Transection of the ventral hippocampal commissure impairs spatial reference but not contextual or spatial working memory.

Plasticity is a neural phenomenon in which experience induces long-lasting changes to neuronal circuits and is at the center of most neurobiological theories of learning and memory. However, too much plasticity is maladaptive and must be balanced with substrate stability. Area CA3 of the hippocampus provides such a balance via hemispheric lateralization, with the left hemisphere dominant in providing plasticity and the right specialized for stability. Left and right CA3 project bilaterally to CA1; however, it is not known whether this downstream merging of lateralized plasticity and stability is functional. We hypothesized that interhemispheric convergence of input from these pathways is essential for integrating spatial memory stored in the left CA3 with navigational working memory facilitated by the right CA3. To test this, we severed interhemispheric connections between the left and right hippocampi in mice and assessed learning and memory. Despite damage to this major hippocampal fiber tract, hippocampus-dependent navigational working memory and short- and long-term memory were both spared. However, tasks that required the integration of information retrieved from memory with ongoing navigational working memory and navigation were impaired. We propose that one function of interhemispheric communication in the mouse hippocampus is to integrate lateralized processing of plastic and stable circuits to facilitate memory-guided spatial navigation.

The rodent hippocampus as a bilateral structure: A review of hemispheric lateralization.

The left and right rodent hippocampi exhibit striking lateralization in some of the very neural substrates considered to be critical for hippocampal cognitive function. Despite this, there is an overwhelming lack of consideration for hemispheric differences in studies of the rodent hippocampus. Asymmetries identified so far suggest that a bilateral model of the hippocampus will be essential for an understanding of this brain region, and perhaps of the brain more widely. Although hypotheses have been proposed to explain how the left and right hippocampi contribute to behavior and cognition, these hypotheses have either been refuted by more recent studies or have been limited in the scope of data they explain. Here, I will first review data on human and rodent hippocampal lateralization. The implications of these data suggest that considering the hippocampus as a bilateral structure with functional lateralization will be critical moving forward in understanding the function and mechanisms of this brain region. In exploring these implications, I will then propose a hypothesis of the hippocampus as a bilateral structure. This discrete-continuous hypothesis proposes that the left and right hippocampi contribute to spatial memory and navigation in a complementary manner. Specifically, the left hemisphere stores spatial information as discrete, salient locations, and the right hemisphere represents space continuously, contributing to route computation and flexible spatial navigation. Consideration of hippocampal lateralization in designing future studies may provide insight into the function of the hippocampus and resolve debates concerning its function.

ITTREAT (Integrated Community Test - Stage - TREAT) Hepatitis C service for people who use drugs: Real-world outcomes.

BACKGROUND/AIMS: Direct-acting antivirals (DAAs) provide an unprecedented opportunity for a "find-and-treat strategy." We aimed to report real-world clinical, patient reported and health economic outcomes of community-based hepatitis C virus (HCV) screening/treatment in people who use drugs (PWUDs). METHODS: Project ITTREAT (2013-2021), established at a drug and alcohol treatment centre, offered a comprehensive service. Generic (SF-12v2 and EQ-5D-5L) and liver-specific (SFLDQoL) health-related quality of life (HRQoL) were assessed before and after HCV treatment. Costs/case detected and cured were calculated. Primary outcome measure was sustained virological response (SVR) (intention to treat). RESULTS: Till March 2018, 573 individuals recruited, 462 (81%) males, mean age 40.5 ± 10.0 years. Of the 125 treated, 115 (92%) had past/current history of injecting drug use, 88 (70%) were receiving opioid agonist treatment and 50 (40%) were homeless. Twenty-six per cent received interferon-based and 74% DAA-only regimens. SVR (ITT) was 87% (90% with DAAs). Service uptake/HCV treatment completion rates were >95%, HCV reinfection being 2.63/100 person years (95% CI 0.67-10.33). HRQoL improved significantly at end of treatment (EOT) in those with SVR: SFLDQoL (symptoms, memory, distress, loneliness, hopelessness, sleep and stigma) (P

Follow-up care after treatment for prostate cancer: evaluation of a supported self-management and remote surveillance programme.

