Gut-Brain Axis: Focus on Sex Differences in Neuroinflammation.

In recent years, there has been a growing interest in the concept of the "gut-brain axis". In addition to well-studied diseases associated with an imbalance in gut microbiota, such as cancer, chronic inflammation, and cardiovascular diseases, research is now exploring the potential role of gut microbial dysbiosis in the onset and development of brain-related diseases. When the function of the intestinal barrier is altered by dysbiosis, the aberrant immune system response interacts with the nervous system, leading to a state of "neuroinflammation". The gut microbiota-brain axis is mediated by inflammatory and immunological mechanisms, neurotransmitters, and neuroendocrine pathways. This narrative review aims to illustrate the molecular basis of neuroinflammation and elaborate on the concept of the gut-brain axis by virtue of analyzing the various metabolites produced by the gut microbiome and how they might impact the nervous system. Additionally, the current review will highlight how sex influences these molecular mechanisms. In fact, sex hormones impact the brain-gut microbiota axis at different levels, such as the central nervous system, the enteric nervous one, and enteroendocrine cells. A deeper understanding of the gut-brain axis in human health and disease is crucial to guide diagnoses, treatments, and preventive interventions.

Changes in Lymphocyte Subpopulations after Remdesivir Therapy for COVID-19: A Brief Report.

Remdesivir (RDV) has demonstrated clinical benefit in hospitalized COronaVIrus Disease (COVID)-19 patients. The objective of this brief report was to assess a possible correlation between RDV therapy and the variation in lymphocyte subpopulations. We retrospectively studied 43 hospitalized COVID-19 patients: 30 men and 13 women (mean age 69.3 ± 15 years); 9/43 had received RDV therapy. Six patients had no need for oxygen (severity group 0); 22 were on oxygen treatment with a fraction of inspired oxygen (FiO2) ≤ 50% (group 1); 7 on not-invasive ventilation (group 2); 3 on invasive mechanical ventilation (group 3); and 5 had died (group 4). Cytofluorimetric assessment of lymphocyte subpopulations showed substantial changes after RDV therapy: B lymphocytes and plasmablasts were significantly increased (p = 0.002 and p = 0.08, respectively). Cytotoxic T lymphocytes showed a robust reduction (p = 0.008). No changes were observed in CD4+-T cells and natural killers (NKs). There was a significant reduction in regulatory T cells (Tregs) (p = 0.02) and a significant increase in circulating monocytes (p = 0.03). Stratifying by disease severity, after RDV therapy, patients with severity 0-2 had significantly higher B lymphocyte and monocyte counts and lower memory and effector cytotoxic T cell counts. Instead, patients with severity 3-4 had significantly higher plasmablast and lower memory T cell counts. No significant differences for CD4+-T cells, Tregs, and NKs were observed. Our brief report showed substantial changes in the lymphocyte subpopulations analyzed between patients who did not receive RDV therapy and those after RDV treatment. Despite the small sample size, due to the retrospective nature of this brief report, the substantial changes in lymphocyte subpopulations reported could lead to speculation on the role of RDV treatment both on immune responses against the virus and on the possible downregulation of the cytokine storm observed in patients with more severe disease.

Antituberculosis drug-induced non-blistering systemic severe reactions: A 10-year (2012-2022) literature review.

Drug reaction with eosinophilia and systemic symptoms (DRESS) and drug-induced liver injury (DILI) can hamper therapeutic strategy, contribute to multiple drug resistance and serious public health burden. Diagnosis (including allergy assessment) and management of these two severe hypersensitivity reactions in clinical practice are somewhat difficult and published scientific evidence is rather weak and limited. The first step is always represented by stopping all anti-tuberculosis (TB) drugs, treating reaction with systemic corticosteroids, and identifying the offending drug, even if it is often complicated by the patient's simultaneous intake of antibiotics. Patch tests and in vitro tests, such as lymphocyte transformation test, could bridge this diagnostic gap, but the available data are scarce and their sensitivity low. The re-challenge test is often necessary but places patients at risk for serious adverse reactions. The desensitization protocols are quite varied and not universally accepted. In this narrative review, we provide an update to the literature data on the management of DRESS and DILI with particular attention to the allergological work-up in the last decade.

No difference in effects of 'PACE steps to success' palliative care program for nursing home residents with and without dementia: a pre-planned subgroup analysis of the seven-country PACE trial.

