Identification of hippocampal area CA2 in hamster and vole brain.

Prairie voles (Microtus ochrogaster) and Syrian, or golden, hamsters (Mesocricetus auratus) are closely related to mice (Mus musculus) and are commonly used in studies of social behavior including social interaction, social memory, and aggression. Hippocampal area CA2 is known to play a key role in these behaviors in mice and responds to social stimuli in rats, but CA2 has yet to be characterized in hamsters or voles, which are also used in studies of social behaviors. Here, we used immunofluorescence to determine whether CA2 could be molecularly identified in tissue from voles and hamsters. We found that  staining for many CA2 markers was similar in these three species, with labeling seen in neurons at the distal end of the mossy fibers . In contrast, although perineuronal nets (PNNs) surround CA2 cells in mice, PNN staining differed across species. In voles, both CA2 and CA3 were labeled, whereas in hamsters, labeling was seen primarily in CA3. These results demonstrate that CA2 can be molecularly distinguished from neighboring CA1 and CA3 areas in voles and hamsters with several antibodies commonly used in mice. However, PNN staining is not useful for identifying CA2 in voles or hamsters, suggestive of differing roles for either PNNs or for the hippocampal subregions in social behavior. These findings reveal commonalities across species in the molecular profile of CA2 and should facilitate future studies of CA2 in these species.

Evaluation of mechanistic serum and urine biomarkers for secondary osteoarthritis associated with developmental dysplasia of the hip.

Objective: Determine measurable differences for mechanistic urine and serum biomarkers in patients with developmental dysplasia of the hip (DDH) prior to, and following, secondary hip osteoarthritis (OA) when compared to controls. Design: Urine and serum were collected from individuals with developmental dysplasia of the hip (n = 39), prior to (Pre-OA DDH, n = 32) and following diagnosis of secondary hip OA (Post-OA DDH, n = 7), age-matched Pre-OA controls (n = 35), and age-matched Post-OA controls (n = 12). Samples were analyzed for protein biomarkers with potential for differentiation of hip status through a Mann-Whitney U test with a Benjamini-Hochberg correction. Results: Several interleukin and degradation related proteins were found to be differentially expressed when comparing DDH-related hip status prior to and following diagnosis of hip OA. In addition, MCP-1 and TIMP-1 were significantly different between younger and older patients in the control cohorts. Conclusion: These results provide initial evidence for serum and urine protein biomarkers that define clinically relevant stages of symptomatic DDH and its progression to secondary hip osteoarthritis categorized by known mechanisms of disease. Level of evidence: III.

Evaluation of Serum and Urine Biomarker Panels for Developmental Dysplasia of the Hip Prior to Onset of Secondary Osteoarthritis.

OBJECTIVE: Evaluate serum and urine biomarker panels for their capabilities in discriminating between individuals (13- to 34-years-olds) with healthy hips versus those with developmental dysplasia of the hip (DDH) prior to diagnosis of secondary hip osteoarthritis (OA). DESIGN: Urine and serum were collected from individuals (15-33 years old) with DDH, prior to and following diagnosis of hip OA, and from age-matched healthy-hip controls. Samples were analyzed for panels of protein biomarkers with potential for differentiation of hip status using receiver operator characteristic curve (area under curve [AUC]) assessments. RESULTS: Multiple urine and serum biomarker panels effectively differentiated individuals with DDH from healthy-hip controls in a population at risk for developing secondary hip OA with the best performing panel demonstrating an AUC of 0.959. The panel comprised of two serum and two urinary biomarkers provided the highest combined values for sensitivity, 0.85, and specificity, 1.00, while a panel of four serum biomarkers provided the highest sensitivity, 0.93, while maintaining adequate specificity, 0.71. CONCLUSION: Results of this study indicate that panels of protein biomarkers measured in urine and serum may be able to differentiate young adults with DDH from young adults with healthy hips. These data suggest the potential for clinical application of a routine diagnostic method for cost-effective and timely screening for DDH in at-risk populations. Further development and validation of these biomarker panels may result in highly sensitive and specific tools for early diagnosis, staging, and prognostication of DDH, as well as treatment decision making and monitoring capabilities. LEVEL OF EVIDENCE: III.

