The need for cybersecurity self-evaluation in healthcare.

The Australian healthcare sector is a complex mix of government departments, associations, providers, professionals, and consumers. Cybersecurity attacks, which have recently increased, challenge the sector in many ways; however, the best approaches for the sector to manage the threat are unclear. This study will report on a semi-structured focus group conducted with five representatives from the Australian healthcare and computer security sectors. An analysis of this focus group transcript yielded four themes: 1) the challenge of securing the Australian healthcare landscape; 2) the financial challenges of cybersecurity in healthcare; 3) balancing privacy and transparency; 4) education and regulation. The results indicate the need for sector-specific tools to empower the healthcare sector to mitigate cybersecurity threats, most notably using a self-evaluation tool so stakeholders can proactively prepare for incidents. Despite the vast amount of research into cybersecurity, little has been conducted on proactive cybersecurity approaches where security weaknesses are identified weaknesses before they occur.

Clinical evaluation of the potential drug-drug interactions of savolitinib: Interaction with rifampicin, itraconazole, famotidine or midazolam.

AIMS: We investigated savolitinib pharmacokinetics (PK) when administered alone or in combination with rifampicin, itraconazole or famotidine, and investigated midazolam PK when administered with or without savolitinib in healthy males. METHODS: Savolitinib PK was evaluated before/after: rifampicin (600 mg once daily [QD] for 5 days); itraconazole (200 mg QD for 5 days); a single dose of famotidine (40 mg QD) 2 hours before savolitinib. Midazolam PK was evaluated before/after midazolam (1 mg QD) with or without savolitinib (600 mg QD). Each study enrolled 20, 16, 16 and 14 volunteers, respectively. Plasma samples were collected to determine the effect on PK. RESULTS: The geometric mean ratios (GMR, %) (90% confidence intervals [CIs]) for savolitinib alone and in combination for Cmax , AUC respectively, were 45.4 (41.4-49.9), 38.5 (34.2-43.3) in the rifampicin study (n = 18); 105.2 (87.7-126.3), 108.4 (96.3-122.1) in the itraconazole study (n = 16); and 78.8 (67.7-91.7), 87.4 (81.2-94.2) in the famotidine study (n = 16). The GMRs (90% CIs) for midazolam alone and in combination with savolitinib for Cmax , AUC respectively, were 84.1 (70.0-101.0), 96.7 (92.4-101.1) (n = 14). Savolitinib alone or in combination was well tolerated. CONCLUSIONS: Co-dosing of rifampicin significantly reduced exposure to savolitinib vs savolitinib alone; co-dosing of itraconazole or midazolam with savolitinib had no clinically significant effect on savolitinib or midazolam PK, respectively. Co-dosing of famotidine with savolitinib reduced exposure to savolitinib, although this was not considered clinically meaningful. No new savolitinib-related safety findings were observed.

Post-operative Rehabilitation for Scapular Muscle Reattachment: A Case Report.

