A consensus viewpoint on the role of direct factor Xa inhibitors in the management of cancer-associated venous thromboembolism in the UK.

OBJECTIVE: Cancer patients are at high risk of venous thromboembolism (VTE), a significant cause of cancer-related death. Historically, low molecular weight heparins (LMWH) were the gold standard therapy for cancer-associated VTE, but recent evidence supports the use of direct factor Xa inhibitors in cancer-associated VTE and this is now reflected in many guidelines. However, uptake of direct factor Xa inhibitors varies and guidance on the use of direct factor Xa inhibitors in specific cancer sub-populations and clinical situations is lacking. This review presents consensus expert opinion alongside evaluation of evidence to support healthcare professionals in the use of direct factor Xa inhibitors in cancer-associated VTE. METHODS: Recent guidelines, meta-analyses, reviews and clinical studies on anticoagulation therapy for cancer-associated VTE were used to direct clinically relevant topics and evidence to be systematically discussed using nominal group technique. The consensus manuscript and recommendations were developed based on these discussions. RESULTS: Considerations when prescribing anticoagulant therapy for cancer-associated VTE include cancer site and stage, systemic anti-cancer therapy (including vascular access), drug-drug interactions, length of anticoagulation, quality of life and needs during palliative care. Treatment of patients with kidney or liver impairment, gastrointestinal disorders, extremes of bodyweight, elevated bleeding or recurrence risk, VTE recurrence and COVID-19 is discussed. CONCLUSION: Anticoagulant therapy for cancer-associated VTE patients should be carefully selected with consideration given to the relative benefits of specific drugs when individualizing care. Direct factor Xa inhibitors are typically the treatment of choice for preventing VTE recurrence in non-cancer patients and should also be considered as such for cancer-associated VTE in most situations.

A Double-blind, Placebo-controlled, Randomized, Single Ascending, and Multiple Dose Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral Dose Isomyosamine Capsules in Healthy Adult Subjects.

BACKGROUND: Aging is tightly linked to chronic disease, frailty, and death. Multi-morbidity, defined as the presence in the same patient of three or more conditions such as neoplastic, cardiovascular, neurodegenerative, metabolic, or autoimmune diseases, becomes more common with age. METHODS: The study was performed in a double-blind fashion. Subjects within each dose cohort (Cohorts 1, 2, 3, and 4) were randomly assigned to receive Isomyosamine doses (between 150 mg to 600 mg or placebo) or placebo in a 3:1 ratio (6 active: 2 placebo). RESULTS: Isomyosamine single daily doses each of 150 mg, 300 mg, and 450 mg for 3 days and multiple daily doses of 600 mg for 6 days were safe and well tolerated in healthy subjects. In one dose group, there was a decrease in TNF-α levels found in Isomyosamine treated subjects, but no change in the levels in subjects given placebo. The increase in Isomyosamine exposure was proportional to dose across the dose range of 300 mg to 600 mg when administered as a single dose. There was minimal accumulation of Isomyosamine following 5 days of once daily dosing of Isomyosamine 600 mg. Isomyosamine half-life ranged from approximately 15 minutes to 45 minutes across all doses in the single ascending dose and multiple ascending dose portion of the study. Elimination of Isomyosamine included the renal pathway as a minor route. CONCLUSION: Isomyosamine will continue to be investigated in phase 2 clinical trials for the treatment of sarcopenia/frailty, hashimoto's thyroiditis and rheumatoid arthritis.

3D - Printed Patient Specific Instrumentation in Corrective Osteotomy of the Femur and Pelvis: A Review of the Literature.

BACKGROUND: The paediatric patient population has considerable variation in anatomy. The use of Computed Tomography (CT)-based digital models to design three-dimensionally printed patient specific instrumentation (PSI) has recently been applied for correction of deformity in orthopedic surgery. This review sought to determine the existing application of this technology currently in use within paediatric orthopaedics, and assess the potential benefits that this may provide to patients and surgeons. METHODS: A review was performed of MEDLINE, EMBASE, and CENTRAL for published literature, as well as Web of Science and clinicaltrials.gov for grey literature. The search strategy revolved around the research question: "What is the clinical impact of using 3D printed PSI for proximal femoral or pelvic osteotomy in paediatric orthopaedics?" Two reviewers, using predetermined inclusion criteria, independently performed title and abstract review in order to select articles for full text review. Data extracted included effect on operating time and intraoperative image use, as well as osteotomy and screw positioning accuracy. Data were combined in a narrative synthesis; meta-analysis was not performed given the diversity of study designs and interventions. RESULTS: In total, ten studies were included: six case control studies, three case series and a case report. Five studies directly compared operating time using PSI to conventional techniques, with two showing a significant decrease in the number of intraoperative images and operative time. Eight studies reported improved accuracy in executing the surgical plan compared to conventional methods. CONCLUSION: Compared to conventional methods of performing femoral or pelvic osteotomy, use of PSI has led to improved accuracy and precision, decreased procedure times, and decreased intra-operative imaging requirements. Additionally, the technology has become more cost effective and accessible since its initial inception and use.