IgG-cleavage protein allows therapeutic AAV gene delivery in passively immunized MPS IIIA mice.

The widespread pre-existing αAAV-Abs in humans pose a critical challenge in translation of AAV gene therapy. The IgG degrading enzyme of Streptococci (IdeS) is demonstrated to specifically cleave IgG of humans and other species (not mouse). This study developed a modified new modified IdeS protein product (IdeSop). When incubated in vitro, IdeSop was shown to completely cleave human and rabbit IgGs within 6 h. To test IdeSop in a disease setting, we established a rabbitized αAAV9-Ab+ mouse by an IV infusion of purified acute αAAV9-Ab+ rabbit IgG into MPS IIIA mice, resulting in serum αAAV9-IgG at 1:6,400 and αAAV9-nAbs at 1:800. IdeSop-Ab-cleavage was shown to be dose-dependent. An IV IdeSop infusion at the effective doses resulted in rapid IgG depletion and clearance of pre-existing αAAV9-IgG and αAAV9-nAbs in rabbitized αAAV9-Abs+ MPS IIIA mice. Importantly, an IV injection of a high dose AAV9-hSGSHop vector (5 × 1013vg/kg) at 24 h post IdeSop treatment led to transduction as effective in αAAV9-Abs+ MPS IIIA mice, as in αAAV9-Abs-negative controls. We believe that transient IdeSop administration may offer a great tool to address the pre-existing-αAAV-Abs for the translation of rAAV gene therapy to treat diseases in humans, making effective rAAV gene therapy available to all patients in need.

Feasibility testing of a standardised virtual clinic for follow-up of patients after hip and knee arthroplasty.

INTRODUCTION: Over 200,000 hip and knee total joint arthroplasties (TJAs) are performed annually in England and Wales. UK guidelines recommend regular follow-up because missed early failure can result in complex revision surgery, which places additional burden on overstretched orthopaedic services. This study evaluated the feasibility and acceptability of an expert, consensus-based, standardised virtual clinic (VC) approach for TJA follow-up. METHODS: Five UK secondary care orthopaedic centres implemented a standardised VC. Feedback was obtained through patient satisfaction questionnaires and telephone interviews with arthroplasty care practitioners. Key stakeholders subsequently attended an expert discussion forum to achieve consensus on the final VC format and to address obstacles identified during testing. RESULTS: From 19 June 2018 to 11 December 2018, 561 TJA patients [mean age (SD) 70 (9.4) years, 57.8% female, 69.0% hip TJA, 1-28 years postsurgery (median 5 years)] completed a VC. Of these 561 patients, 82.2% were discharged without attending an outpatient appointment and 46 (8.8%) required early face-to-face consultant review. Patient satisfaction with the VC was high (156/188; 83.0%); over 70% of patients indicated a preference for the VC. DISCUSSION: This feasibility study suggested significant resource savings, including time spent by consultant orthopaedic surgeons in outpatient clinics, hospital transport and an estimated saving of up to two-thirds of usual clinic-allotted time. The expert discussion forum provided helpful feedback for supporting more efficient implementation of the VC. CONCLUSIONS: A standardised VC is a feasible alternative to outpatient clinics for the follow-up of hip and knee TJA patients, and is acceptable to key stakeholders, including patients.

An analysis of the experiences of bereaved relatives and health care providers following palliative sedation: a study protocol for a qualitative international multicenter case study.