BACKGROUND AND PURPOSE: Scapular muscle detachment is a rare orthopedic problem that has been described in the literature in patients following traumatic events involving traction, direct trauma, or a motor vehicle accident. The purpose of this case report is to describe the post-operative rehabilitation following scapular muscle reattachment surgery. Unique to this case report is the patient's perspective, an orthopedic physical therapist with 25 years of experience. CASE DESCRIPTION: A 47-year-old female physical therapist experienced a traction injury to bilateral upper extremities during a medical procedure resulting in bilateral rhomboid, and bilateral lower trapezius muscles were detached from the medial scapular border. Reconstruction of the left scapulothoracic musculature occurred five and one-half years post-injury with the right repaired one year later. This case report describes the rehabilitation program that took one-year to recover for each arm with a period of protected motion for 16-weeks and gradual return to function as a manual physical therapist over a period of one-year. OUTCOMES: The American Shoulder and Elbow Surgeons (ASES) Standardized Assessment Form and pain-free range of motion was used pre- and postoperatively. Left and right shoulder pre-operative ASES scores were 68 and 72, respectively. At the one-year post-operative the left shoulder was rated at 82 and the right shoulder was 90. Pain-free range of motion was achieved in both arms by one year. Functional limitations requiring strength overhead were the slowest to return and were not completely back at one year following either surgery. DISCUSSION: Rehabilitation protocols for scapular muscle reattachment surgery are not commonly available to allow physical therapists to guide their patients and structure a rehabilitation program. This case report provides a sample pre-operative set of educational guidelines and a post-operative protocol for use after scapular reattachment surgery. This case report is unique because it offers a patient perspective who is a physical therapist and underwent this surgery twice. Therefore, providing insight on how to prepare for such a unique operation. The slow recovery is due to three issues 1) the prolonged time from injury to diagnosis created significant muscle wasting and muscular imbalance of surrounding tissues, 2) once this tissue was repaired it requires months of protection to recover, 3) the involved scapulothoracic muscle have to regain adequate strength as the foundation for upper extremity functions. LEVEL OF EVIDENCE: Level 5.

Pharmacokinetics and safety of olaparib tablets as monotherapy and in combination with paclitaxel: results of a Phase I study in Chinese patients with advanced solid tumours.

PURPOSE: Chinese patients have been enrolled in multiple Phase III trials of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (Lynparza); however, the pharmacokinetic (PK) profile of olaparib has not been investigated in this population. This two-part, open-label Phase I study was, therefore, carried out to determine the PK and safety profile of olaparib (tablet formulation) in Chinese patients with advanced solid tumours as monotherapy and in combination with paclitaxel (NCT02430311). METHODS: The PK profile of olaparib 300 mg (twice daily [bid]; Cohort 1) as monotherapy after a single dose and at steady state, and 100 mg (bid; Cohort 2) as monotherapy (single dose and at steady state) and in combination (at steady state) with weekly paclitaxel (80 mg/m2) was assessed during Part A. Patients could continue to receive treatment (monotherapy, Cohort 1; combination therapy, Cohort 2) in Part B, which assessed safety and tolerability. RESULTS: Twenty and 16 patients were enrolled into Cohorts 1 and 2, respectively. Steady-state olaparib exposure increased slightly less than proportionally with increasing monotherapy dose and inter-patient variability was high. A statistically significant decrease in olaparib exposure was seen when given in combination with paclitaxel. Discontinuation due to adverse events (AEs) was rare and haematological AEs were more common in patients receiving combination treatment. CONCLUSIONS: The PK and safety profile of olaparib monotherapy in Chinese patients is consistent with that seen previously in Western and Japanese patients, and the recommended Phase III monotherapy tablet dose (300 mg bid) is suitable for use in this population.

A Randomised Phase 2 Study of AZD2014 Versus Everolimus in Patients with VEGF-Refractory Metastatic Clear Cell Renal Cancer.