BACKGROUND: Alternative models of cancer follow-up care are needed to ameliorate pressure on services and better meet survivors' long-term needs. This paper reports an evaluation of a service improvement initiative for the follow-up care of prostate cancer patients based on remote monitoring and supported self-management. METHODS: This multi-centred, historically controlled study compared patient reported outcomes of men experiencing the new Programme with men experiencing a traditional clinic appointment model of follow-up care, who were recruited in the period immediately prior to the introduction of the Programme. Data were collected by self-completed questionnaires, with follow up measurement at four and eight months post-baseline. The primary outcome was men's unmet survivorship needs, measured by the Cancer Survivors' Unmet Needs Survey. Secondary outcomes included cancer specific quality of life, psychological wellbeing and satisfaction with care. The analysis was intention to treat. Regression analyses were conducted for outcomes at each time point separately, controlling for pre-defined clinical and demographic variables. All outcome analyses are presented in the paper. Costs were compared between the two groups. RESULTS: Six hundred and twenty-seven men (61%) were consented to take part in the study (293 in the Programme and 334 in the comparator group.) Regarding the primary measure of unmet survivorship needs, 25 of 26 comparisons favoured the Programme, of which 4 were statistically significant. For the secondary measures of activation for self-management, quality of life, psychological well-being and lifestyle, 20 of 32 comparisons favoured the Programme and 3 were statistically significant. There were 22 items on the satisfaction with care questionnaire and 13 were statistically significant. Per participant costs (British pounds, 2015) in the 8 month follow up period were slightly lower in the programme than in the comparator group (£289 versus £327). The Programme was acceptable to patients. CONCLUSION: The Programme is shown to be broadly comparable to traditional follow-up care in all respects, adding to evidence of the viability of such models.

Measuring health-related quality of life of care home residents: comparison of self-report with staff proxy responses.

INTRODUCTION: care home residents are often unable to complete health-related quality of life questionnaires for themselves because of prevalent cognitive impairment. This study compared care home resident and staff proxy responses for two measures, the EQ-5D-5L and HowRU. METHODS: a prospective cohort study recruited residents ≥60 years across 24 care homes who were not receiving short stay, respite or terminal care. Resident and staff proxy EQ-5D-5L and HowRu responses were collected monthly for 3 months. Weighted kappa statistics and intra-class correlation coefficients (ICCs) adjusted for clustering at the care home level were used to measure agreement between resident and proxies for each time point. The effect of staff and resident baseline variables on agreement was considered using a multilevel mixed effect regression model. RESULTS: 117, 109 and 104 matched pairs completed the questionnaires at 1, 2 and 3 months, respectively. When clustering was controlled for, agreement between resident and staff proxy EQ-5D-5L responses was fair for mobility (ICC: 0.29) and slight for all other domains (ICC ≤ 0.20). EQ-5D Index and Quality-Adjusted Life Year scores (proxy scores higher than residents) showed better agreement than EQ-5D-VAS (residents scores higher than proxy). HowRU showed only slight agreement (ICC ≤ 0.20) between residents and proxies. Staff and resident characteristics did not influence level of agreement for either index. DISCUSSION: the levels of agreement for EQ-5D-5L and HowRU raise questions about their validity in this population.

Optimal healthcare delivery to care homes in the UK: a realist evaluation of what supports effective working to improve healthcare outcomes.

INTRODUCTION: care home residents have high healthcare needs not fully met by prevailing healthcare models. This study explored how healthcare configuration influences resource use. METHODS: a realist evaluation using qualitative and quantitative data from case studies of three UK health and social care economies selected for differing patterns of healthcare delivery to care homes. Four homes per area (12 in total) were recruited. A total of 239 residents were followed for 12 months to record resource-use. Overall, 181 participants completed 116 interviews and 13 focus groups including residents, relatives, care home staff, community nurses, allied health professionals and General Practitioners. RESULTS: context-mechanism-outcome configurations were identified explaining what supported effective working between healthcare services and care home staff: (i) investment in care home-specific work that legitimises and values work with care homes; (ii) relational working which over time builds trust between practitioners; (iii) care which 'wraps around' care homes; and (iv) access to specialist care for older people with dementia. Resource use was similar between sites despite differing approaches to healthcare. There was greater utilisation of GP resource where this was specifically commissioned but no difference in costs between sites. CONCLUSION: activities generating opportunities and an interest in healthcare and care home staff working together are integral to optimal healthcare provision in care homes. Outcomes are likely to be better where: focus and activities legitimise ongoing contact between healthcare staff and care homes at an institutional level; link with a wider system of healthcare; and provide access to dementia-specific expertise.