BACKGROUND: Patients at the end-of-life may experience refractory symptoms of which pain, delirium, vomiting and dyspnea are the most frequent. Palliative sedation can be considered a last resort option to alleviate one or more refractory symptoms. There are only a limited number of (qualitative) studies exploring the experiences of relatives of sedated patients and their health care professionals (HCPs). The aims of this study protocol are: 1) to elicit the experiences of bereaved relatives and health care professionals of patients treated with palliative sedation and 2) to explore the understanding of the decision-making process to start palliative sedation across care settings in 5 European countries. METHODS: This study protocol is part of the larger HORIZON 2020 Palliative Sedation project. Organisational case study methodology will be used to guide the study design. In total, 50 cases will be conducted in five European countries (10 per country). A case involves a semi-structured interview with a relative and an HCP closely involved in the care of a deceased patient who received some type of palliative sedation at the end-of-life. Relatives and health care professionals of deceased patients participating in a linked observational cohort study of sedated patients cared for in hospital wards, palliative care units and hospices will be recruited. The data will be analyzed using a framework analysis approach. The first full case will be analyzed by all researchers after being translated into English using a pre-prepared code book. Afterwards, bimonthly meetings will be organized to coordinate the data analysis. DISCUSSION: The study aims to have a better understanding of the experiences of relatives and professional caregivers regarding palliative sedation and this within different settings and countries. Some limitations are: 1) the sensitivity of the topic may deter some relatives from participation, 2) since the data collection and analysis will be performed by at least 5 different researchers in 5 countries, some differences may occur which possibly makes it difficult to compare cases, but using a rigorous methodology will minimize this risk.

An opioid-gated thalamoaccumbal circuit for the suppression of reward seeking in mice.

Suppression of dangerous or inappropriate reward-motivated behaviors is critical for survival, whereas therapeutic or recreational opioid use can unleash detrimental behavioral actions and addiction. Nevertheless, the neuronal systems that suppress maladaptive motivated behaviors remain unclear, and whether opioids disengage those systems is unknown. In a mouse model using two-photon calcium imaging in vivo, we identify paraventricular thalamostriatal neuronal ensembles that are inhibited upon sucrose self-administration and seeking, yet these neurons are tonically active when behavior is suppressed by a fear-provoking predator odor, a pharmacological stressor, or inhibitory learning. Electrophysiological, optogenetic, and chemogenetic experiments reveal that thalamostriatal neurons innervate accumbal parvalbumin interneurons through synapses enriched with calcium permeable AMPA receptors, and activity within this circuit is necessary and sufficient for the suppression of sucrose seeking regardless of the behavioral suppressor administered. Furthermore, systemic or intra-accumbal opioid injections rapidly dysregulate thalamostriatal ensemble dynamics, weaken thalamostriatal synaptic innervation of downstream neurons, and unleash reward-seeking behaviors in a manner that is reversed by genetic deletion of thalamic µ-opioid receptors. Overall, our findings reveal a thalamostriatal to parvalbumin interneuron circuit that is both required for the suppression of reward seeking and rapidly disengaged by opioids.

A Novel Assay Allowing Drug Self-Administration, Extinction, and Reinstatement Testing in Head-Restrained Mice.

Multiphoton microscopy is one of several new technologies providing unprecedented insight into the activity dynamics and function of neural circuits. Unfortunately, some of these technologies require experimentation in head-restrained animals, limiting the behavioral repertoire that can be integrated and studied. This issue is especially evident in drug addiction research, as no laboratories have coupled multiphoton microscopy with simultaneous intravenous drug self-administration, a behavioral paradigm that has predictive validity for treatment outcomes and abuse liability. Here, we describe a new experimental assay wherein head-restrained mice will press an active lever, but not inactive lever, for intravenous delivery of heroin or cocaine. Similar to freely moving animals, we find that lever pressing is suppressed through daily extinction training and subsequently reinstated through the presentation of relapse-provoking triggers (drug-associative cues, the drug itself, and stressors). Finally, we show that head-restrained mice will show similar patterns of behavior for oral delivery of a sucrose reward, a common control used for drug self-administration experiments. Overall, these data demonstrate the feasibility of combining drug self-administration experiments with technologies that require head-restraint, such as multiphoton imaging. The assay described could be replicated by interested labs with readily available materials to aid in identifying the neural underpinnings of substance use disorder.

Bacterial DNA screening to characterize surgical site infection risk in orthopaedic patients.

