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INTRODUCTION: Bone metastases occur frequently in castration-resistant prostate cancer (CRPC) and may lead to skeletal-related events (SREs), including symptomatic skeletal events (SSEs). Bone-modifying agents (BMAs) delay SREs and SSEs. However, the real-world use of BMAs is debated given the absence of demonstrated survival advantage and potential adverse events (AEs). Our retrospective study examined BMA use and SSE rates in Australian patients with CRPC. METHODS: Patients with CRPC and bone metastases were identified from the electronic CRPC Australian Database. Patient characteristics, treatment patterns and AEs were analysed. Descriptive statistics reported baseline characteristics, SSE rates and BMA use. Comparisons between groups used t-tests and Chi-square analyses. Overall survival was calculated by the Kaplan-Meier method. RESULTS: A total of 532 eligible patients were identified with a median age of 73 years (range: 44-97 years). BMAs were prescribed in 232 men (46%), 183 of whom received denosumab. Patients receiving first-line docetaxel for CRPC were more likely to commence BMAs than those receiving abiraterone or enzalutamide (51% vs 31% vs 38%; p = 0.004). SSEs occurred in 148 men (28%), most commonly symptomatic lesions requiring intervention (75%). At the time of initial SSEs, only 28% were receiving BMAs. Patients treated at sites with lower BMA use (

Vadadustat is an investigational hypoxia-inducible factor prolyl hydroxylase inhibitor that increases endogenous erythropoietin production and has been shown to decrease hepcidin levels, ameliorate iron restriction, and increase hemoglobin concentrations in anemic patients with chronic kidney disease (CKD). In studies of physiological responses to other erythropoietic stimuli, erythropoietin induced erythroblast secretion of erythroferrone (ERFE), which acts on the liver to suppress hepcidin production and mobilize iron for erythropoiesis. We therefore investigated whether vadadustat effects on erythropoiesis and iron metabolism are dependent on ERFE. Wild type and ERFE knockout mice with and without CKD were treated with vadadustat or vehicle. In both wild type and ERFE knockout CKD models, vadadustat was similarly effective, as evidenced by normalized hemoglobin concentrations, increased expression of duodenal iron transporters, lower serum hepcidin levels, and decreased tissue iron concentrations. This is consistent with ERFE-independent increased iron mobilization. Vadadustat treatment also lowered serum urea nitrogen and creatinine concentrations and decreased expression of kidney fibrosis markers. Lastly, vadadustat affected fibroblast growth factor 23 (FGF23) profiles: in non-CKD mice, vadadustat increased plasma total FGF23 out of proportion to intact FGF23, consistent with the known effects of hypoxia-inducible factor-1α and erythropoietin on FGF23 production and metabolism. However, in the mice with CKD, vadadustat markedly decreased both total and intact FGF23, effects likely contributed to by the reduced loss of kidney function. Thus, in this CKD model, vadadustat ameliorated anemia independently of ERFE, improved kidney parameters, and decreased FGF23. How vadadustat affects CKD progression in humans warrants future studies.

Background Ramucirumab-an IgG1 vascular endothelial growth factor receptor 2 antagonistplus docetaxel was previously reported to improve progression-free survival in platinum-refractory, advanced urothelial carcinoma. Here, we report the secondary endpoint of overall survival results for the RANGE trial.Methods We did a randomised, double-blind, phase 3 trial in patients with advanced or metastatic urothelial carcinoma who progressed during or after platinum-based chemotherapy. Patients were enrolled from 124 investigative sites (hospitals, clinics, and academic centres) in 23 countries. Previous treatment with one immune checkpoint inhibitor was permitted. Patients were randomly assigned (1:1) using an interactive web response system to receive intravenous ramucirumab 10 mg/kg or placebo 10 mg/kg volume equivalent followed by intravenous docetaxel 75 mg/m 2 (60 mg/m 2 in Korea, Taiwan, and Japan) on day 1 of a 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Randomisation was stratified by geographical region, Eastern Cooperative Oncology Group performance status at baseline, and visceral metastasis. Progression-free survival (the primary endpoint) and overall survival (a key secondary endpoint) were assessed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT02426125; patient enrolment is complete and the last patient on treatment is being followed up for safety issues.Findings Between July 20, 2015, and April 4, 2017, 530 patients were randomly allocated to ramucirumab plus docetaxel (n=263) or placebo plus docetaxel (n=267) and comprised the intention-to-treat population. At database lock (March 21, 2018) for the final overall survival analysis, median follow-up was 7.4 months (IQR 3.5-13.9). In our sensitivity analysis of investigator-assessed progression-free survival at the overall survival database lock, median progression-free survival remained significantly improved with ramucirumab compared with placebo (4.1 months [95% CI 3.3-4.8] vs 2.8 months [2.6-2.9]; HR 0.696 [95% CI 0.573-0.845]; p=0.0002). Median overall survival was 9.4 months (95% CI 7.9-11.4) in the ramucirumab group versus 7.9 months (7.0-9.3) in the placebo group (stratified HR 0.887 [95% CI 0.724-1.086]; p=0.25). Grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients and with an incidence more than 2% higher with ramucirumab than with placebo were febrile neutropenia (24 [9%] of 258 patients in the ramucirumab group vs 16 [6%] of 265 patients in the placebo group) and neutropenia (17 [7%] of 258 vs six [2%] of 265). Serious adverse events were similar between groups (112 [43%] of 258 patients in the ramucirumab group vs 107 [40%] of 265 patients in the placebo group). Adverse events related to study treatment and leading to death occurred in eight (3%) patients in the ramucirumab group versus five (2%) patients in the placebo group.Interpretation Additional follow-up supports that ramucirumab plus docetaxel significantly improves progression-free survival, without a significant improvement in overall survival, for patients with platinum-refractory advanced urothelial carcinoma. Clinically meaningful benefit might be restricted in an unselected population. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

