Priorities for research in multiple conditions in later life (multi-morbidity): findings from a James Lind Alliance Priority Setting Partnership.

INTRODUCTION: multiple conditions in later life (multi-morbidity) is a major challenge for health and care systems worldwide, is of particular relevance for older people, but has not (until recently) received high priority as a topic for research. We have identified the top 10 research priorities from the perspective of older people, their carers, and health and social care professionals using the methods of a James Lind Alliance Priority Setting Partnership. METHODS: in total, 354 participants (162 older people and carers, 192 health professionals) completed a survey and 15 older people and carers were interviewed to produce 96 'unanswered questions'. These were further refined by survey and interviews to a shortlist of 21 topics, and a mix of people aged 80+ living with three or more conditions, carers and health and social care providers to prioritised the top 10. RESULTS: the key priorities were about the prevention of social isolation, the promotion of independence and physical and emotional well-being. In addition to these broad topics, the process also identified detailed priorities including the role of exercise therapy, the importance of falls (particularly fear of falling), the recognition and management of frailty and Comprehensive Geriatric Assessment. CONCLUSION: these topics provide a unique perspective on research priorities on multiple conditions in later life and complement existing UK and International recommendations about the optimisation of health and social care systems to deliver essential holistic models of care and the prevention and treatment of multiple co-existing conditions.

Treatment and outcomes for glioblastoma in elderly compared with non-elderly patients: a population-based study.

PURPOSE: Elderly patients make up a large percentage of the individuals newly diagnosed with glioblastoma (gbm), but they face particular challenges in tolerating standard therapy, and compared with younger patients, they experience significantly shorter survival. We set out to compare clinical characteristics, treatment patterns, and outcomes in a non-elderly group (<65 years) and an elderly group (≥65 years) of patients diagnosed with gbm. METHODS: This retrospective population-based study used a province-wide cancer registry to identify patients with a new diagnosis of gbm within a 6-year period (2006-2012). Of the 138 patients identified, 56 (40.6%) were 65 years of age or older. Demographic characteristics, treatment patterns, and overall survival (os) in the elderly and non-elderly groups were compared. Predictors of os were determined using multivariate analysis. RESULTS: Elderly patients were more likely to present with a poor performance status (Eastern Cooperative Oncology Group ≥ 2), to undergo biopsy without resection, and to receive whole-brain or hypofractionated radiotherapy. Compared with non-elderly patients, the elderly patients were less likely to receive adjuvant temozolomide. Survival time was significantly shorter in the elderly than in the non-elderly patients (7.2 months vs. 11.2 months). In multivariate analysis, surgical resection, hypofractionated radiotherapy (compared with whole-brain or conventional radiotherapy), and chemotherapy were predictive of os in older patients. Among elderly patients receiving radiation, survival was improved with the use of combined therapy compared with the use of radiation only (11.3 months vs. 4.6 months). CONCLUSIONS: Overall survival was shorter for elderly patients with gbm than for non-elderly patients; the elderly patients were also less likely to receive intensive surgical or adjuvant therapy. Our population-based analysis demonstrated improved os with surgical resection, hypofractionated radiotherapy, and temozolomide, and supports the results of recent clinical trials demonstrating a benefit for combination chemoradiotherapy in older patients.

Using tablet-based technology in patient education about systemic therapy options for early-stage breast cancer: a pilot study.

BACKGROUND: Patient education in early-stage breast cancer has been shown to improve patient well-being and quality of life, but it poses a challenge given the increasingly complex regimens and time constraints in clinical practice. Technology-aided teaching in the clinic could help to improve the understanding of adjuvant systemic therapy for patients. In this prospective pilot study, we used a clinician-administered, tablet-based teaching aid to teach patients with early-stage breast cancer about adjuvant systemic therapy. METHODS: Participation was offered to newly diagnosed patients with early-stage breast cancer presenting for their first medical oncology visit at a provincial cancer centre. Participants were shown a tablet-based presentation describing procedures, rationales, risks, and benefits of adjuvant systemic therapy as an adjunct to a discussion with the medical oncologist. After the clinic visit, participants completed a questionnaire measuring satisfaction with the visit and knowledge of the treatment plan discussed. RESULTS: The 25 patients recruited for the study had a mean age of 57 years. An offer of upfront chemotherapy alone was made to 12 participants (48%), chemotherapy with trastuzumab to 4 (16%), and hormonal therapy to 9 (36%). Correct answers to all questions related to treatment knowledge were given by 22 patients (88%). Satisfaction with the clinic visit was high (mean satisfaction score: 4.53 ± 0.1 of a possible 5). CONCLUSIONS: We found that a tablet-based presentation about adjuvant systemic therapy was satisfactory to patients with early-stage breast cancer and that knowledge retention after the clinic visit was high. Tablet-based teaching could be a feasible and effective way of educating patients in the breast oncology clinic and warrants further investigation in randomized studies.