PURPOSE: To provide an initial characterization of relevant bacterial DNA profiles for patients undergoing closed-fracture fixation or total joint arthroplasties. PATIENTS AND METHODS: Swabs were collected and analyzed using Polymerase Chain Reaction from adult patients undergoing closed-fracture fixation or total shoulder, knee, or hip arthroplasties. RESULTS: Bacterial DNA profiles varied across the different orthopaedic patient populations, and produced uncharacteristic profile shifts with direct relevance to each clinical infection. CONCLUSION: Findings provide a foundational dataset regarding bacterial colonization of relevant anatomic sites that can act as sources of surgical site infections for patients.

Specialized coding patterns among dorsomedial prefrontal neuronal ensembles predict conditioned reward seeking.

Non-overlapping cell populations within dorsomedial prefrontal cortex (dmPFC), defined by gene expression or projection target, control dissociable aspects of reward seeking through unique activity patterns. However, even within these defined cell populations, considerable cell-to-cell variability is found, suggesting that greater resolution is needed to understand information processing in dmPFC. Here, we use two-photon calcium imaging in awake, behaving mice to monitor the activity of dmPFC excitatory neurons throughout Pavlovian reward conditioning. We characterize five unique neuronal ensembles that each encodes specialized information related to a sucrose reward, reward-predictive cues, and behavioral responses to those cues. The ensembles differentially emerge across daily training sessions - and stabilize after learning - in a manner that improves the predictive validity of dmPFC activity dynamics for deciphering variables related to behavioral conditioning. Our results characterize the complex dmPFC neuronal ensemble dynamics that stably predict reward availability and initiation of conditioned reward seeking following cue-reward learning.

The prevalence of potential drug-drug interactions in adults with intellectual disability.

BACKGROUND: There is a high use of medications in adults with intellectual disability (ID). One implication of taking multiple medications is the potential for drug-drug interactions (DDIs). However, despite this being well highlighted in the mainstream literature, little is known about the incidence or associations of DDIs in the ID population. METHODS: This study describes the prevalence, patterns and associations of potential DDIs in a total administrative sample of adults with ID known to services in Jersey. Demographic, health-related and medication data were collected from 217 adults known to ID services. Data were collected using a face-to-face survey. The Anatomical Therapeutic Chemical classification system was used to categorise medications, and Stockley's Drug Interaction Checker was used to classify potential DDIs. Drug-drug pairings were considered to be of clinical significance if they were to be 'avoided, adjusted, monitored or required further information'. RESULTS: Potential DDIs of clinical significance were common. Exposure to potential DDIs of clinical significance was associated with being female, taking more than five medications (polypharmacy), living in residential care and having more health conditions. A simple regression was used to understand the effect of number of prescribed medications on potential DDIs of clinical significance. Every prescribed drug led to a 0.87 (95% confidence interval: 0.72-1.00) increase in having a potential DDI of clinical significance. CONCLUSION: Adults with ID who live in residential care, who are female, exposed to polypharmacy and have more health conditions may be more likely to have potential DDIs of clinical significance. Urgent consideration needs to be given to the potential of DDIs in this population given their exposure to high levels of medication.

Targeting the Root Cause of Mucopolysaccharidosis IIIA with a New scAAV9 Gene Replacement Vector.

No treatment is available to address the unmet needs of mucopolysaccharidosis (MPS) IIIA patients. Targeting the root cause, we developed a new self-complementary adeno-associated virus 9 (scAAV9) vector to deliver the human N-sulfoglucosamine sulfohydrolase (hSGSH) gene driven by a miniature cytomegalovirus (mCMV) promoter. In pre-clinical studies, the vector was tested at varying doses by a single intravenous (i.v.) infusion into MPS IIIA mice at different ages. The vector treatments resulted in rapid and long-term expression of functional recombinant SGSH (rSGSH) enzyme and elimination of lysosomal storage pathology throughout the CNS and periphery in all tested animals. Importantly, MPS IIIA mice treated with the vector at up to 6 months of age showed significantly improved behavior performance in a hidden task in the Morris water maze, as well as extended lifespan, with most of the animals surviving within the normal range, indicating that the vector treatment can prevent and reverse MPS IIIA disease progression. Notably, 2.5 × 1012 vector genomes (vg)/kg was functionally effective. Furthermore, the vector treatment did not lead to detectable systemic toxicity or adverse events in MPS IIIA mice. These data demonstrate the development of a safe and effective new gene therapy product for treating MPS IIIA, which further support the extended clinical relevance of platform recombinant AAV9 (rAAV9 gene delivery for treating broad neurogenetic diseases.

