Understanding the extent to which PROMs and PREMs used with older people with severe frailty capture their multidimensional needs: A scoping review.

BACKGROUND: Older people with severe frailty are nearing the end of life but their needs are often unknown and unmet. Systematic ways to capture and measure the needs of this group are required. Patient reported Outcome Measures (PROMs) & Patient reported Experience Measures (PREMs) are possible tools to assist this. AIM: To establish whether, and in what ways, the needs of older people living with severe frailty are represented within existing PROMs and PREMs and to examine the extent to which the measures have been validated with this patient group. DESIGN: The scoping review follows the method of Arksey and O'Malley. RESULTS: Seventeen papers from 9 countries meeting the inclusion criteria and 18 multi-dimensional measures were identified: 17 PROMs, and 1 PROM with PREM elements. Seven out of the 18 measures had evidence of being tested for validity with those with frailty. No measure was developed specifically for a frail population. Using the adapted framework of palliative need, five measures covered all five domains of palliative need (IPOS, ICECAP-SCM, PDI, WHOQOL-BREF, WHOQOL-OLD). The coverage of items within the domains varied between the measures. CONCLUSION: Existing PROMs and PREMs are not well designed for what we know about the needs of older people with severe frailty. Future research should firstly focus on adapting and validating the existing measures to ensure they are fit for purpose, and secondly on developing a better understanding of how measures are used to deliver/better person-centred care.

Nanobugs as Drugs: Bacterial Derived Nanomagnets Enhance Tumor Targeting and Oncolytic Activity of HSV-1 Virus.

The survival strategies of infectious organisms have inspired many therapeutics over the years. Indeed the advent of oncolytic viruses (OVs) exploits the uncontrolled replication of cancer cells for production of their progeny resulting in a cancer-targeting treatment that leaves healthy cells unharmed. Their success against inaccessible tumors however, is highly variable due to inadequate tumor targeting following systemic administration. Coassembling herpes simplex virus (HSV1716) with biocompatible magnetic nanoparticles derived from magnetotactic bacteria enables tumor targeting from circulation with magnetic guidance, protects the virus against neutralizing antibodies and thereby enhances viral replication within tumors. This approach additionally enhances the intratumoral recruitment of activated immune cells, promotes antitumor immunity and immune cell death, thereby inducing tumor shrinkage and increasing survival in a syngeneic mouse model of breast cancer by 50%. Exploiting the properties of such a nanocarrier, rather than tropism of the virus, for active tumor targeting offers an exciting, novel approach for enhancing the bioavailability and treatment efficacy of tumor immunotherapies for disseminated neoplasms.

Targeting circulating monocytes with CCL2-loaded liposomes armed with an oncolytic adenovirus.

Oncolytic viruses (OVs) selectively replicate in and destroy cancer cells resulting in anti-tumor immunity. However, clinical use remains a challenge because of virus clearance upon intravenous delivery. OV packaging using a nanomedicine approach could overcome this. Here we encapsulate an oncolytic adenovirus (Ad[I/PPT-E1A]) into CCL2-coated liposomes in order to exploit recruitment of CCR2-expressing circulating monocytes into tumors. We demonstrate successful encapsulation of Ad[I/PPT-E1A] into CCL2-coated liposomes that were preferentially taken up by CCR2-expressing monocytes. No complex-related toxicities were observed following incubation with prostate tumor cells and the encapsulation did not affect virus oncolytic activity in vitro. Furthermore, intravenous administration of our nanomedicine resulted in a significant reduction in tumor size and pulmonary metastasis in prostate cancer-bearing mice whereby a 1000-fold less virus was needed compared to Ad[I/PPT-E1A] alone. Taken together our data provide an opportunity to target OVs via circulation to inaccessible tumors using liposome-assisted drug delivery.

Preferred Place of Death Discussions: Are They Informing and Empowering Patients and their Family Caregivers?

Factors influencing preferred place of death (PPoD) are variable between individuals. However, there is little understanding of how these preferences are formed and how consistent they are in the final months of life. In particular, the expectation and responsibility of family caregivers to provide unpaid caregiving support to their dying loved one in the home is often overlooked. There is a need for clinicians to take an individualised approach to PPoD conversations that is inclusive of the needs of both the patient and the family caregiver. More Good Deaths - A Change Programme responds to this gap in care by advancing the skills of clinicians having PPoD conversations with patients and their family caregivers. This paper describes the programme, providing insight into its benefits to advanced care planning and communication, as well as to our newest service - Cottage Hospice.