Follow-up care after treatment for prostate cancer: protocol for an evaluation of a nurse-led supported self-management and remote surveillance programme.

BACKGROUND: As more men survive a diagnosis of prostate cancer, alternative models of follow-up care that address men's enduring unmet needs and are economical to deliver are needed. This paper describes the protocol for an ongoing evaluation of a nurse-led supported self-management and remote surveillance programme implemented within the secondary care setting. METHODS/DESIGN: The evaluation is taking place within a real clinical setting, comparing the outcomes of men enrolled in the Programme with the outcomes of a pre-service change cohort of men, using a repeated measures design. Men are followed up at four and 8 months post recruitment on a number of outcomes, including quality of life, unmet need, psychological wellbeing and activation for self-management. An embedded health economic analysis and qualitative evaluation of implementation processes are being undertaken. DISCUSSION: The evaluation will provide important information regarding the effectiveness, cost effectiveness and implementation of an integrated supported self-management follow-up care pathway within secondary care.

A crossover randomised controlled trial of oral mandibular advancement devices for obstructive sleep apnoea-hypopnoea (TOMADO).

RATIONALE: Mandibular advancement devices (MADs) are used to treat obstructive sleep apnoea-hypopnoea syndrome (OSAHS) but evidence is lacking regarding their clinical and cost-effectiveness in less severe disease. OBJECTIVES: To compare clinical- and cost-effectiveness of a range of MADs against no treatment in mild to moderate OSAHS. MEASUREMENTS AND METHODS: This open-label, randomised, controlled, crossover trial was undertaken at a UK sleep centre. Adults with Apnoea-Hypopnoea Index (AHI) 5-<30/h and Epworth Sleepiness Scale (ESS) score ≥9 underwent 6 weeks of treatment with three non-adjustable MADs: self-moulded (SleepPro 1; SP1); semi-bespoke (SleepPro 2; SP2); fully-bespoke MAD (bMAD); and 4 weeks no treatment. Primary outcome was AHI scored by a polysomnographer blinded to treatment. Secondary outcomes included ESS, quality of life, resource use and cost. MAIN RESULTS: 90 patients were randomised and 83 were analysed. All devices reduced AHI compared with no treatment by 26% (95% CI 11% to 38%, p=0.001) for SP1, 33% (95% CI 24% to 41%) for SP2 and 36% (95% CI 24% to 45%, p<0.001) for bMAD. ESS was 1.51 (95% CI 0.73 to 2.29, p<0.001, SP1) to 2.37 (95% CI 1.53 to 3.22, p<0.001, bMAD) lower than no treatment (p<0.001 for all). Compliance was lower for SP1, which was the least preferred treatment at trial exit. All devices were cost-effective compared with no treatment at a £20,000/quality-adjusted life year (QALY) threshold. SP2 was the most cost-effective up to £39,800/QALY. CONCLUSIONS: Non-adjustable MADs achieve clinically important improvements in mild to moderate OSAHS and are cost-effective. Of those trialled, the semi-bespoke MAD is an appropriate first choice. TRIAL REGISTRATION NUMBER: ISRCTN02309506.

Visual causal models enhance clinical explanations of treatments for generalized anxiety disorder.

A daily challenge in clinical practice is to adequately explain disorders and treatments to patients of varying levels of literacy in a time-limited situation. Drawing jointly upon research on causal reasoning and multimodal theory, the authors asked whether adding visual causal models to clinical explanations promotes patient learning. Participants were 86 people currently or formerly diagnosed with a mood disorder and 104 lay people in Boston, Massachusetts, USA, who were randomly assigned to receive either a visual causal model (dual-mode) presentation or auditory-only presentation of an explanation about generalized anxiety disorder and its treatment. Participants' knowledge was tested before, immediately after, and 4 weeks after the presentation. Patients and lay people learned significantly more from visual causal model presentations than from auditory-only presentations, and visual causal models were perceived to be helpful. Participants retained some information 4 weeks after the presentation, although the advantage of visual causal models did not persist in the long term. In conclusion, dual-mode presentations featuring visual causal models yield significant relative gains in patient comprehension immediately after the clinical session, at a time when the authors suggest that patients may be most willing to begin the recommended treatment plan.

