Evaluation of an end-of-life teaching programme for unregistered domiciliary care staff.

BACKGROUND: With increased focus on people being supported to die at home, and increased numbers of people predicted to die in the coming years in the UK, it is recognised that domiciliary carers need to be trained and supported to give end-of-life care. Recent reports suggest that this is not happening. AIM: To introduce and evaluate a training programme to upskill unregulated domiciliary care agency staff and integrate them into the palliative care teams, supporting registered nurses in caring for end-of-life patients. METHOD: A training course was devised and implemented. This report covers the first 3 years of running the course, and evaluates the difference that it made to the first 210 recipients' ability and confidence in delivering end-of-life care, using a mixed-methods approach. RESULTS: Pre- and post-course confidence questionnaires, evaluations, post-course testimonials, and managers' comments all identified improvements in knowledge, skills and attitudes following training. Agency policies were re-written with up-to-date guidance on how to respond to death in the community. CONCLUSION: This article demonstrates that this model is effective in achieving its aims.

Managing symptoms at the end of life: a guide for non-palliative care nurses.

Nurses, regardless of their area of practice, may have to care for a person in their last days and hours of life. However, many nurses outside of specialist palliative and end of life care settings do not feel adequately prepared for this. Nurses can usually obtain advice from specialists working in local hospices or palliative care centres, but they may still find it challenging to act on that advice if it is not underpinned by their own knowledge base. This article provides a guide to assist non-palliative care nurses in recognising dying and managing common symptoms at the end of life.

How do hospice nurses prepare to give end-of-life care? A grounded theory study of nurses in one UK hospice.

BACKGROUND: Literature for preparing hospice nurses to deliver end-of-life care is sparse. AIM: To investigate how nurses in one UK hospice prepared to deliver end-of-life care in their role. METHODS: A classic grounded theory approach was used to investigate the experiences of 22 registered nurses in one UK hospice, to discover how they prepared for their role. A total of 17 individual interviews and one focus group were conducted. Constant comparison of data and member checking were performed to establish validity. FINDINGS: Findings were synthesised into five categories: the 'shared ideal', feeling good at the job, making a difference, experience/exposure to hospice work and the importance of role models. The shared ideal formed the core category, which explained how hospice nurses feel a sense of 'fit' with their work. CONCLUSION: The feeling of a nurse feeling well-suited to the work and that there the work was a good 'fit' for them was identified as a core element to nurses' feelings of preparedness to provide end-of-life care.

Prepared for end-of-life care: a concept analysis.

BACKGROUND: Recent international documents have highlighted the importance of preparing the nursing workforce for end of life care. However, these documents do not make clear what prepared in the context of end-of-life care actually means. Searching the literature failed to retrieve any papers defining prepared in this context. AIM: A concept analysis, using Walker and Avant's model, was conducted to help address this gap in the knowledge base. RESULTS: From this analysis many attributes and antecedents were synthesised. These include that a prepared nurse would be confident to: assess the dying patient, communicate with empathy, identify and manage symptoms, recognise and deal with death and dying, understand the holistic elements of dying, be comfortable with the effects of loss and bereavement on patients and self, and be self-competent. CONCLUSIONS: From this analysis, a clearer idea of what is needed to prepare nurses for end-of-life care is offered and suggestions for future research are made.

Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial.

Importance: Aggregated α-synuclein is believed to be central to the pathogenesis of Parkinson disease (PD). PRX002/RG7935 (PRX002) is a humanized monoclonal antibody designed to target aggregated forms of α-synuclein, thereby inhibiting neuron-to-neuron transfer of presumed pathogenic forms of α-synuclein, potentially resulting in neuronal protection and slowing disease progression. Objective: To evaluate the safety and tolerability of multiple intravenous infusions of PRX002 in patients with idiopathic PD. Design, Setting, and Participants: Multicenter, randomized, double-blind, placebo-controlled, multiple ascending-dose trial at 8 US study centers from July 2014 to September 2016. Eligible participants were aged 40 to 80 years with mild to moderate idiopathic PD (Hoehn and Yahr stages 1-3). Interventions: Participants were enrolled into 6 ascending-dose cohorts and randomly assigned to receive PRX002 (0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, 10 mg/kg, 30 mg/kg, or 60 mg/kg) or placebo. Participants received 3 intravenous infusions every 4 weeks of PRX002 or placebo and were monitored during a 24-week observational period. Main Outcomes and Measures: Safety and tolerability assessments included physical and neurological examinations, laboratory tests, vital signs, and adverse events. Pharmacokinetic parameters included maximum PRX002 concentration, area under the curve, and half-life. Results: Of the 80 participants, most were white (97.5%; n = 78) and male (80%; n = 64); median (SD) age was 58 (8.4) years. PRX002 was generally safe and well tolerated; no serious or severe PRX002-related treatment-emergent adverse events (TEAEs) were reported. The TEAEs experienced by at least 5% of patients receiving PRX002, irrespective of relatedness to study drug, were constipation (9.1%; n = 5), infusion reaction (7.3%; n = 4), diarrhea (5.5%; n = 3), headache (5.5%; n = 3), peripheral edema (5.5%; n = 3), post-lumbar puncture syndrome (5.5%; n = 3), and upper respiratory tract infection (5.5%; n = 3). No antidrug antibodies were detected. Serum PRX002 levels increased in an approximately dose-proportional manner; mean terminal elimination half-life was similar across all doses (10.2 days). Rapid dose- and time-dependent mean reductions from baseline vs placebo in free serum α-synuclein levels of up to 97% were seen after a single infusion at the highest dose (F78,284 = 1.66; P = .002), with similar reductions after 2 additional infusions. Mean cerebrospinal fluid PRX002 concentration increased with PRX002 dose and was approximately 0.3% relative to serum across all dose cohorts. Conclusions and Relevance: Single and multiple doses of PRX002 were generally safe and well tolerated and resulted in robust binding of peripheral α-synuclein and dose-dependent increases of PRX002 in cerebrospinal fluid, reaching cerebrospinal fluid concentrations that may be expected to engage extracellular aggregated α-synuclein in the brain. Findings support the design of an ongoing phase 2 clinical study (NCT03100149). Trial Registration: ClinicalTrials.gov Identifier: NCT02157714.