The flipped classroom for medical students.

BACKGROUND: The objectives of this curricular innovation project were to implement a flipped classroom curriculum for the gynaecologic oncology topics of the obstetrics and gynaecology medical student clerkship, and to evaluate student satisfaction with the change. METHODS: Four short online videos on the topics of endometrial hyperplasia, cervical dysplasia, evaluation of an adnexal mass, and ovarian cancer were created, and students were instructed to view them prior to a class-time active learning session. The Learning Activity Management System (lams) open-source online platform was used to create an active learning class-time activity that consisted of a coached discussion of cases. Student satisfaction with the two aspects of the flipped curriculum was obtained. In addition, lecture assessment for the gynaecologic oncology topics and aggregate student performance on the gynaecological oncology questions of the US National Board of Medical Examiners (NBME) Subject Examination were compared before and after implementation of the curriculum. RESULTS: Eighty-nine students rotated on the clerkship during the pilot period of analysis. Seventy-one students (80%) viewed the videos prior to the class session, and 84 (94%) attended the session. Student satisfaction was very high for both parts of the curriculum. There was no significant difference in aggregate student performance on the gynaecological oncology questions of the NBME Subject Examination. The flipped classroom curriculum demonstrates a promising platform for using technology to make better use of students' time DISCUSSION: Our implementation of the flipped classroom curriculum for the gynaecologic oncology topics successfully demonstrates a promising platform for using technology to make better use of our students' time, and for increasing their satisfaction with the necessary didactic learning of the clerkship.

N-terminal modification of VEGF-A C terminus-derived peptides delineates structural features involved in neuropilin-1 binding and functional activity.

The interaction between VEGF-A and its neuropilin (NRP) receptors mediates a number of important biological effects. NRP1 and the related molecule NRP2 are widely expressed on multiple tumour types and throughout the tumour vasculature, and are emerging as critical molecules required for the progression of angiogenic diseases. Given the increasing evidence supporting a role for NRP1 in tumour development, there is growing interest in developing inhibitors of NRP1 interactions with VEGF and its other ligands. In order to probe the interaction we synthesised a number of exon 7- and 8-derived bicyclic peptides with N-terminal lipophilic groups and found a simple N-octanoyl derivative (EG00086) to be the most potent and functionally active. Detailed modelling studies indicated that new intramolecular hydrogen bonds were formed, stabilising the structure and possibly contributing to the potency. Removal of a salt bridge between D142 and R164 implicated in VEGF-A binding to neuropilin-1 had a minor effect on potency. Isothermal calorimetry was used to assess binding of EG00086 to NRP1 and NRP2, and the stability of the peptide in serum and in vivo was investigated. EG00086 is a potent blocker of VEGF-promoted cellular adhesion to extracellular matrices, and phosphorylation of p130Cas contributes to this effect.

Online learning applied to a course on rational therapeutics: an international comparison between final year students of two medical schools.

INTRODUCTION: Poor prescribing is probably the most common cause of preventable medication errors and many of these events involve junior doctors. In 2009, an electronic problem-based therapeutics course developed at the University of Michigan Medical School (UMMS) was translated and adapted for use at the University of Zagreb Medical School (UZMS). METHODS: After students from both schools took the course in 2010, we compared their responses with an online questionnaire addressing the course quality and its effectiveness. RESULTS: There were no statistically significant differences in the overall average grades awarded for the course (UZMS 4.11 ± 0.86 vs. UMMS 3.96 ± 0.93; 95% CI mean difference (MD) -0.36, 0.07; P = 0.175) with both student groups expressing high satisfaction rates with its quality, accessibility and overall design. UZMS students reported spending less time working through the course than their American colleagues (2.14 ± 1.01 vs. 2.89 ± 1.02 on a five point Likert scale; 95% CI MD 0.51, 0.99; P < 0.05). Furthermore, Croatian students indicated greater difficulty with course materials (3.54 ± 0.59 vs. 3.25 ± 0.59; 95% CI MD -0.42, -0.15; P < 0,05) and weekly multiple choice questions (3.83 ± 0.62 vs. 3.4 ± 0.61; 95% CI MD -0.58, -0.29; P < 0,05) compared with the UMMS students. CONCLUSION: It is possible to adapt and translate successfully whole online teaching resources and implement them internationally in different countries and health care systems, achieving similar, high student satisfaction rates while decreasing administrative and cost burdens. Web based learning may have great potential to offer a cost effective and safe environment in which prescribing skills can be improved.