Delayed formation of neural representations of space in aged mice.

Aging is associated with cognitive deficits, with spatial memory being very susceptible to decline. The hippocampal dentate gyrus (DG) is important for processing spatial information in the brain and is particularly vulnerable to aging, yet its sparse activity has led to difficulties in assessing changes in this area. Using in vivo two-photon calcium imaging, we compared DG neuronal activity and representations of space in young and aged mice walking on an unfamiliar treadmill. We found that calcium activity was significantly higher and less tuned to location in aged mice, resulting in decreased spatial information encoded in the DG. However, with repeated exposure to the same treadmill, both spatial tuning and information levels in aged mice became similar to young mice, while activity remained elevated. Our results show that spatial representations of novel environments are impaired in the aged hippocampus and gradually improve with increased familiarity. Moreover, while the aged DG is hyperexcitable, this does not disrupt neural representations of familiar environments.

Delayed formation of neural representations of space in aged mice.

Aging is associated with cognitive deficits, with spatial memory being very susceptible to decline. The hippocampal dentate gyrus (DG) is important for processing spatial information in the brain and is particularly vulnerable to aging, yet its sparse activity has led to difficulties in assessing changes in this area. Using in vivo two-photon calcium imaging, we compared DG neuronal activity and representations of space in young and aged mice walking on an unfamiliar treadmill. We found that calcium activity was significantly higher and less tuned to location in aged mice, resulting in decreased spatial information encoded in the DG. However, with repeated exposure to the same treadmill, both spatial tuning and information levels in aged mice became similar to young mice, while activity remained elevated. Our results show that spatial representations of novel environments are impaired in the aged hippocampus and gradually improve with increased familiarity. Moreover, while the aged DG is hyperexcitable, this does not disrupt neural representations of familiar environments.

Treadmill-based task for assessing spatial memory in head-fixed mice.

Several mouse in vivo neuronal recording techniques require head fixation. Head-fixed treadmill walking can be used to design tasks that enable the study of neural activity in the context of behavior. Here, we provide a detailed protocol for constructing a treadmill with tactile spatial cues, training mice on a rewarded behavioral task, and analyzing behavioral data. We discuss common problems and solutions we have developed to optimize training. Finally, we demonstrate how to test spatial memory performance using this task.

Holistic needs assessment and care plans for women with gynaecological cancer: do they improve cancer-specific health-related quality of life? A randomised controlled trial using mixed methods.

OBJECTIVES: Holistic needs assessment (HNA) and care planning are proposed to address unmet needs of people treated for cancer. We tested whether HNA and care planning by an allied health professional improved cancer-specific quality of life for women following curative treatment for stage I-III gynaecological cancer. METHODS: Consecutive women were invited to participate in a randomised controlled study (HNA and care planning vs usual care) at a UK cancer centre. Data were collected by questionnaire at baseline, 3 and 6 months. The outcomes were 6-month change in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-C30 (version 3), global score (primary) and, in EORTC subscales, generic quality of life and self-efficacy (secondary). The study was blinded for data management and analysis. Differences in outcomes were compared between groups. Health service utilisation and quality-adjusted life years (QALY) (from Short Form-6) were gathered for a cost-effectiveness analysis. Thematic analysis was used to interpret data from an exit interview. RESULTS: 150 women consented (75 per group); 10 undertook interviews. For 124 participants (61 intervention, 63 controls) with complete data, no statistically significant differences were seen between groups in the primary endpoint. The majority of those interviewed reported important personal gains they attributed to the intervention, which reflected trends to improvement seen in EORTC functional and symptom scales. Economic analysis suggests a 62% probability of cost-effectiveness at a £30 000/QALY threshold. CONCLUSION: Care plan development with an allied health professional is cost-effective, acceptable and useful for some women treated for stage I-III gynaecological cancer. We recommend its introduction early in the pathway to support person-centred care.