BACKGROUND: 'PACE Steps to Success' is a multicomponent training program aiming to integrate generalist and non-disease-specific palliative care in nursing homes. This program did not improve residents' comfort in the last week of life, but it appeared to improve quality of care and dying in their last month of life. Because this program included only three dementia-specific elements, its effects might differ depending on the presence or stage of dementia. We aimed to investigate whether the program effects differ between residents with advanced, non-advanced, and no dementia. METHODS: Pre-planned subgroup analysis of the PACE cluster-randomized controlled trial in 78 nursing homes in seven European countries. Participants included residents who died in the previous 4 months. The nursing home staff or general practitioner assessed the presence of dementia; severity was determined using two highly-discriminatory staff-reported instruments. Using after-death questionnaires, staff assessed comfort in the last week of life (Comfort Assessment in Dying-End-of-Life in Dementia-scale; primary outcome) and quality of care and dying in the last month of life (Quality of Dying in Long-Term Care scale; secondary outcome). RESULTS: At baseline, we included 177 residents with advanced dementia, 126 with non-advanced dementia and 156 without dementia. Post-intervention, respectively in the control and the intervention group, we included 136 and 104 residents with advanced dementia, 167 and 110 with non-advanced dementia and 157 and 137 without dementia. We found no subgroup differences on comfort in the last week of life, comparing advanced versus without dementia (baseline-adjusted mean sub-group difference 2.1; p-value = 0.177), non-advanced versus without dementia (2.7; p = 0.092), and advanced versus non-advanced dementia (- 0.6; p = 0.698); or on quality of care and dying in the last month of life, comparing advanced and without dementia (- 0.6; p = 0.741), non-advanced and without dementia (- 1.5; p = 0.428), and advanced and non-advanced dementia (0.9; p = 0.632). CONCLUSIONS: The lack of subgroup difference suggests that while the program did not improve comfort in dying residents with or without dementia, it appeared to equally improve quality of care and dying in the last month of life for residents with dementia (regardless of the stage) and those without dementia. A generalist and non-disease-specific palliative care program, such as PACE Steps to Success, is a useful starting point for future palliative care improvement in nursing homes, but to effectively improve residents' comfort, this program needs further development. TRIAL REGISTRATION: ISRCTN, ISRCTN14741671 . Registered 8 July 2015 - Retrospectively registered.

Decreased costs and retained QoL due to the 'PACE Steps to Success' intervention in LTCFs: cost-effectiveness analysis of a randomized controlled trial.

BACKGROUND: The number of residents in long-term care facilities (LTCFs) in need of palliative care is growing in the Western world. Therefore, it is foreseen that significantly higher percentages of budgets will be spent on palliative care. However, cost-effectiveness analyses of palliative care interventions in these settings are lacking. Therefore, the objective of this paper was to assess the cost-effectiveness of the 'PACE Steps to Success' intervention. PACE (Palliative Care for Older People) is a 1-year palliative care programme aiming at integrating general palliative care into day-to-day routines in LTCFs, throughout seven EU countries. METHODS: A cluster RCT was conducted. LTCFs were randomly assigned to intervention or usual care. LTCFs reported deaths of residents, about whom questionnaires were filled in retrospectively about resource use and quality of the last month of life. A health care perspective was adopted. Direct medical costs, QALYs based on the EQ-5D-5L and costs per quality increase measured with the QOD-LTC were outcome measures. RESULTS: Although outcomes on the EQ-5D-5L remained the same, a significant increase on the QOD-LTC (3.19 points, p value 0.00) and significant cost-savings were achieved in the intervention group (€983.28, p value 0.020). The cost reduction mainly resulted from decreased hospitalization-related costs (€919.51, p value 0.018). CONCLUSIONS: Costs decreased and QoL was retained due to the PACE Steps to Success intervention. Significant cost savings and improvement in quality of end of life (care) as measured with the QOD-LTC were achieved. A clinically relevant difference of almost 3 nights shorter hospitalizations in favour of the intervention group was found. This indicates that timely palliative care in the LTCF setting can prevent lengthy hospitalizations while retaining QoL. In line with earlier findings, we conclude that integrating general palliative care into daily routine in LTCFs can be cost-effective. TRIAL REGISTRATION: ISRCTN14741671 .