The human body is a large reservoir for bacterial viruses known as bacteriophages (phages), which participate in dynamic interactions with their bacterial and human hosts that ultimately affect human health. The current growing interest in human resident phages is paralleled by new uses of phages, including the design of engineered phages for therapeutic applications. Despite the increasing number of clinical trials being conducted, the understanding of the interaction of phages and mammalian cells and tissues is still largely unknown. The presence of phages in compartments within the body previously considered purely sterile, suggests that phages possess a unique capability of bypassing anatomical and physiological barriers characterized by varying degrees of selectivity and permeability. This review will discuss the direct evidence of the accumulation of bacteriophages in various tissues, focusing on the unique capability of phages to traverse relatively impermeable barriers in mammals and its relevance to its current applications in therapy.

Objective To examine the tolerability and antitumor activity of trebananib plus pegylated liposomal doxorubicin (PLD) or topotecan in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Methods In this open-label phase 1b study, patients received trebananib 10mg/kg or 15mg/kg IV QW plus PLD 50mg/m 2 (cohorts A1 and A3, respectively) or topotecan 4mg/m 2 (cohorts B1 and B3, respectively). Endpoints were dose-limiting toxicity (DLT; primary); treatment-emergent adverse events (AEs), overall response rate, anti-trebananib antibodies, and pharmacokinetics (secondary). Results 103 patients were enrolled. One patient in A1 and B1 had DLTs. Across all cohorts, the most common AEs were nausea, fatigue, and peripheral edema. Across both trebananib plus PLD cohorts (A1/A3), grade 4 AEs were pulmonary embolism, disease progression, and anemia. Two patients had grade 5 intestinal perforation (n=1) and sudden death (n=1). Across both trebananib plus topotecan cohorts (B1/B3), grade 4 AEs were neutropenia, hypokalemia, decreased granulocyte count, chest pain, dyspnea, decreased neutrophil count, and pulmonary embolism. Two patients had grade 5 disease progression. One patient had grade 5 pleural effusion associated with progressive disease. Confirmed objective response rates were 36.0% (A1), 34.8% (A3), 16.7% (B1), and 0.0% (B3). Median progression-free survival duration (months) was 7.4 (A1), 7.1 (A3), 3.5 (B1), and 3.1 (B3), respectively. No drug–drug interactions were apparent. Conclusions Trebananib 10mg/kg and 15mg/kg IV QW plus PLD or topotecan appear to have acceptable toxicity profiles in recurrent platinum-resistant or partially platinum-sensitive ovarian cancer. Antitumor activity was evident across all cohorts.

Palliative chemotherapy has an increasing role in the management of recurrent high-grade gliomas. Temozolomide is a well-tolerated agent that results in objective responses and stabilisation of disease. Theoretically, temozolomide may be more effective when given in a prolonged schedule rather than the standard 5 days-monthly schedule. This Phase II study examined the efficacy and toxicity of temozolomide when given in a two-weekly schedule. Twenty-five patients received 150 mg/m2 temozolomide daily for seven days alternating with seven days of no treatment. One cycle of temozolomide was a total of two weeks treatment in every 28 days. Of the 25 evaluable patients, there was one complete response (4%), four partial responses (16%) and 10 patients had disease stablisation (40%). The progression free survival at 6 months was 56%. Two-weekly temozolomide was well tolerated with only four episodes of Grade 3 thrombocytopenia. Overall, two-weekly temozolomide is an active and well tolerated schedule, but does not appear to improve on the activity of temozolomide using the standard 5-day schedule.