Evaluating the cost implications of integrating SARS-CoV-2 genome sequencing for infection prevention and control investigation of nosocomial transmission within hospitals.

BACKGROUND: The COG-UK hospital-onset COVID-19 infection (HOCI) trial evaluated the impact of SARS-CoV-2 whole-genome sequencing (WGS) on acute infection, prevention, and control (IPC) investigation of nosocomial transmission within hospitals. AIM: To estimate the cost implications of using the information from the sequencing reporting tool (SRT), used to determine likelihood of nosocomial infection in IPC practice. METHODS: A micro-costing approach for SARS-CoV-2 WGS was conducted. Data on IPC management resource use and costs were collected from interviews with IPC teams from 14 participating sites and used to assign cost estimates for IPC activities as collected in the trial. Activities included IPC-specific actions following a suspicion of healthcare-associated infection (HAI) or outbreak, as well as changes to practice following the return of data via SRT. FINDINGS: The mean per-sample costs of SARS-CoV-2 sequencing were estimated at £77.10 for rapid and £66.94 for longer turnaround phases. Over the three-month interventional phases, the total management costs of IPC-defined HAIs and outbreak events across the sites were estimated at £225,070 and £416,447, respectively. The main cost drivers were bed-days lost due to ward closures because of outbreaks, followed by outbreak meetings and bed-days lost due to cohorting contacts. Actioning SRTs, the cost of HAIs increased by £5,178 due to unidentified cases and the cost of outbreaks decreased by £11,246 as SRTs excluded hospital outbreaks. CONCLUSION: Although SARS-CoV-2 WGS adds to the total IPC management cost, additional information provided could balance out the additional cost, depending on identified design improvements and effective deployment.

Targeting triple-negative breast cancer: optimising therapeutic outcomes.

BACKGROUND: Triple-negative breast cancer (TNBC) is a distinct subset of breast cancer (BC) defined by the lack of immunohistochemical expression of the estrogen and progesterone receptors and human epidermal growth factor receptor 2. It is highly heterogeneous and displays overlapping characteristics with both basal-like and BC susceptibility gene 1 and 2 mutant BCs. This review evaluates the activity of emerging targeted agents in TNBC. DESIGN: A systematic review of PubMed and conference databases was carried out to identify randomised clinical trials reporting outcomes in women with TNBC treated with targeted and platinum-based therapies. RESULTS AND DISCUSSION: Our review identified TNBC studies of agents with different mechanisms of action, including induction of synthetic lethality and inhibition of angiogenesis, growth, and survival pathways. Combining targeted agents with chemotherapy in TNBC produced only modest gains in progression-free survival, and had little impact on survival. Six TNBC subgroups have been identified and found to differentially respond to specific targeted agents. The use of biological preselection to guide therapy will improve therapeutic indices in target-bearing populations. CONCLUSION: Ongoing clinical trials of targeted agents in unselected TNBC populations have yet to produce substantial improvements in outcomes, and advancements will depend on their development in target-selected populations.

Immunology in the Clinic Review Series; focus on host responses: T cell responses to herpes simplex viruses.

Herpes virus infections are chronic and co-exist with acquired immune responses that generally prevent severe damage to the host, while allowing periodic shedding of virus and maintenance of its transmission in the community. Herpes simplex viruses type 1 and 2 (HSV-1, HSV-2) are typical in this regard and are representative of the viral subfamily Alphaherpesvirinae, which has a tropism for neuronal and epithelial cells. This review will emphasize recent progress in decoding the physiologically important CD8(+) and CD4(+) T cell responses to HSV in humans. The expanding data set is discussed in the context of the search for an effective HSV vaccine as therapy for existing infections and to prevent new infections.