First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers.

BACKGROUND: α-Synuclein is a major component of pathologic inclusions that characterize Parkinson's disease. PRX002 is an antibody that targets α-synuclein, and its murine parent antibody 9E4 has been shown in preclinical studies to reduce α-synuclein pathology and to protect against cognitive and motor deteriorations and progressive neurodegeneration in human α-synuclein transgenic mice. METHODS: This first-in-human, randomized, double-blind, placebo-controlled, phase 1 study assessed the impact of PRX002 administered to 40 healthy participants in 5 ascending-dose cohorts (n = 8/cohort) in which participants were randomly assigned to receive a single intravenous infusion of study drug (0.3, 1, 3, 10, or 30 mg/kg; n = 6/cohort) or placebo (n = 2/cohort). RESULTS: PRX002 demonstrated favorable safety, tolerability, and pharmacokinetic profiles at all doses tested, with no immunogenicity. No serious adverse events, discontinuations as a result of adverse events, or dose-limiting toxicities were reported. Serum PRX002 exposure was dose proportional; the average terminal half-life across all doses was 18.2 days. A significant dose-dependent reduction in free serum α-synuclein (unbound to PRX002) was apparent within 1 hour after PRX002 administration, whereas total α-synuclein (free plus bound) increased dose-dependently, presumably because of the expected change in kinetics following antibody binding. CONCLUSIONS: This study demonstrates that serum α-synuclein can be safely modulated in a dose-dependent manner after single intravenous infusions of an anti-α-synuclein antibody. These findings support continued development of PRX002, including further characterization of its safety, tolerability, pharmacokinetics, and pharmacodynamic effects in the central nervous system in patients with Parkinson's disease. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Multiple ascending dose study with the new renin inhibitor VTP-27999: nephrocentric consequences of too much renin inhibition.

This study compared the pharmacodynamic/pharmacokinetic profile of the new renin inhibitor VTP-27999 in salt-depleted healthy volunteers, administered once daily (75, 150, 300, and 600 mg) for 10 days, versus placebo and 300 mg aliskiren. VTP-27999 was well tolerated with no significant safety issues. It was rapidly absorbed, attaining maximum plasma concentrations at 1 to 4 hours after dosing, with a terminal half-life of 24 to 30 hours. Plasma renin activity remained suppressed during the 24-hour dosing interval at all doses. VTP-27999 administration resulted in a dose-dependent induction of renin, increasing the concentration of plasma renin maximally 350-fold. This induction was greater than with aliskiren, indicating greater intrarenal renin inhibition. VTP-27999 decreased plasma angiotensin II and aldosterone. At 24 hours and later time points after dosing on day 10 in the 600-mg group, angiotensin II and aldosterone levels were increased, and plasma renin activity was also increased at 48 and 72 hours, compared with baseline. VTP-27999 decreased urinary aldosterone excretion versus placebo on day 1. On day 10, urinary aldosterone excretion was higher in the 300- and 600-mg VTP-27999 dose groups compared with baseline. VTP-27999 decreased blood pressure to the same degree as aliskiren. In conclusion, excessive intrarenal renin inhibition, obtained at VTP-27999 doses of 300 mg and higher, is accompanied by plasma renin rises, that after stopping drug intake, exceed the capacity of extrarenal VTP-27999 to block fully the enzymatic reaction. This results in significant rises of angiotensin II and aldosterone. Therefore, renin inhibition has an upper limit.

Using action research to investigate and improve hospice staff participation in workplace education.