Postoperative acute confusion (ACS) is a significant problem among older surgical patients; its incidence is greater in orthopaedic than in general surgery. This descriptive prospective study described the hospital recovery pattern of older confused and non-confused patients after hip surgery. The study sample included 54 patients aged 60 years or older consecutively admitted to a teaching hospital for emergency or elective hip surgery. Their cognitive status assessed by the Confusion Assessment Method (CAM), physiological status, functional ability, sleep satisfaction, and perceived discomfort were evaluated at baseline. These assessments were repeated on the first 4 postoperative days. The incidence of ACS over 4 postoperative days was 35%, 37%, 28% and 12%, respectively. Confused and non-confused patients differed significantly in age, admission diagnosis, and length of hospital stay ( P

Cardiovascular disease (CVD) is the leading cause of death and disability among women. The present investigation analyzed data from the National Population Health Survey to examine the prevalence trends of self-reported lifestyle CVD risk factors in adult women. Results indicated an upward prevalence trend in physical activity and high blood pressure, and significant increased prevalence rates in obesity in the lower middle and middle income groups. Logistic regression analysis showed that increased physical activity and advancing age were significant predictors of CVD; age confers more than a one-fold risk for developing heart disease and hypertension. Implications of the study results for nursing practice are discussed.

The study addressed two research questions: Were patients ‘home-ready' at the time of discharge from the acute care hospital following total hip replacement (THR) surgery? and what was their pattern of recovery? The research was descriptive in design, using a sample of 50 post THR patients. Four days after surgery, nurses assessed patient's home-readiness using the Post Total Hip Replacement Discharge Scoring Scale (PTHRDSS). They were considered hypothetically ‘home-ready' if they scored >-25 on the PTHRDSS, and ‘not home-ready' if their total score was The study showed that the hypothetically ‘home-ready' patients were younger, had better postoperative functional and psychological status and were discharged to home on day 8. A substantial proportion (35%) of patients who were hypothetically ‘not home-ready' were sent directly to their home on day 9 after THR. Hip function, Activities of Daily Living (ADLs), age and psychological status were significant factors related to home-readiness, whereas social support and hip function were significant determinants of recovery. It was concluded that psychosocial factors in addition to the functional status should be considered when assessing the patient's ‘home-readiness' and recovery after THR.

Coronary heart disease (CHD) is known as a disease of postmenopausal women. While hormone replacement therapy is recommended increasingly to postmenopausal women for the prevention of CHD, the potential impact of non-pharmacologic interventions on cardiovascular disease reduction has been largely unexplored. The purpose of this article is to develop the understanding of the research literature on three risk factors by which estrogen and physical activity, a non-pharmacologic intervention, may confer cardiovascular protection in postmenopausal women. Three risk factors are lipoproteins, systolic pressure, and changes in the vascular endothelial functions. Effects of estrogen and physical activity on these biological factors are compared.

The present study set out to examine the contribution of basic sciences to academic success in nursing education. A number of regression analysis models were used to analyze the relationships among predictor and criterion variables. Data analyses showed that basic sciences and grade point average of nursing courses in year 3 and 4 contributed significantly to student success in the program (p < 0.001). The cumulative grade point average was the only significant predictor of the licensure examination success. These results suggested that the content in science courses may have unique relevance to nursing and, therefore, may have a factor in their predictive value.

Gene therapy depends on the successful transfer of genetic material into the nuclei of targeted human cells. Non-viral strategies address the safety concerns of viral gene delivery, but generally suffer from low transfection efficiencies. We previously constructed an enhanced linear covalently closed (LCC) minivector, a DNA ministring, which confers improved efficiency and safety over its plasmid, and even its isogenic circular counterparts. DNA minivectors are comprised solely of the eukaryotic expression cassette without the bulk of an immunogenic bacterial backbone, thus ensuring greater bioavailability, higher transfection efficiency, and prolonged duration of gene expression. The linear nature of DNA ministrings minimizes the potential for insertional mutagenesis from random genomic integration.DNA ministrings are produced through a bacteriophage (phage) -derived recombination system in recombinant Escherichia coli (Fig. 1A). The phage-derived protelomerase, Tel, regulated via a temperature-inducible expression system, acts on a parent plasmid to produce DNA ministrings in vivo, later purified for gene transfer applications. We report further development in DNA ministring production. By encoding a homing endonuclease under control of a separate promoter, and its respective target site onto the backbone of the parent plasmid, we eliminate residual parent plasmid and LCC backbone, simplifying ministring purification.We also began construction of a novel platform utilizing filamentous phage M13 to produce phage-encapsulated DNA ministrings as a one-step therapeutic production system, termed BEAM (Bacteriophage Encapsulated & Assisted Ministring) (Fig. 1B). Phages are exploited for drug delivery because they are safe, easy to produce, and genetically versatile. Since M13 packages single-stranded DNA (ssDNA), the parent plasmid must produce an ssDNA molecule that encodes both the ministring base sequence and its complementary sequence, which can anneal to form the double-stranded DNA (dsDNA) ministring prior to packaging. We report our initial developments for this plasmid.Last, we examine the applicability of DNA ministrings towards ovarian cancer therapy. We encoded negative dominant topoisomerase alleles, hypothesized to produce DNA-damaging derivatives mimicking the effect of common chemotherapeutics such as topotecan. We present the results of ministring delivery of such alleles in the treatment of ovarian cancer cell lines. View Large Image | Download PowerPoint Slide