Outcomes of ureteroscopy for stone disease in pregnancy: results from a systematic review of the literature.

INTRODUCTION: Our aim was to evaluate the clinical efficacy and safety of ureteroscopy as a primary treatment for pregnant women with symptomatic ureteric stones who have failed conservative management. MATERIALS AND METHODS: A systematic review of the literature from January 1990 to June 2011 was performed, including all English language articles. Outcome measures were clinical efficacy, in terms of stone clearance and need for additional procedures, and safety in terms of complications. RESULTS: A total of 239 abstracts were screened and 15 studies were identified reporting on 116 procedures. The surgical methods of stone management employed were stone extraction with basket only (n = 55, 47%), laser fragmentation (n = 27, 23%; holmium, n = 20, pulse dye, n = 7), impact lithotripsy (n = 21, 18%), ureteroscopic lithotripsy (n = 6, 5%) and a combination of methods (n = 6, 5%). A post-operative stent was inserted in 64 of 116 procedures (55%). Complete stone clearance was seen in 100 of the 116 procedures (86%). There were 2 major complications (1 ureteral perforation and 1 case of premature uterine contraction) and 7 minor complications (5 urinary tract infections and 2 cases of post-operative pain). CONCLUSION: This review suggests that stone clearance using ureteroscopy is a relatively safe option in pregnancy with a high success rate.

Whole genome-expression profiling reveals a role for immune and inflammatory response in abdominal aortic aneurysm rupture.

OBJECTIVES: This study used the whole transcriptome approach to investigate the role of genes involved in immune and inflammatory response at the site of aneurysm rupture. MATERIALS AND METHODS: Rupture site and paired anterior sac biopsies (internal control) of ruptured abdominal aortic aneurysms (AAAs) (n=10) were analysed with Affymetrix Human Genome U133A plus 2.0 microarray. Twenty-one differentially expressed genes were selected for validation using quantitative reverse transcriptase polymerase chain reaction (QRT-PCR). RESULTS: A total of 139 genes (123 upregulated, 16 downregulated) at the aneurysm rupture site were differentially expressed (>2.5-fold, P<0.005). Immune and inflammatory responses (Gene Ontology Classification) were frequently associated with the differentially expressed genes. Genes with immune and inflammatory functions that were confirmed, by QRT-PCR, to be overexpressed at the aneurysm rupture site were interleukins-6 and -8 (IL-6 and -8), Selectin E (SELE), prostaglandin-endoperoxidase synthase 2 (COX2) and prokineticin 2 (PROK2). IL-6 (pro-immune) and IL-8 (pro-immune and pro-inflammatory) have previously been linked to aneurysm rupture; and SELE and COX2 (pro-inflammatory) have previous associations with aneurysm development but not rupture. CONCLUSIONS: The differential expression of genes involved in immune and inflammatory responses was confirmed at AAA rupture site. These genes may represent novel targets for treatment of aneurysms.

Screening for new primary cancers in patients with metastatic breast cancer: a provincial analysis of the Choosing Wisely Canada recommendations.

Introduction: Patients with metastatic cancer have a decreased life expectancy, and with screening and surveillance for new primary cancers, they run the risk of immediate harm with little chance of any benefit. Choosing Wisely Canada therefore recommends that such investigations be avoided in patients with metastatic disease. Methods: We examined cancer screening practices in a subset of patients with metastatic cancer in Newfoundland and Labrador. Patients with metastatic breast cancer seen at the provincial cancer clinic during 2014-2016 were identified from the Newfoundland and Labrador Cancer Registry. For each patient, we assessed whether any one or a combination of screening mammography, Pap (Papanicolaou) test, flexible sigmoidoscopy or colonoscopy, or fecal immunohistochemical test were performed at any point after the diagnosis of metastatic disease. Results: Of 305 patients with metastatic breast cancer, 114 (37.4%) underwent at least 1 screening investigation (mean: 2.92 investigations per screened patient). The most common screening investigations were mammography (n = 197) and Pap test (n = 107). Primary care providers ordered most of the screening investigations (70%); oncology specialists ordered 14%, and other specialists, 12%. Median overall survival for patients with breast cancer after a diagnosis of metastatic disease was 42 months, with a 5-year overall survival of 35.9%. Conclusions: A significant proportion of patients with metastatic breast cancer in Newfoundland and Labrador are still undergoing screening for new primary malignancies, which is discordant with oncology guidelines from Choosing Wisely Canada. Increased education strategies are needed if the Choosing Wisely Canada recommendations are to be implemented into routine clinical practice.