BACKGROUND: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor used in vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma (mRCC). It acts on only part of the mTOR complex (TORC1 alone). In vitro data support the use of mTOR inhibitors with broader activity (TORC1 and TORC2). OBJECTIVE: The purpose of this study was to determine whether combined TORC1 and TORC2 inhibition with AZD2014 has superior activity to everolimus in VEGF-refractory clear cell mRCC. DESIGN, SETTING, AND PARTICIPANTS: Patients with measurable mRCC and VEGF-refractory disease were eligible for this trial. INTERVENTION: Starting in February 2013, patients were randomised (1:1) to AZD2014 (50 mg twice daily) or everolimus (10 mg once daily) until progression of disease at 10 centres across the United Kingdom. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Progression-free survival (PFS) was the primary end point and was compared using the stratified log-rank test. Secondary end points included tolerability, response rates, overall survival (OS), and pharmacokinetics (PK) analysis. The study was planned to recruit 120 patients. RESULTS AND LIMITATIONS: Recruitment into the trial was stopped early (June 2014) due to lack of efficacy of AZD2014. At that point, 49 patients were randomised (26 to AZD2014 and 23 to everolimus). The PFS for AZD2014 and everolimus was 1.8 and 4.6 mo, respectively (hazard ratio: 2.8 [95% confidence interval (CI), 1.2-6.5]; p=0.01). Progression of disease as the best response to therapy was 69% for AZD2014 and 13% for everolimus (p<0.001). Grade 3-4 adverse events (AEs) occurred in 35% of AZD2014 and 48% of everolimus patients (p=0.3). Only 4% of patients stopped AZD2014 due to AEs. PK analysis suggested concentrations of AZD2014 were compatible with the therapeutic range. Final stratified OS hazard ratio at the time of trial closure (January 2015) was 3.1 (95% CI, 1.1-8.4; p<0.02). CONCLUSIONS: The PFS and OS of AZD2014 were inferior to everolimus in this setting despite acceptable AE and PK profiles. PATIENT SUMMARY: There is a strong rationale for testing mTOR inhibitors with a broader spectrum of activity than everolimus in metastatic clear cell renal cell carcinoma. AZD2014 is such an agent, but in this study, it was inferior to everolimus despite its attractive toxicity profile.

High resolution MRI evaluation of meniscal volume and anthropometric correlations.

The purpose of this study was to digitally determine meniscal volumes, and compare them with linear and surface area anthropometric measurements to evaluate these measurements for meniscal allograft sizing. Eighteen subjects (10 male and 8 female; mean age 37.5 years) underwent 3.0 T knee magnetic resonance imaging (MRI) of the dominant leg. The following morphometric measurements were evaluated: medial meniscal volume (MMV), lateral meniscal volume (LMV), tibial plateau width (TPW), width of the femoral condyles (WFC), and tibial plateau surface area (TPSA). MMV and LMV were compared to TPW, WFC, and TPSA. Meniscal volume and TPW were correlated to height and body-mass index (BMI) and stratified by gender. Statistical analysis included coefficient of determination (r(2)) between MRI-based MMV, LMV, TPW, TPSA, WFC, height, BMI, and gender. Significance was set at the P = 0.05 level. The mean MMV was 2275 mm(3) and the mean LMV was 2102 mm(3). TPW correlated well with meniscal volumes (r(2) > 0.62). WFC and TPSA correlated with meniscal volumes in the range of 0.40 < r(2) < 0.61. Height, BMI, and gender correlated poorly with total meniscal volume and TPW with values of r(2) < 0.44. Medial and lateral menisci have statistically similar volumes. TPW had the greatest utility for volumetric meniscal sizing. MRI-based TPW can be considered as a statistically accurate measurement for determining meniscal volumes and meniscal size.

First-in-Human Pharmacokinetic and Pharmacodynamic Study of the Dual m-TORC 1/2 Inhibitor AZD2014.

PURPOSE: AZD2014 is a novel, oral, m-TORC 1/2 inhibitor that has shown in vitro and in vivo efficacy across a range of preclinical human cancer models. EXPERIMENTAL DESIGN: A rolling six-dose escalation was performed to define an MTD (part A), and at MTD a further cohort of patients was treated to further characterize toxicities and perform pre- and posttreatment biopsies (part B). AZD2014 was administered orally twice a day continuously. Flow cytometry, ELISA, and immunohistochemistry were used to quantify pharmacodynamic biomarkers. Pharmacokinetic analysis was carried out by mass spectrometry. RESULTS: A total of 56 patients were treated across a dose range of 25 to 100 mg. The MTD was 50 mg twice daily. The dose-limiting toxicities were fatigue and mucositis. At the MTD, the most common adverse events (AE) were fatigue (78%), nausea (51%), and mucositis (49%), but these were equal to or greater than grade 3 in only 5% of patients. Drug levels achieved at the MTD (AUC SS: 6686 ng·h/mL, Cmax ss 1,664 ng/mL) were consistent with activity in preclinical models. A reduction in p-S6 levels and Ki67 staining was observed in 8 of 8 and 5 of 9 evaluable paired biopsy samples. Partial responses were seen in a patient with pancreatic cancer and a patient with breast cancer, who were found to have a PDGFR and ERBB2 mutation, respectively. CONCLUSIONS: The recommended phase II dose for further evaluation of AZD2014 is 50 mg twice daily, and at this dose it has been possible to demonstrate pharmacologically relevant plasma concentrations, target inhibition in tumor, and clinical responses.