Development of clinically relevant in vivo metastasis models using human bone discs and breast cancer patient-derived xenografts.

BACKGROUND: Late-stage breast cancer preferentially metastasises to bone; despite advances in targeted therapies, this condition remains incurable. The lack of clinically relevant models for studying breast cancer metastasis to a human bone microenvironment has stunted the development of effective treatments for this condition. To address this problem, we have developed humanised mouse models in which breast cancer patient-derived xenografts (PDXs) metastasise to human bone implants with low variability and high frequency. METHODS: To model the human bone environment, bone discs from femoral heads of patients undergoing hip replacement surgery were implanted subcutaneously into NOD/SCID mice. For metastasis studies, 7 patient-derived xenograft tumours (PDX: BB3RC32, ER+ PR+ HER2-; BB2RC08, ER+ PR+ ER2-; BB6RC37, ER- PR- HER2- and BB6RC39, ER+ PR+ HER2+), MDA-MB-231-luc2, T47D-luc2 or MCF7-Luc2 cells were injected into the 4th mammary ducts and metastases monitored by luciferase imaging and confirmed on histological sections. Bone integrity, viability and vascularisation were assessed by uCT, calcein uptake and histomorphometry. Expression profiling of genes/proteins during different stages of metastasis were assessed by whole genome Affymetrix array, real-time PCR and immunohistochemistry. Importance of IL-1 was confirmed following anakinra treatment. RESULTS: Implantation of femoral bone provided a metabolically active, human-specific site for tumour cells to metastasise to. After 4 weeks, bone implants were re-vascularised and demonstrated active bone remodelling (as evidenced by the presence of osteoclasts, osteoblasts and calcein uptake). Restricting bone implants to the use of subchondral bone and introduction of cancer cells via intraductal injection maximised metastasis to human bone implants. MDA-MB-231 cells specifically metastasised to human bone (70% metastases) whereas T47D, MCF7, BB3RC32, BB2RC08, and BB6RC37 cells metastasised to both human bone and mouse bones. Importantly, human bone was the preferred metastatic site especially from ER+ PDX (100% metastasis human bone compared with 20-75% to mouse bone), whereas ER-ve PDX developed metastases in 20% of human and 20% of mouse bone. Breast cancer cells underwent a series of molecular changes as they progressed from primary tumours to bone metastasis including altered expression of IL-1B, IL-1R1, S100A4, CTSK, SPP1 and RANK. Inhibiting IL-1B signalling significantly reduced bone metastasis. CONCLUSIONS: Our reliable and clinically relevant humanised mouse models provide significant advancements in modelling of breast cancer bone metastasis.

Development of a Personalised Device for Systemic Magnetic Drug Targeting to Brain Tumours.

Delivering therapies to deeply seated brain tumours (BT) is a major clinical challenge. Magnetic drug targeting (MDT) could overcome this by rapidly transporting magnetised drugs directly into BT. We have developed a magnetic device for application in murine BT models using an array of neodymium magnets with a combined strength of 0.7T. In a closed fluidic system, the magnetic device trapped magnetic nanoparticles (MNP) up to distances of 0.8cm. In mice, the magnetic device guided intravenously administered MNP (<50nm) from the circulation into the brain where they localised within mouse BT. Furthermore, MDT of magnetised Temozolomide (TMZmag+) significantly reduced tumour growth and extended mouse survival to 48 days compared to the other treatment groups. Using the same principles, we built a proof of principle scalable magnetic device for human use with a strength of 1.1T. This magnetic device demonstrated trapping of MNP undergoing flow at distances up to 5cm. MDT using our magnetic device provides an opportunity for targeted delivery of magnetised drugs to human BT.

Inconsistencies in Modeling the Efficacy of the Oncolytic Virus HSV1716 Reveal Potential Predictive Biomarkers for Tolerability.

