ensuring allocation concealment. Primary outcomes: catheter failure (composite endpoint) for reasons of: occlusion, infiltration/extravasation, phlebitis/thrombophlebitis, dislodgement, localised or catheter-associated bloodstream infections. SECONDARY OUTCOMES: first time insertion success, types of PIVC failure, device colonisation, insertion pain, functional dwell time, adverse events, mortality, cost-utility and consumer acceptability. One PIVC per patient will be included, with intention-to-treat analysis. Baseline group comparisons will be made for potentially clinically important confounders. The proportional hazards assumption will be checked, and Cox regression will test the effect of group, patient, device and clinical variables on failure. An as-treated analysis will assess the effect of protocol violations. Kaplan-Meier survival curves with log-rank tests will compare failure by group over time. Secondary endpoints will be compared between groups using parametric/non-parametric techniques. ETHICS AND DISSEMINATION: Ethical approval from the Royal Brisbane and Women's Hospital Human Research Ethics Committee (HREC/16/QRBW/527), Griffith University Human Research Ethics Committee (Ref No. 2017/002) and the South Metropolitan Health Services Human Research Ethics Committee (Ref No. 2016-239). Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12617000089336.

Exposure Characteristics of Hantavirus Pulmonary Syndrome Patients, United States, 1993-2015.

Those at highest risk are persons in occupations with potential for rodent exposure and American Indian women 40--64 years of age.

Examining the effectiveness of a culturally adapted social-emotional intervention for African American males in an urban setting.

The purpose of the present study was to assess the efficacy of a culturally adapted version of the Strong Start intervention program on the social-emotional outcomes of African American male students. Externalizing behavior problems of children, specifically African American males, are of great concern for schools. Punitive discipline polices such as expulsion and suspension have proved to be ineffective and harmful. Consequently, school-based social-emotional learning (SEL) interventions have been proposed to teach children coping skills that can help them increase positive social behaviors and emotional regulation. Sixty-one African American male students enrolled in an urban elementary school participated in this intervention. This study employed a randomized delayed treatment control design. Results indicated positive effects in the areas of self-regulation and self-competence. However the intervention did not have an impact on student's empathy, responsibility, or externalizing behavior. Implications are discussed in terms of developing culturally relevant school-based interventions for African American males. (PsycINFO Database Record

A focus on building information modelling.

With the Government Construction Strategy requiring a strengthening of the public sector's capability to implement Building Information Modelling (BIM) protocols, the goal being that all central government departments will be adopting, as a minimum, collaborative Level 2 BIM by 2016, Alison Ryan, of consulting engineers, DSSR, explains the principles behind BIM, its history and evolution, and some of the considerable benefits it can offer. These include lowering capital project costs through enhanced co-ordination, cutting carbon emissions, and the ability to manage facilities more efficiently.

Mock juror sensitivity to forensic evidence in drug facilitated sexual assaults.

Mock jurors' reactions to variations in the quality of toxicological evidence regarding the presence of drugs in a sexual assault trial were examined. In Study 1, participants received a trial summary in which a negative test result, a negative test result plus expert testimony, or no test result was presented. The time taken by the complainant to report the alleged sexual assault was manipulated. The negative test result influenced participants' judgments, but this effect was minimized by the presence of expert testimony. The complainant's delay in reporting had little impact on judgments. In Study 2, complainant time to report was again manipulated along with the outcome of the test result (negative finding and no result). Results revealed that men were less conviction prone when the negative test result was obtained early as opposed to late. In contrast, when the test result was unavailable, men were more conviction prone when the complainant reported late as oppose to early.

Targeted deletion of the zebrafish obscurin A RhoGEF domain affects heart, skeletal muscle and brain development.

Obscurin is a giant structural and signaling protein that participates in the assembly and structural integrity of striated myofibrils. Previous work has examined the physical interactions between obscurin and other cytoskeletal elements but its in vivo role in cell signaling, including the functions of its RhoGTPase Exchange Factor (RhoGEF) domain have not been characterized. In this study, morpholino antisense oligonucleotides were used to create an in-frame deletion of the active site of the obscurin A RhoGEF domain in order to examine its functions in zebrafish development. Cardiac myocytes in the morphant embryos lacked the intercalated disks that were present in controls by 72 and, in the more severely affected embryos, the contractile filaments were not organized into mature sarcomeres. Neural abnormalities included delay or loss of retinal lamination. Rescue of the phenotype with co-injection of mini-obscurin A expression constructs demonstrated that the observed effects were due to the loss of small GTPase activation by obscurin A. The immature phenotype of the cardiac myocytes and the retinal neuroblasts observed in the morphant embryos suggests that obscurin A-mediated small GTPase signaling promotes tissue-specific cellular differentiation. This is the first demonstration of the importance of the obscurin A-mediated RhoGEF signaling in vertebrate organogenesis and highlights the central role of obscurin A in striated muscle and neural development.