The feasibility of increasing physical activity in care home residents: Active Residents in Care Homes (ARCH) programme.

OBJECTIVES: Maintaining physical activity for older residents in care homes maximises their physical and mental health and wellbeing, independence, dignity and quality of life. Unfortunately, most residents do not participate in regular physical activity. Active Residents in Care Homes, ARCH, was designed to increase physical activity by facilitating whole-system change in a care home. We evaluated whether ARCH can be delivered, its effects on resident's physical activity, wellbeing and costs. DESIGN: Feasibility study. SETTING: Three residential care homes. PARTICIPANTS: Care home residents and staff. INTERVENTION: Occupational and physiotherapists implemented ARCH over 4 months with an 8-month follow-up. MAIN OUTCOME MEASURES: Assessment of Physical Activity, Pool Activity Level, EQ5D-5L, Dementia Care Mapping, cost of implementing ARCH, health and social care utilisation. RESULTS: After implementing ARCH, residents displayed more positive behaviours, better mood and engagement and higher physical activity levels, but these improvements were not sustained at 8-month follow-up. The cost (2016 prices) of implementing ARCH was £61,037, which equates to £1,650/resident. Healthcare utilisation was £295/resident (SD320) in the 4 months prior to ARCH, £308/resident (SD406) during the 4-month implementation and £676/resident (SD438) in the 8-month follow-up. CONCLUSIONS: The ARCH programme can be delivered, it may have some short-term benefits and is affordable. Rather than have unrealistic increases in the health and longevity of older care home residents, ARCH may slow the decline in physical, mental and emotional well-being usually seen in older people in care homes, return some dignity and improve their quality of life in their last months or years.

Behavioral state-dependent lateralization of dorsal dentate gyrus c-Fos expression in mice.

Hemispheric lateralization is a fundamental organizing principle of nervous systems across taxonomic groups with bilateral symmetry. The mammalian hippocampus is lateralized anatomically, physiologically, and chemically; however, functional asymmetries are not yet well understood. Imaging studies in humans have implicated the left and right hippocampus in specialized processing. However, it is not clear if lateralized activity occurs in the rodent hippocampus. c-Fos imaging in animals provides a measure of neuronal activity with a resolution at the level of single cells. The aim of the present study was to determine whether lateralized activity-dependent c-Fos expression occurs in the rodent hippocampus. To understand functional lateralization of hippocampal processing, we compared interhemispheric expression of c-Fos in the dentate gyrus (DG), a structure involved in encoding new experiences, in mice that ran on a wheel, encoded a novel object, or remained in home cages. We found that wheel running (WR) induced the greatest amount of DG c-Fos expression in both hemispheres, with no difference between hemispheres. Object exploration (OB) resulted in left-lateralized DG c-Fos expression, whereas control (CON) mice were not lateralized. We then sought to determine whether differential consideration of hemispheres might influence the conclusions of a study by simulating common cell quantitation methods. We found that different approaches led to different conclusions. These data demonstrate lateralization of neuronal activity in the mouse DG corresponding to the experience of the animal and show that differentially considering hemisphere leads to alternative conclusions.

Measuring health-related quality of life of care home residents, comparison of self-report with staff proxy responses for EQ-5D-5L and HowRu: protocol for assessing proxy reliability in care home outcome testing.

INTRODUCTION: Research into interventions to improve health and well-being for older people living in care homes is increasingly common. Health-related quality of life (HRQoL) is frequently used as an outcome measure, but collecting both self-reported and proxy HRQoL measures is challenging in this setting. This study will investigate the reliability of UK care home staff as proxy respondents for the EQ-5D-5L and HowRu measures. METHODS AND ANALYSIS: This is a prospective cohort study of a subpopulation of care home residents recruited to the larger Proactive Healthcare for Older People in Care Homes (PEACH) study. It will recruit residents ≥60 years across 24 care homes and not receiving short stay or respite care. The sample size is 160 participants. Resident and care home staff proxy EQ-5D-5L and HowRu responses will be collected monthly for 3 months. Weighted kappa statistics and intraclass correlation adjusted for clustering at the care home level will be used to measure agreement between resident and proxy responses. The extent to which staff variables (gender, age group, length of time caring, role, how well they know the resident, length of time working in care homes and in specialist gerontological practice) influence the level of agreement between self-reported and proxy responses will be considered using a multilevel mixed-effect regression model. ETHICS AND DISSEMINATION: The PEACH study protocol was reviewed by the UK Health Research Authority and University of Nottingham Research Ethics Committee and was determined to be a service development project. We will publish this study in a peer-reviewed journal with international readership and disseminate it through relevant national stakeholder networks and specialist societies.