Identification of the Physiologically Difficult Airway in the Pediatric Emergency Department.

BACKGROUND: The risk factors for peri-intubation cardiac arrest in critically ill children are incompletely understood. The study objective was to derive physiologic risk factors for deterioration during tracheal intubation in a pediatric emergency department (PED). METHODS: This was a retrospective cohort study of patients undergoing emergency tracheal intubation in a PED. Using the published literature and expert opinion, a multidisciplinary team developed high-risk criteria for peri-intubation arrest: 1) hypotension, 2) concern for cardiac dysfunction, 3) persistent hypoxemia, 4) severe metabolic acidosis (pH < 7.1), 5) post-return of spontaneous circulation (ROSC), and 6) status asthmaticus. We completed a structured review of the electronic health record for a historical cohort of patients intubated in the PED. The primary outcome was peri-intubation arrest. Secondary outcomes included tracheal intubation success rate, extracorporeal membrane oxygenation (ECMO) activation, and in-hospital mortality. We compared outcomes between patients meeting one or more versus no high-risk criteria. RESULTS: Peri-intubation cardiac arrest occurred in 5.6% of patients who met at least one high-risk criterion compared to 0% in patients meeting none (5.6% difference, 95% confidence interval [CI] = 1.0 to 18.1, p = 0.028). Patients meeting at least one criterion had higher rates of any postintubation cardiac arrest in the PED (11.1% vs. 0%, 11.1% difference, 95% CI = 4.1 to 25.3, p = 0.0007), in-hospital mortality (25% vs. 2.3%, 22.7% difference, 95% CI = 11.0 to 38.9, p < 0.0001), ECMO activation (8.3% vs. 0%, 8.3% difference, 95% CI = 2.5 to 21.8, p = 0.004), and lower likelihood of first-pass intubation success (47.2% vs. 66.1%, -18.9% difference, 95% CI = -35.5 to -1.5, p = 0.038), respectively. CONCLUSIONS: We have developed criteria that successfully identify physiologically difficult airways in the PED. Children with hypotension, persistent hypoxemia, concern for cardiac dysfunction, severe metabolic acidosis, status asthmaticus or who are post-ROSC are at higher risk for peri-intubation cardiac arrest and in-hospital mortality. Further multicenter investigation is needed to validate our findings.

Endogenous carbohydrate esterases of Clostridium thermocellum are identified and disrupted for enhanced isobutyl acetate production from cellulose.

Medium-chain esters are versatile chemicals with broad applications as flavors, fragrances, solvents, and potential drop-in biofuels. Currently, these esters are largely produced by the conventional chemical process that uses harsh operating conditions and requires high energy input. Alternatively, the microbial conversion route has recently emerged as a promising platform for sustainable and renewable ester production. The ester biosynthesis pathways can utilize either lipases or alcohol acyltransferase (AAT), but the AAT-dependent pathway is more thermodynamically favorable in an aqueous fermentation environment. Even though a cellulolytic thermophile Clostridium thermocellum harboring an AAT-dependent pathway has recently been engineered for direct conversion of lignocellulosic biomass into esters, the production is not efficient. One potential bottleneck is the ester degradation caused by the endogenous carbohydrate esterases (CEs) whose functional roles are poorly understood. The challenge is to identify and disrupt CEs that can alleviate ester degradation while not negatively affecting the efficient and robust capability of C. thermocellum for lignocellulosic biomass deconstruction. In this study, by using bioinformatics, comparative genomics, and enzymatic analysis to screen a library of CEs, we identified and disrupted the two most critical CEs, Clo1313_0613 and Clo1313_0693, that significantly contribute to isobutyl acetate degradation in C. thermocellum. We demonstrated that an engineered esterase-deficient C. thermocellum strain not only reduced ester hydrolysis but also improved isobutyl acetate production while maintaining effective cellulose assimilation.