3.0-Tesla MRI and arthroscopy for assessment of knee articular cartilage lesions.

The purpose of this study was to evaluate the ability of 3.0-Tesla magnetic resonance imaging (MRI) to accurately assess knee articular cartilage lesions. Sixteen patients who had knee 3.0-T MRI and underwent knee arthroscopy for partial meniscectomy were included. Three fellowship-trained sports medicine orthopedic surgeons reviewed all images. Articular lesions on MRI were graded from I to IV and compared with arthroscopic grading using the Outerbridge and the International Cartilage Repair Society (ICRS) classifications. The articular surface was divided into 6 regions. Based on MRI findings, of the 288 articular surface evaluations, 113 (39%) surface evaluations were classified as disease-positive (grade 2 to 4). Kappa interrater reliability scores for MRI evaluation, Outerbridge classification, and ICRS classification were 0.13, 0.54, and 0.41, respectively. Using the Outerbridge classification as a reference standard, the sensitivity, specificity, and accuracy were 57%, 71%, and 63%, respectively. Using the ICRS classification, sensitivity, specificity, and accuracy were 59%, 71%, and 69%, respectively. When isolating the articular grading to the senior author on MRI evaluation vs Outerbridge classification, the sensitivity, specificity, and accuracy were 54%, 92%, and 75%, respectively. Based on the current findings, 3.0-T MRI is as an invaluable noninvasive tool with good diagnostic value for assessing articular cartilage lesions of the knee, although it may not be as sensitive and accurate as previously reported.

Partnering for change.

Nurse leaders and telemetry unit staff work together to change the way nurses conduct shift report. This is the first article in a new series on leadership, coordinated by the American Organization of Nurse Executives (AONE), highlighting how nurses are leading change efforts in hospitals. It describes work done in conjunction with the AONE's Care Innovation and Transformation initiative, which provides leadership development and educational opportunities to nurse managers and staff aimed at supporting nurses at the point of care in making changes to improve the quality and safety of patient care.

An investigation into the utility of a multi-compartmental, dynamic, system of the upper gastrointestinal tract to support formulation development and establish bioequivalence of poorly soluble drugs.

In recent years mechanical systems have been developed that more closely mimic the full dynamic, physical and biochemical complexity of the GI Tract. The development of these complex systems raises the possibility that they could be used to support formulation development of poorly soluble compounds and importantly may be able to replace clinical BE studies in certain circumstances. The ability of the TNO Simulated Gastro-Intestinal Tract Model 1 (TIM-1) Dynamic Artificial Gastrointestinal System in the 'lipid membrane' configuration to support the development of Biopharmaceutics Classification System Class 2 compounds was investigated by assessing the performance of various AZD8055 drug forms and formulations in the TIM-1 system under standard fasting and achlorhydric physiological conditions. The performance data were compared with exposure data from the phase 1 clinical study. Analysis of the AZD8055 plasma concentrations after tablet administration supported the conclusions drawn from the TIM-1 experiments and confirmed that these complex systems can effectively support the product development of poorly soluble drugs. Particularly, the TIM-1 system was able to show that AZD8055 exposure would increase in an approximately dose proportional manner and not be limited by the solubility or dissolution. Additionally, the investigations also showed that the exposure produced by a solution and a tablet would be the same. Specific instances when the TIM-1 system may not be predictive of clinical product performance have also been identified.