Correction to: Palliative long-term abdominal drains versus repeated drainage in individuals with untreatable ascites due to advanced cirrhosis: study protocol for a feasibility randomised controlled trial.

Following publication of the original article [1], the authors reported that the figure legend for Figure 3 was absent. In addition, they have requested additional funding information to be added. In this Correction the initial and updated funding information are shown. The original publication of this article has been corrected.

Palliative long-term abdominal drains versus repeated drainage in individuals with untreatable ascites due to advanced cirrhosis: study protocol for a feasibility randomised controlled trial.

BACKGROUND: UK deaths due to chronic liver diseases such as cirrhosis have quadrupled over the last 40 years, making this condition now the third most common cause of premature death. Most patients with advanced cirrhosis (end-stage liver disease [ESLD]) develop ascites. This is often managed with diuretics, but if refractory, then the fluid is drained from the peritoneal cavity every 10-14 days by large volume paracentesis (LVP), a procedure requiring hospital admissions. As the life expectancy of patients with ESLD and refractory ascites (if ineligible for liver transplantation) is on average ≤ 6 months, frequent hospital visits are inappropriate from a palliative perspective. One alternative is long-term abdominal drains (LTADs), used successfully in patients whose ascites is due to malignancy. Although inserted in hospital, these drains allow ascites management outside of a hospital setting. LTADs have not been formally evaluated in patients with refractory ascites due to ESLD. METHODS/DESIGN: Due to uncertainty about appropriate outcome measures and whether patients with ESLD would wish or be able to participate in a study, a feasibility randomised controlled trial (RCT) was designed. Patients were consulted on trial design. We plan to recruit 48 patients with refractory ascites and randomise them (1:1) to either (1) LTAD or (2) current standard of care (LVP) for 12 weeks. Outcomes of interest include acceptability of the LTAD to patients, carers and healthcare professionals as well as recruitment and retention rates. The Integrated Palliative care Outcome Scale, the Short Form Liver Disease Quality of Life questionnaire, the EuroQol 5 dimensions instrument and carer-reported (Zarit Burden Interview) outcomes will also be assessed. Preliminary data on cost-effectiveness will be collected, and patients and healthcare professionals will be interviewed about their experience of the trial with a view to identifying barriers to recruitment. DISCUSSION: LTADs could potentially improve end-of-life care in patients with refractory ascites due to ESLD by improving symptom control, reducing hospital visits and enabling some self-management. Our trial is designed to see if such patients can be recruited, as well as to inform the design of a subsequent definitive trial. TRIAL REGISTRATION: ISRCTN, ISRCTN30697116 . Registered on 7 October 2015.

KardiaTool: An Integrated POC Solution for Non-invasive Diagnosis and Therapy Monitoring of Heart Failure Patients.

The aim of this work is to present KardiaTool platform, an integrated Point of Care (POC) solution for noninvasive diagnosis and therapy monitoring of Heart Failure (HF) patients. The KardiaTool platform consists of two components, KardiaPOC and KardiaSoft. KardiaPOC is an easy to use portable device with a disposable Lab-on-Chip (LOC) for the rapid, accurate, non-invasive and simultaneous quantitative assessment of four HF related biomarkers, from saliva samples. KardiaSoft is a decision support software based on predictive modeling techniques that analyzes the POC data and other patient's data, and delivers information related to HF diagnosis and therapy monitoring. It is expected that identifying a source comparable to blood, for biomarker information extraction, such as saliva, that is cost-effective, less invasive, more convenient and acceptable for both patients and healthcare professionals would be beneficial for the healthcare community. In this work the architecture and the functionalities of the KardiaTool platform are presented.