Content analysis of Advance Directives completed by patients with advanced cancer as part of an Advance Care Planning intervention: insights gained from the ACTION trial.

PURPOSE: Writing an Advance Directive (AD) is often seen as a part of Advance Care Planning (ACP). ADs may include specific preferences regarding future care and treatment and information that provides a context for healthcare professionals and relatives in case they have to make decisions for the patient. The aim of this study was to get insight into the content of ADs as completed by patients with advanced cancer who participated in ACP conversations. METHODS: A mixed methods study involving content analysis and descriptive statistics was used to describe the content of completed My Preferences forms, an AD used in the intervention arm of the ACTION trial, testing the effectiveness of the ACTION Respecting Choices ACP intervention. RESULTS: In total, 33% of 442 patients who received the ACTION RC ACP intervention completed a My Preferences form. Document completion varied per country: 10.4% (United Kingdom), 20.6% (Denmark), 29.2% (Belgium), 41.7% (the Netherlands), 61.3% (Italy) and 63.9% (Slovenia). Content analysis showed that 'maintaining normal life' and 'experiencing meaningful relationships' were important for patients to live well. Fears and worries mainly concerned disease progression, pain or becoming dependent. Patients hoped for prolongation of life and to be looked after by healthcare professionals. Most patients preferred to be resuscitated and 44% of the patients expressed maximizing comfort as their goal of future care. Most patients preferred 'home' as final place of care. CONCLUSIONS: My Preferences forms provide some insights into patients' perspectives and preferences. However, understanding the reasoning behind preferences requires conversations with patients.

Developing a standardized approach to virtual clinic follow-up of hip and knee arthroplasty.

AIMS: This study aimed to develop a virtual clinic for the purpose of reducing face-to-face orthopaedic consultations. PATIENTS AND METHODS: Anonymized experts (hip and knee arthroplasty patients, surgeons, physiotherapists, radiologists, and arthroplasty practitioners) gave feedback via a Delphi Consensus Technique. This consisted of an iterative sequence of online surveys, during which virtual documents, made up of a patient-reported questionnaire, standardized radiology report, and decision-guiding algorithm, were modified until consensus was achieved. We tested the patient-reported questionnaire on seven patients in orthopaedic clinics using a 'think-aloud' process to capture difficulties with its completion. RESULTS: A patient-reported 13-item questionnaire was developed covering pain, mobility, and activity. The radiology report included up to ten items (e.g. progressive periprosthetic bone loss) depending on the type of arthroplasty. The algorithm concludes in one of three outcomes: review at surgeon's discretion (three to 12 months); see at next available clinic; or long-term follow-up/discharge. CONCLUSION: The virtual clinic approach with attendant documents achieved consensus by orthopaedic experts, radiologists, and patients. The robust development and testing of this standardized virtual clinic provided a sound platform for organizations in the United Kingdom to adopt a virtual clinic approach for follow-up of hip and knee arthroplasty patients. Cite this article: Bone Joint J 2019;101-B:951-959.

Development of a parent-reported questionnaire evaluating upper limb activity limitation in children with cerebral palsy.

BACKGROUND AND PURPOSE: Upper limb activity measures for children with cerebral palsy have a number of limitations, for example, lack of validity and poor responsiveness. To overcome these limitations, we developed the Children's Arm Rehabilitation Measure (ChARM), a parent-reported questionnaire validated for children with cerebral palsy aged 5-16 years. This paper describes both the development of the ChARM items and response categories and its psychometric testing and further refinement using the Rasch measurement model. METHODS: To generate valid items for the ChARM, we collected goals of therapy specifically developed by therapists, children with cerebral palsy, and their parents for improving activity limitation of the upper limb. The activities, which were the focus of these goals, formed the basis for the items. Therapists typically break an activity into natural stages for the purpose of improving activity performance, and these natural orders of achievement formed each item's response options. Items underwent face validity testing with health care professionals, parents of children with cerebral palsy, academics, and lay persons. A Rasch analysis was performed on ChARM questionnaires completed by the parents of 170 children with cerebral palsy from 12 hospital paediatric services. The ChARM was amended, and the procedure repeated on 148 ChARMs (from children's mean age: 10 years and 1 month; range: 4 years and 8 months to 16 years and 11 months; 85 males; Manual Ability Classification System Levels I = 9, II = 26, III = 48, IV = 45, and V = 18). RESULTS: The final 19-item unidimensional questionnaire displayed fit to the Rasch model (chi-square p = .18), excellent reliability (person separation index = 0.95, α = 0.95), and no floor or ceiling effects. Items showed no response bias for gender, distribution of impairment, age, or learning disability. DISCUSSION: The ChARM is a psychometrically sound measure of upper limb activity validated for children with cerebral palsy aged 5-16 years. The ChARM is freely available for use to clinicians and nonprofit organisations.