Finding ways to make good quality education available to all staff in an expanding and increasingly busy hospice organisation is a real challenge. Constantly providing learning opportunities that are then poorly attended owing to the pressure of work is equally disappointing, and leads to questions of cost-effectiveness. An action research project was undertaken to investigate the reasons for low attendance rates at learning events in one hospice. Having identified time and conflict with patient need as major issues, a second cycle of research using literature review and a survey methodology was conducted to find a contemporary and innovative solution to this problem in an attempt to establish a vibrant learning culture. As a result a virtual learning environment--ORACLE (Online Research and Care Learning Environment)--was created to augment the face-to-face sessions and provide staff with access to appropriate learning materials 24 hours per day, 365 days per year.Although unique to this organisation, ORACLE has potential application to any other work environment.

Improving practice using action research: resolving the problem of kinking with non-metal cannulae.

In one UK hospice, inpatient unit records showed that over 8 years 12 needlestick injuries related to continuous subcutaneous infusion of medication occurred. Following a change-over to Teflon cannulae no further incidents were reported. However, when the more sensitive and accurate McKinley T34 syringe drivers were introduced in 2007 a new problem of recurrent occlusion alarm sounding manifested. Investigation revealed that the Teflon cannulae were often kinking, delaying medication delivery and necessitating re-siting of the cannula. The action research approach was used to find an alternative device to improve practice and ensure that both staff and patients were safeguarded. This paper explains how that process was followed until a satisfactory alternative was sourced and evidenced, including an account of the problems that were experienced along the way.

Abeta42 immunization in Alzheimer's disease generates Abeta N-terminal antibodies.

Serum samples from Alzheimer's disease (AD) patients immunized with Abeta42 (AN1792) were analyzed to determine the induced antibody properties including precise amyloid-beta peptide (Abeta) epitopes and amyloid plaque-binding characteristics. The predominant response in these patients is independent of whether or not meningoencephalitis developed and is against the free amino terminus of Abeta. The immunostaining of amyloid plaques in brain tissue by patient sera is adsorbable by a linear Abeta1-8 peptide, demonstrating that the antibodies are directed predominantly to this epitope and not dependent on Abeta conformations or aggregates specific to plaques. Furthermore, the antibodies are not capable of binding amyloid precursor protein and would be predicted to be competent in facilitating clearance of amyloid plaques in AD brains.

Effect of zonisamide on the pharmacokinetics and pharmacodynamics of a combination ethinyl estradiol-norethindrone oral contraceptive in healthy women.

BACKGROUND: Several antiepileptic drugs have clinically significant pharmacokinetic interactions with oral contraceptives (OCs) that may result in contraceptive failure. OBJECTIVE: The aim of this study was to assess the effect of zonisamide on the pharmacokinetics of the individual components of a combination OC (ethinyl estradiol [EE] 0.035 mg and norethindrone [NOR] 1 mg) and on pharmacodynamic variables that may be increased in the event of reduced contraceptive efficacy (concentrations of serum luteinizing hormone [LH], follicle-stimulating hormone [FSH], and progesterone). METHODS: This was a single-center, open-label, 1-sequence, crossover study. Healthy, premenopausal women received the combination OC for three 28-day cycles (combination OC for 21 days, followed by placebo for 7 days). Following stabilization on the OC during the first cycle, blood was collected during cycle 2 for the determination of serum EE and NOR profiles (day 14) and serum LH, FSH, and progesterone concentrations (days 13-15). Starting on day 15 of cycle 2, zonisamide was administered orally at 100 mg/d and titrated to a target dose of 400 mg/d. EE and NOR profiles and serum LH, FSH, and progesterone concentrations were obtained again in cycle 3 (in the presence of zonisamide) and compared with those from cycle 2 (in the absence of zonisamide). RESULTS: Thirty-seven healthy premenopausal women (mean age, 26.1 years [range, 18-51 years]; mean body weight, 65.5 kg [range, 50.4-93.1 kg]; mean height, 165.8 cm [range, 152.4-182.9 cm]) received > or =1 dose of zonisamide. Of the 33 subjects (89.2%) who completed the study, 26 (78.8%) underwent titration to a stable zonisamide dose of 400 mg/d. For EE, the mean (SD) AUC over a 24-hour dosing interval (AUC(tau)) was 1139 (317) pg.h/mL in cycle 2 and 1143 (312) pg.h/mL in cycle 3; the mean C(max) in the respective cycles was 133 (39) and 141 (46) pg/mL. For NOR, the corresponding values were 140 (48) and 159 (46) ng.h/mL for AUC(tau) and 21 (5.4) and 23 (6.7) ng/mL for C(max). The 90% Cls for the geometric mean ratios (cycle 3:cycle 2) for AUC(tau) and C(max) fell within the accepted range for lack of interaction (0.80-1.25). There were no increases in LH, FSH, or progesterone concentrations between cycle 2 and cycle 3. CONCLUSIONS: In these healthy volunteers, steady-state zonisamide dosing had no clinically significant effect on the pharmacokinetics of EE or NOR. There was no pharmacodynamic evidence that zonisamide is likely to reduce the contraceptive effectiveness of OCs containing EE and NOR.