Comparison of scanning Kelvin probe with SEM/EPMA techniques for fingermark recovery from metallic surfaces.

Most traditional techniques to recover latent fingermarks from metallic surfaces do not consider the metal surface properties and instead focus on the fingermark chemistry. The scanning Kelvin probe (SKP) technique is a non-contact, non-destructive method, used under ambient conditions, which can be utilised to recover latent prints from metallic surfaces and does not require any enhancement techniques or prevent subsequent forensic analysis. Where a fingermark ridge contacted the metal, the contact potential difference (CPD) contrast between the background surface and the fingermark contact area was 10-50mV. Measurements were performed on the untreated brass, nickel-coated brass and copper metal surfaces and compared to traditional forensic enhancement techniques such as Vacuum Metal Deposition (VMD) using Au-Zn and Au-Ag. Using VMD, the CPD change ranged from 0 to 150mV between the dissimilar metal surfaces affected by the fingermark. In general, SKP worked best without additional enhancement techniques. Scanning Electron Microscope (SEM) scans were used to identify the fingermark contact areas through a sodium, chlorine and oxygen electron probe micro-analyzer (EPMA). The fingermark was observed in the backscattered electron image as the carbon deposits scattered the electrons less than the surrounding metal surface. The fingermark is shown clearly in a Cathodoluminescence scan on the copper sample as it blocks the photon emission at band gap (2.17eV) from the underlying copper oxide (Cu2O) surface. For the first time, SEM, EPMA and Cathodoluminescence techniques were compared to SKP data. Visible and latent fingermarks were tested with latent, eccrinous fingermarks more easily imaged by SKP. Results obtained were very encouraging and suggest that the scanning Kelvin probe technique, which does not need vacuum, could have a place as a first stage analysis tool in serious crime investigation.

Inhibition of cytokine-stimulated thymic lymphocyte proliferation by fatty acids: the role of eicosanoids.

The effect of individual fatty acids on the proliferation of thymic lymphocytes in response to interleukin-1 (IL-1) was investigated. Proliferation was estimated by measuring [3H]thymidine incorporation into the acid insoluble fraction of the thymocytes. A concentration-dependent inhibition (in the range 1-100 microM) in the IL-1-stimulated proliferation was observed with the C20 fatty acids dihomo-gamma-linolenic acid (DGLA), arachidonic acid and eicosapentaenoic acid (EPA). A less pronounced concentration-dependent inhibitory response was observed with the C18 fatty acids linoleic acid, alpha-linolenic acid and gamma-linolenic acid. Palmitic acid and oleic did not have any effect on either basal or IL-1-stimulated proliferation at concentrations up to 100 microM. The potencies of each fatty acid for this effect at a concentration of 100 microM were: arachidonic acid > EPA > or = DGLA > linoleic acid. DGLA, arachidonic acid and EPA also attenuated IL-2-stimulated proliferation. The inhibitory action of these fatty acids was not mediated by conversion to prostaglandins or other eicosanoids as the cyclooxygenase inhibitor, ketoprofen and NDGA did not alter their action. Incubation of thymocytes with radiolabelled DGLA and EPA followed by reverse-phase HPLC analysis revealed that DGLA is predominantly converted to a more polar metabolite which is not PGE1 whereas EPA does not appear to be converted to any other detectable metabolite. The data indicate that the inhibitory actions of fatty acids on cell proliferation do not occur as a result of conversion to other metabolites but may be direct effects. The inhibition of cytokine-stimulated lymphocyte proliferation by unsaturated fatty acids would imply that they may attenuate cell-mediated immune reactions.

Regulation of the interferon-inducible eIF-2 alpha protein kinase by small RNAs.