Human knee synovial fluid cytokines correlated with grade of knee osteoarthritis--a pilot study.

UNLABELLED: The purpose of this pilot study was to evaluate the cytokine profile of human knee synovial fluid and correlate this with the subject's degree of articular cartilage degradation, radiographic score, and synovial histology. MATERIALS AND METHODS: Synovial fluid was withdrawn before knee meniscectomy in 12 subjects with varying degrees of osteoarthritis and assayed for 21 cytokines, using a multiplex cytokine assay and flow cytometry instrumentation. Articular cartilage surfaces were scored by a single orthopaedic surgeon on the basis of the International Cartilage Repair Society (ICRS) classification during the arthroscopy, and posterior-anterior knee radiographs were graded using the Kellgren-Lawrence (KL) classification. Synovial biopsies were taken in four zones at the time of surgery for histological analysis. RESULTS: Significant concentration differences in IL-2, IL-5, MCP-1, and MIP-1 were found between subjects with advanced arthritis and subjects with little or no arthritis on the ICRS scale (p < .05). No such differences could be appreciated using KL scores. There was no correlation between histology samples and visualized surface osteoarthritis. CONCLUSION: This data suggests a molecular basis of disease progression, with higher levels of cytokines indicative of greater degrees of osteoarthritis. These results add pilot data that can assist investigators in conducting a comparative observational study of the levels of inflammatory cytokines with radiologic and arthroscopic assessments of osteoarthritis.

Autologous hematopoietic stem cell transplantation in 48 patients with end-stage chronic liver diseases.

The only presently viable treatment for end-stage liver disease is whole organ transplantation. However, there are insufficient livers available. The aim of the present study is to provide autologous bone marrow-derived stem cells as a potential therapeutic for patients with end-stage cirrhosis. This is a retrospective chart review of autologous stem cell treatment in 48 patients, 36 with chronic end-stage hepatitis C-induced liver disease and 12 with end-stage autoimmune liver disease. For all patients, granulocyte colony-stimulating factor was administered to mobilize their hematopoietic stem cells. Following leukapheresis, CD34(+) stem cells were isolated, amplified, and partially differentiated in culture, then reinjected into each subject via their hepatic artery or portal vein. Treatment was generally well tolerated with the expected moderate but transient bone pain from G-CSF in less than half of the patients. Three patients had serious treatment-related complications, and only 20.8% of these end-stage liver disease patients died during 12 months of follow up. For all patients there was a statistically significant decrease in ascites. There was clinical and biochemical improvement in a large percentage of patients who received the transplantation. In the viral group, there were marked changes in albumin (p = 0.0003), bilirubin (p = 0.04), INR (p = 0.0003), and ALT levels (p = 0.02). In the autoimmune group, values also improved significantly for albumin (p = 0.001), bilirubin (p = 0.002), INR (p = .0005), and ALT levels (p = 0.003). These results suggest that autologous CD34(+) stem cell transplantation may be safely administered and appears to offer some therapeutic benefit to patients with both viral and autoimmune-induced end-stage liver disease.

Quantification of two-dimensional glenohumeral rhythm in persons with and without symptoms of shoulder impingement.

A repeated-measures design was used to assess glenohumeral rhythm in 10 patients with shoulder impingement and 10 pain-free persons and to assess the effects of subacromial injection on glenohumeral rhythm within the impingement group. Scapular-plane anterior-to-posterior x-rays of the scapula and humerus were obtained at 5 angles of arm elevation (resting, 30 degrees, 60 degrees, 90 degrees, 120 degrees). For the impingement group, x-rays were repeated after subacromial injection (10 mL of 1% lidocaine). No significant differences in glenohumeral rhythm were found between the impingement and control groups across all arm-elevation angles.