Integrated palliative care in Europe: a qualitative systematic literature review of empirically-tested models in cancer and chronic disease.

BACKGROUND: Integrated Palliative Care (PC) strategies are often implemented following models, namely standardized designs that provide frameworks for the organization of care for people with a progressive life-threatening illness and/or for their (in)formal caregivers. The aim of this qualitative systematic review is to identify empirically-evaluated models of PC in cancer and chronic disease in Europe. Further, develop a generic framework that will consist of the basis for the design of future models for integrated PC in Europe. METHODS: Cochrane, PubMed, EMBASE, CINAHL, AMED, BNI, Web of Science, NHS Evidence. Five journals and references from included studies were hand-searched. Two reviewers screened the search results. Studies with adult patients with advanced cancer/chronic disease from 1995 to 2013 in Europe, in English, French, German, Dutch, Hungarian or Spanish were included. A narrative synthesis was used. RESULTS: 14 studies were included, 7 models for chronic disease, 4 for integrated care in oncology, 2 for both cancer and chronic disease and 2 for end-of-life pathways. The results show a strong agreement on the benefits of the involvement of a PC multidisciplinary team: better symptom control, less caregiver burden, improvement in continuity and coordination of care, fewer admissions, cost effectiveness and patients dying in their preferred place. CONCLUSION: Based on our findings, a generic framework for integrated PC in cancer and chronic disease is proposed. This framework fosters integration of PC in the disease trajectory concurrently with treatment and identifies the importance of employing a PC-trained multidisciplinary team with a threefold focus: treatment, consulting and training.

Patient-reported outcome measures for use in gynaecological oncology: a systematic review.

BACKGROUND: Patient-reported outcome measures (PROMs) are used to assess the impact of health care on a patient's health. Within the gynaecological oncology setting, multiple PROMs have been adopted but no assessment has been made in terms of their psychometric qualities and robustness. OBJECTIVES: To undertake a systematic review to identify the most psychometrically robust and appropriate PROM used in the gynaecological oncology setting. SEARCH STRATEGY: A search of the bibliographic database of the Oxford PROM group, plus nine additional databases, was carried out along with citation-tracking and hand searches. SELECTION CRITERIA: Studies examining the psychometric properties of outcome measures tested in gynaecological cancer populations were selected by three blinded reviewers. DATA COLLECTION AND ANALYSIS: Studies were independently assessed and data extracted. Analysis included an appraisal of the psychometric properties and functionality of the included PROMs to guide recommendations. MAIN RESULTS: Eighteen PROMs tested in gynaecological oncology settings were identified. These were categorised into seven areas of focus, and the most psychometrically robust tools were identified: (1) generic (no recommendation); (2) general cancer (EORTC QLQ-C30 and FACT-G); (3) pelvic cancer (QUEST GY); (4) ovarian cancer (EORTC QLQ-OV28); (5) cervical cancer (EORTC QLQ-CX24); (6) endometrial cancer (EORTC QLQ-EN 24); and (7) vulval cancer (FACT-V). AUTHOR'S CONCLUSIONS: Seven PROMs were recommended for use in six gynaecological populations. No single tool was identified that had been tested in all disease groups. Some showed promise, but a lack of conceptual clarity about the core outcomes and the rationale for use will require further testing using well-constructed studies.