Chondroitin lyase products of aggrecan and small proteoglycans from normal and osteoarthritic cartilages were analyzed for chain internal Δdisaccharides and terminal mono- or disaccharides. Chondroitin and dermatan sulfate chains from arthritic cartilages were of essentially normal size and internal sulfation but had significantly altered sulfation of the terminal residues. Whereas in normal cartilage, ∼60% of terminal GalNAc4S was 4,6-disulfated, it was reduced to ∼30% in osteoarthritic cartilage. This is most likely due to a lower terminal GalNAc4,6S-disulfotransferase activity and reveals that metabolic changes in osteoarthritis can affect this distinct sulfation step during chondroitin and dermatan sulfate synthesis. GlcAβ1,3GalNAc6S-, the mimotope for antibody 3B3(−), was present on ∼8 and ∼10% of chains from normal and osteoarthritic cartilages, respectively. 3B3(−) assayed by immunodot blot was within the normal range for most osteoarthritic samples, with only 5 of 24 displaying elevated reactivity. This resulted not from a higher content of mimotope, but possibly from other structural changes in the proteoglycan that increase mimotope reactivity. In summary, chemical determination of sulfation isomers at the non-reducing termini of chondroitin and dermatan sulfate provides a reliable assay for monitoring proteoglycan metabolism not only during normal growth of cartilage but also during remodeling of cartilage in osteoarthritis.

Samples of aggrecan chondroitin sulfate, isolated from normal human knee cartilages of individuals from fetal to 72 years of age, were digested with chondroitin lyases. The products were analyzed by fluorescence-based anion exchange high performance liquid chromatography to separate and quantitate nonreducing terminal structures, in addition to internal unsaturated disaccharide products. The predominant terminal structures were the monosaccharides, GalNAc4S and GalNAc4,6S as they were present on 85-90% of all chains. The remaining chains terminated with the disaccharides GlcAbeta1,3GalNAc4S and GlcAbeta1,3GalNAc6S. Marked changes in the relative abundance of these terminals were identified in the transition from growth cartilage to adult articular cartilage. First, terminal GalNAc residues were almost exclusively 4-sulfated in aggrecan from fetal through 15 years of age, but were approximately 50% 4,6-disulfated in aggrecans from adults (22-72 years of age). Second, the terminal disaccharide GlcAbeta1,3GalNAc4S was on approximately 7% of chains on aggrecan from fetal through 15 years of age, but on only approximately 3% of chains on adult aggrecan. In contrast, the proportion of chains terminating in GlcAbeta1,3GalNAc6S, approximately 9%, was unchanged from fetal to 72 years of age. This terminal disaccharide is proposed to be recognized by the widely used monoclonal antibody 3B3. However, chemical quantitation of the structure together with solid phase 3B3(-) immunoassay of fetal and adult aggrecans showed that the content of the terminal disaccharide does not necessarily correlate with immunoreactivity of the proteoglycan, as chain density and presentation on the solid phase are critical factors for recognition of chain terminals by 3B3. The quantitative results obtained from chemical analyses of all nonreducing termini of aggrecan chondroitin sulfate chains revealed important changes in chain termination that occur when cellular activities are altered as adult articular cartilage is formed after removal of growth cartilage. These findings are discussed in relation to specific enzymatic steps that generate the nonreducing termini of chains in the biosynthesis pathway of chondroitin sulfate proteoglycans and their modulation in tissue development and pathology.