The immediate and long-term effects of exercise and patient education on physical, functional, and quality-of-life outcome measures after single-level lumbar microdiscectomy: a randomized controlled trial protocol.

BACKGROUND: Low back pain remains a costly quality-of-life-related health problem. Microdiscectomy is often the surgical procedure of choice for a symptomatic, single-level, lumbar disc herniation in younger and middle-aged adults. The question of whether a post-microdiscectomy exercise program enhances function, quality of life, and disability status has not been systematically explored. Thus, the overall purpose of this study is to assess immediate and long-term outcomes of an exercise program, developed at University of Southern California (USC), targeting the trunk and lower extremities (USC Spine Exercise Program) for persons who have undergone a single-level microdiscectomy for the first time. METHODS/DESIGN: One hundred individuals between the ages of 18 and 60 who consent to undergo lumbar microdiscectomy will be recruited to participate in this study. Subjects will be randomly assigned to one of two groups: 1) one session of back care education, or 2) a back care education session followed by the 12-week USC Spine Exercise Program. The outcome examiners (evaluators), as well as the data managers, will be blinded to group allocation. Education will consist of a one-hour "one-on-one" session with the intervention therapist, guided by an educational booklet specifically designed for post-microdiscectomy care. This session will occur four to six weeks after surgery. The USC Spine Exercise Program consists of two parts: back extensor strength and endurance, and mat and upright therapeutic exercises. This exercise program is goal-oriented, performance-based, and periodized. It will begin two to three days after the education session, and will occur three times a week for 12 weeks. Primary outcome measures include the Oswestry Disability Questionnaire, Roland-Morris Disability Questionnaire, SF-36 quality of life assessment, Subjective Quality of Life Scale, 50-foot Walk, Repeated Sit-to-Stand, and a modified Sorensen test. The outcome measures in the study will be assessed before and after the 12-week post-surgical intervention program. Long-term follow up assessments will occur every six months beginning one year after surgery and ending five years after surgery. Immediate and long-term effects will be assessed using repeated measures multivariate analysis of variance (MANOVA). If significant interactions are found, one-way ANOVAs will be performed followed by post-hoc testing to determine statistically significant pairwise comparisons. DISCUSSION: We have presented the rationale and design for a randomized controlled trial evaluating the effectiveness of a treatment regimen for people who have undergone a single-level lumbar microdiscectomy.

Rehabilitation following repair of a torn latissimus dorsi tendon.

BACKGROUND AND PURPOSE: This report describes the rehabilitation of a patient following surgical repair of a torn latissimus dorsi tendon. The scientific rationale for the treatment progression is discussed. CASE DESCRIPTION: A 35-year-old man with a ruptured latissimus dorsi tendon 6 weeks following surgical repair was referred for physical therapy to recover range of motion and strength sufficient for return to work as a police officer on the SWAT team. A review of tendon healing in animal studies is presented and related to the development of the plan of care for this patient. OUTCOMES: Latissimus dorsi muscle isometric force generation on the injured side was 92% of that of the uninjured side. The patient returned to work as a SWAT team member. DISCUSSION: No detailed reports of postoperative latissimus dorsi tendon rehabilitation are available. The program for this patient was based on research demonstrating the timeline for recovery of tensile strength in healing tendons. This approach can direct rehabilitation following repair of other tendons, especially in uncommon injuries where specific guidelines have not been developed.

Strengthening the supraspinatus: a clinical and biomechanical review.

Rotator cuff weakness has been implicated as a cause of subacromial impingement. Numerous exercises have been advocated to strengthen the rotator cuff, particularly the supraspinatus. The clinical rationale and two exercises advocated for strengthening the supraspinatus, the empty can and the full can, were evaluated. By understanding how these exercises vary from a biomechanical perspective, it is hoped that clinicians can minimize the forces experienced by the supraspinatus during the rehabilitation process.