Treatment with HSV1716 via intralesional administration has proven successful for melanoma patients with the hope that oncolytic virotherapy would become another weapon in the systemic anticancer therapy (SACT) arsenal. In addition to challenges surrounding the systemic delivery of oncolytic viruses (OVs), problems associated with its in vivo modeling have resulted in low predictive power, contributing to the observed disappointing clinical efficacy. As OV's efficacy is elicited through interaction with the immune system, syngeneic orthotopic mouse models offer the opportunity to study these with high reproducibility and at a lower cost; however, inbred animals display specific immune characteristics which may confound results. The systemic delivery of HSV1716 was, therefore, assessed in multiple murine models of breast cancer. Tolerability to the virus was strain-dependent with C57/Bl6, the most tolerant and Balb/c experiencing lethal side effects, when delivered intravenously. Maximum tolerated doses were not enough to demonstrate efficacy against tumor growth rates or survival of Balb/c and FVB mouse models; therefore; the most susceptible strain (Balb/c mice) was treated with immunomodulators prior to virus administration in an attempt to reduce side effects. These studies demonstrate the number of variables to consider when modeling the efficacy of OVs and the complexities involved in their interpretation for translational purposes. By reporting these observations, we have potentially revealed a role for T-cell helper polarization in viral tolerability. Importantly, these findings were translated to human studies, whereby a Th1 cytokine profile was expressed in pleural effusions of patients that responded to HSV1716 treatment for malignant pleural mesothelioma with minimal side effects, warranting further investigation as a biomarker for predictive response.

Understanding Immune Responses to Viruses-Do Underlying Th1/Th2 Cell Biases Predict Outcome?

Emerging and re-emerging viral diseases have increased in number and geographical extent during the last decades. Examples include the current COVID-19 pandemic and the recent epidemics of the Chikungunya, Ebola, and Zika viruses. Immune responses to viruses have been well-characterised within the innate and adaptive immunity pathways with the outcome following viral infection predominantly attributed to properties of the virus and circumstances of the infection. Perhaps the belief that the immune system is often considered as a reactive component of host defence, springing into action when a threat is detected, has contributed to a poorer understanding of the inherent differences in an individual's immune system in the absence of any pathology. In this review, we focus on how these host factors (age, ethnicity, underlying pathologies) may skew the T helper cell response, thereby influencing the outcome following viral infection but also whether we can use these inherent biases to predict patients at risk of a deviant response and apply strategies to avoid or overcome them.

Urinary incontinence in women: quality of life and help-seeking.

Urinary incontinence on its own is not considered life-threatening, yet it has been shown to negatively affect a patient's wellbeing. While it is considered a common problem, with approximately 3 million women in the UK affected, the number of those women seeking help is much lower. This article will explore the relationship between urinary incontinence, quality of life (QoL), and barriers to help-seeking behaviour. Developing an understanding of this patient group will highlight implications for nursing practice. A number of factors appear to contribute to how women experience urinary incontinence, and how it impacts on QoL. While not all of these can be fully explored, the predominant factors appear to be: severity of urinary incontinence; type of urinary incontinence; age; and the actual QoL score itself. QoL 'scores' are significant when women decide whether or not to seek help for urinary incontinence. Seeking help often depends on beliefs and an understanding of how the condition can be treated. Health promotion, the training of health professionals, and further research are required to improve the understanding of women's experiences, and to develop appropriate services with which to manage this condition.

Designer nanocarriers for navigating the systemic delivery of oncolytic viruses.

Nanotechnology is paving the way for new carrier systems designed to overcome the greatest challenges of oncolytic virotherapy; systemic administration and subsequent implications of immune responses and specific cell binding and entry. Systemic administration of oncolytic agents is vital for disseminated neoplasms, however transition of nanoparticles (NP) to virotherapy has yielded modest results. Their success relies on how they navigate the merry-go-round of often-contradictory phases of NP delivery: circulatory longevity, tissue permeation and cellular interaction, with many studies postulating design features optimal for each phase. This review discusses the optimal design of NPs for the transport of oncolytic viruses within these phases, to determine whether improved virotherapeutic efficacy lies in the pharmacokinetic/pharmacodynamics characteristics of the NP-oncolytic viruses complexes rather than manipulation of the virus and targeting ligands.