This review describes the structure and function of the double-stranded RNA-dependent protein kinase (PKR) and its interaction with RNA activators and inhibitors. The abilities of small virally-encoded RNAs such as VAI RNA of adenovirus, the Epstein-Barr virus encoded (EBER) RNAs and the Tat-responsive region RNA of HIV-1 to bind to and regulate PKR are reviewed, and the physiological implications of such regulation for the control of viral replication and cell growth are discussed. The potential effects on the activity of PKR of other proteins that bind double-stranded RNA and/or small viral and cellular RNAs are also considered.

Expression of an inducible nitric oxide synthase gene in rainbow trout Oncorhynchus mykiss.

Using oligonucleotide primers based on mammalian nitric oxide synthases (NOS), expression of an inducible NOS (iNOS) gene was detected in head kidney and gill tissue of bacterially-challenged rainbow trout. Three overlapping fragments were amplified by RT-PCR and used to construct a contiguous sequence of 1410bp, with high nucleotide homology to iNOS in birds (61%) and mammals (57-59%). The nucleotide sequence translated in one reading frame to produce a partial peptide containing 470 amino acids, with 69-71% amino acid homology with mammalian iNOS, 81% homology with chicken iNOS and 85% homology with a partial (492bp) goldfish iNOS sequence. In vitro stimulation of head kidney macrophages with LPS also induced expression of the trout iNOS RNA, with optimal expression seen using 20-50 microg/ml LPS at 2h to 6h post-stimulation. The evolutionary and functional significance of the trout iNOS sequence are discussed.

Cloning and sequencing of caspase 6 in rainbow trout, Oncorhynchus mykiss, and analysis of its expression under conditions known to induce apoptosis.

The rainbow trout caspase 6 gene has been cloned and sequenced. The open reading frame consisted of 906bp, which translated into a protein of 302 amino acids, containing the caspase active site pentapeptide (QACRG) and the caspase family signature (HADADCFVCVFLSHG). Amino acids involved in catalysis and those known to form the P1 carbohydrate binding pocket were conserved. Phylogenetic tree analysis showed a tight grouping with other known caspase 6 genes. Conserved aspartic acid residues at positions 33, 191 and 202 suggested that this molecule is produced as a proenzyme that is subsequently cleaved to release active subunits, with the region between Asp-191 and Ala-203 acting as a linker that is cleaved out. RT-PCR analysis revealed that the trout caspase 6 gene was expressed in brain, blood, gill, liver, head kidney and spleen. Addition of LPS or cortisol to head kidney leucocyte cultures had no effect upon caspase 6 expression. However, addition of LPS after preincubation with cortisol increased expression relative to control cultures. Incubation with RU486 abrogated this effect, confirming it was mediated via glucocorticoid receptors. Lastly, a confinement stress in vivo increased caspase 6 expression. The data are discussed with respect to the immunoregulatory role of apoptosis in fish immune responses.

Dopamine stimulates rat cortical somatostatin release.

Release of somatostatin from slices of rat frontal cortex was studied. Increasing the potassium ion concentration in the medium from 6 mM to 55 mM resulted in a significantly increased release of somatostatin. Dopamine increased the release of somatostatin from cortex and this effect of dopamine was blocked by haloperidol and other dopaminergic antagonists. Other catecholamines as well as serotonin, histamine and acetylcholine failed to stimulate the release of somatostatin. The stimulatory effect of dopamine on release of somatostatin from cortical slices provides an approach for examination of the receptor properties and function of dopamine in this brain region.

TGF-beta3 exists in bony fish.

A partial nucleotide sequence of transforming growth factor-beta3 (TGF-beta3) has been isolated from the Siberian sturgeon (Acipenser baeri), rainbow trout (Oncorhynchus mykiss) and European eel (Anguilla anguilla), confirming a ubiquitous presence in the ray-finned (Actinopterygian) bony fish. The bony fish TGF-beta3 is highly conserved, with some 83-84% nucleotide identity (coding region) and 90-95% predicted amino acid identity to known homeotherm TGF-beta3's. Far lower homologies are apparent with other known TGF-beta isoforms in fish (e.g. 64-66% and 81-82% amino acid identity to trout TGF-beta 1/5 and carp TGF-beta2 respectively). Phylogenetic tree analysis showed that the fish TGF-beta3's clustered with the known homeotherm TGF-beta3's. The relatively tight clustering of TGF-beta1, TGF-beta2 and TGF-beta3 was in contrast to the TGF-beta5's, which are clearly a more heterogenous group.