The intracellular compartmentalization of enzyme activities involved in the elongation and sulfation of glycosaminoglycans on aggrecan, decorin, and fibromodulin was investigated using brefeldin A, a compound with known inhibitory action on normal vesicular transport and secretion of macromolecules. Treatment of bovine chondrocyte cultures with the compound resulted in greater than 98% inhibition of Na 35 SO 4 incorporation into macromolecules, whereas [ 3 H]leucine or [ 3 H]glucosamine continued at 60-70% of the levels measured in control cultures. The release of newly synthesized products into the medium was also decreased markedly by brefeldin A to 7 and 2% of control levels for [ 3 H]leucine- and [ 3 H]glucosamine-labeled macromolecules, respectively. Analysis of [ 3 H]glucosamine-labeled products in these cultures showed that synthesis of sulfated glycosaminoglycans (chondroitin/dermatan sulfate and keratan sulfate) was inhibited in response to brefeldin A, whereas hyaluronan synthesis was essentially unaffected. Significant amounts of elongated chondroitin continued to be synthesized in the presence of brefeldin A. Immunoprecipitation of [ 3 H]leucine-labeled decorin, aggrecan, and fibromodulin from cells showed that aggrecan and fibromodulin were not substituted with glycosaminoglycans, whereas all decorin molecules synthesized under these conditions were substituted with chondroitin. The results suggest that in articular chondrocytes, elongation of the glycosaminoglycan chains on decorin, but not their sulfation, occurs in a Golgi compartment unaffected by disruption of vesicular core protein transport. This is in contrast to glycosaminoglycan elongation and sulfation on aggrecan and fibromodulin, where both processes apparently occur in the trans -Golgi network, which becomes inaccessible to these core proteins in the presence of brefeldin A. The results further suggest that in brefeldin A-treated cells decorin is contained in a discrete ER-Golgi compartment separated from aggrecan; this compartment is accessible to p -nitrophenyl-β-D-xylosides, since β-xylosides become elongated with chondrotin even in the presence of brefeldin A.

The cartilage matrix glycoprotein fibromodulin contains four N-linked glycosylation sites which act as acceptors for the addition of sulfated polylactosamine (keratan sulfate). In the present study we examined the biosynthetic processing of these N-linked oligosaccharides for subsequent addition of polylactosamine. Chondrocytes were treated with castanospermine, 1-(+)deoxymannojirimycin, and swainsonine, radiolabeled with [3,4,5-3H]leucine, [2-3H]mannose, or [6-3H]glucosamine, and newly synthesized fibromodulin was immunoprecipitated for analysis. Castanospermine and 1-(+)deoxymannojirimycin inhibited polylactosamine addition, whereas swainsonine was not effective. This indicated that the linkage regions must be processed to GlcNAc(Man)5(GlcNAc)2Asn but do not require further modification to GlcNAc(Man)3(GlcNAc)2Asn. In both control and swainsonine-treated cells one or two N-linked oligosaccharides per molecule were modified with polylactosamine containing 4-6 repeating disaccharide units. Moreover, a single short chain was added either to the C-3 or the C-6 branch in control cultures, whereas only the C-3 branch was substituted in the presence of swainsonine. Analysis of endo-beta-galactosidase and keratanase II digestion products of the polylactosamine chains synthesized in both culture conditions showed that only about 25% of the hexosamine residues and less than 5% of the adjacent galactose residues were substituted with sulfate. These findings are discussed in relation to the regulation of fibromodulin glycosylation and the likely influence of polylactosamine structure on the extracellular interactions and turnover of fibromodulin.

It has been suggested that the JT rather than QT interval properly reflects repolarization duration in ventricular conduction defects (VCD). The authors examined the influence of QRS duration on the JT and QT intervals in 20,687 normal adult subjects and 2,865 subjects with various categories of VCD. Estimates for coefficients for multiple regression of QRS duration on QT and JT intervals combined with a correction term for heart rate (HR) were determined for each VCD category. QRS duration accounted for about 16% of total QT variation, but had a practically negligible effect on JT interval in complete bundle branch blocks. A single-parameter formula was derived for the JT prolongation index of the form JTI = JT(HR + 100)/518, with a JTI > or = 112 identifying repolarization prolongation in all VCD categories. It is concluded that it is preferable to predict JT rather than QT as a more appropriate index of duration of repolarization in VCD.

This paper reports the results of a study evaluating the effects of an experimental program on post-hospital adjustment of early discharged patients after total hip arthroplasties. This experimental program consisted of patient teaching by means of a pamphlet and videotape, and regular home visits by a community health nurse. A significant difference was found between the experimental and control patients in perceived preparedness for discharge and post-hospital exercise compliance. The early discharged experimental patients demonstrated post-hospital objective and subjective functional capabilities equal to those of the control patients. This study is seen to have implications for nursing service and nursing education.