Intensity-modulated radiotherapy for tumors of the nasal cavity and paranasal sinuses: clinical outcomes and patterns of failure.

PURPOSE: To report outcomes in patients treated with intensity-modulated radiotherapy (IMRT) for tumors of the paranasal sinuses and nasal cavity (PNS/NC). METHODS/MATERIALS: Between June 2000 and December 2009, 52 patients with tumors of the PNS/NC underwent postoperative or definitive radiation with IMRT. Twenty-eight (54%) patients had squamous cell carcinoma (SCC). Twenty-nine patients (56%) received chemotherapy. The median follow-up was 26.6 months (range, 2.9-118.4) for all patients and 30.9 months for living patients. RESULTS: Eighteen patients (35%) developed local-regional failure (LRF) at median time of 7.2 months. Thirteen local failures (25%) were observed, 12 in-field and 1 marginal. Six regional failures were observed, two in-field and four out-of-field. No patients treated with elective nodal radiation had nodal regional failure. Two-year local-regional control (LRC), in-field LRC, freedom from distant metastasis (FFDM), and overall survival (OS) were 64%, 74%, 71%, and 66% among all patients, respectively, and 43%, 61%, 61%, and 53% among patients with SCC, respectively. On multivariate analysis, SCC and >1 subsite involved had worse LRC (p = 0.0004 and p = 0.046, respectively) and OS (p = 0.003 and p = 0.046, respectively). Cribriform plate invasion (p = 0.005) and residual disease (p = 0.047) also had worse LRC. Acute toxicities included Grade ≥3 mucositis in 19 patients (37%), and Grade 3 dermatitis in 8 patients (15%). Six patients had Grade ≥3 late toxicity including one optic toxicity. CONCLUSIONS: IMRT for patients with PNS/NC tumors has good outcomes compared with historical series and is well tolerated. Patients with SCC have worse LRC and OS. LRF is the predominant pattern of failure.

Risks associated with crack cocaine smoking among exotic dancers in Baltimore, MD.

BACKGROUND: There is a dearth of research focusing on sex work in exotic dance clubs. We conducted a cross-sectional study to examine the prevalence and correlates of crack cocaine smoking among a sample of exotic dancers. METHODS: The "block," a historical red-light district in downtown Baltimore, MD, is comprised of 30 adult-entertainment establishments. Between 01/09 and 08/09, we conducted a survey with exotic dancers (N=98). The survey explored demographic, and drug and sexual/drug risk behaviors. Bivariate and multivariate analysis was conducted using Poisson regression with robust variance estimates to examine correlates of current crack smoking. RESULTS: Crack cocaine smokers compared to non-crack cocaine smokers were significantly more likely to report: older age (29 vs. 23 years, respectively, p<0.0001); being White (79% vs. 50%, respectively, p=0.008); having been arrested (93% vs. 67%, respectively, p=0.008); daily alcohol consumption (36% vs. 17%, p=0.047); current heroin injection (57% vs. 13%, p<0.001); and current sex exchange (79% vs. 30%, p<0.001). In the presence of other variables, crack cocaine smokers compared to non-crack cocaine smokers were significantly older, more likely to report current heroin injection, and more likely to report current sex exchange. DISCUSSION: We found high levels of drug use and sexual risk behaviors as well as a number of risks behaviors associated with crack cocaine smoking among this very under-studied population. Targeted interventions are greatly needed.

Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction.

We report the molecular design and synthesis of EG00229, 2, the first small molecule ligand for the VEGF-A receptor neuropilin 1 (NRP1) and the structural characterization of NRP1-ligand complexes by NMR spectroscopy and X-ray crystallography. Mutagenesis studies localized VEGF-A binding in the NRP1 b1 domain and a peptide fragment of VEGF-A was shown to bind at the same site by NMR, providing the basis for small molecule design. Compound 2 demonstrated inhibition of VEGF-A binding to NRP1 and attenuated VEGFR2 phosphorylation in endothelial cells. Inhibition of migration of endothelial cells was also observed. The viability of A549 lung carcinoma cells was reduced by 2, and it increased the potency of the cytotoxic agents paclitaxel and 5-fluorouracil when given in combination. These studies provide the basis for design of specific small molecule inhibitors of ligand binding to NRP1.