Comfort and clinical events at the end of life of nursing home residents with and without dementia: The six-country epidemiological PACE study.

OBJECTIVES: We aimed to investigate the occurrence rates of clinical events and their associations with comfort in dying nursing home residents with and without dementia. METHODS: Epidemiological after-death survey was performed in nationwide representative samples of 322 nursing homes in Belgium, Finland, Italy, the Netherlands, Poland, and England. Nursing staff reported clinical events and assessed comfort. The nursing staff or physician assessed the presence of dementia; severity was determined using two highly discriminatory staff-reported instruments. RESULTS: The sample comprised 401 residents with advanced dementia, 377 with other stages of dementia, and 419 without dementia (N = 1197). Across the three groups, pneumonia occurred in 24 to 27% of residents. Febrile episodes (unrelated to pneumonia) occurred in 39% of residents with advanced dementia, 34% in residents with other stages of dementia and 28% in residents without dementia (P = .03). Intake problems occurred in 74% of residents with advanced dementia, 55% in residents with other stages of dementia, and 48% in residents without dementia (P < .001). Overall, these three clinical events were inversely associated with comfort. Less comfort was observed in all resident groups who had pneumonia (advanced dementia, P = .04; other stages of dementia, P = .04; without dementia, P < .001). Among residents with intake problems, less comfort was observed only in those with other stages of dementia (P < .001) and without dementia (P = .003), while the presence and severity of dementia moderated this association (P = .03). Developing "other clinical events" was not associated with comfort. CONCLUSIONS: Discomfort was observed in dying residents who developed major clinical events, especially pneumonia, which was not specific to advanced dementia. It is crucial to identify and address the clinical events potentially associated with discomfort in dying residents with and without dementia.

Opioid underuse in terminal care of long-term care facility residents with pain and/or dyspnoea: A cross-sectional PACE-survey in six European countries.

BACKGROUND/OBJECTIVES: Opioids relieve symptoms in terminal care. We studied opioid underuse in long-term care facilities, defined as residents without opioid prescription despite pain and/or dyspnoea, 3 days prior to death. DESIGN AND SETTING: In a proportionally stratified randomly selected sample of long-term care facilities in six European Union countries, nurses and long-term care facility management completed structured after-death questionnaires within 3 months of residents' death. MEASUREMENTS: Nurses assessed pain/dyspnoea with Comfort Assessment in Dying with Dementia scale and checked opioid prescription by chart review. We estimated opioid underuse per country and per symptom and calculated associations of opioid underuse by multilevel, multivariable analysis. RESULTS: Nurses' response rate was 81.6%, 95.7% for managers. Of 901 deceased residents with pain/dyspnoea reported in the last week, 10.6% had dyspnoea, 34.4% had pain and 55.0% had both symptoms. Opioid underuse per country was 19.2% (95% confidence interval: 12.9-27.2) in the Netherlands, 25.2% (18.3-33.6) in Belgium, 29.3% (16.9-45.8) in England, 33.7% (26.2-42.2) in Finland, 64.6% (52.0-75.4) in Italy and 79.1% (71.2-85.3) in Poland (p < 0.001). Opioid underuse was 57.2% (33.0-78.4) for dyspnoea, 41.2% (95% confidence interval: 21.9-63.8) for pain and 37.4% (19.4-59.6) for both symptoms (p = 0.013). Odds of opioid underuse were lower (odds ratio: 0.33; 95% confidence interval: 0.20-0.54) when pain was assessed. CONCLUSION: Opioid underuse differs between countries. Pain and dyspnoea should be formally assessed at the end-of-life and taken into account in physicians orders.

Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and prognosis of hypertensive patients hospitalised with COVID-19.

BACKGROUND: Among hypertensive patients, the association between treatment with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) and the clinical severity of COVID-19, remains uncertain. AIMS: To determine whether hypertensive patients hospitalised with COVID-19 are at risk of worse outcomes if on treatment with ACEI or ARB compared to other anti-hypertensive medications. METHODS: This is a retrospective study conducted at a single academic medical centre (Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy) from 1 to 31 March 2020. We compared patients on treatment with an ACEI/ARB (ACEI/ARB group) to patients receiving other anti-hypertensive medications (No-ACEI/ARB group). The end-points of the study were the all-cause in-hospital death and the combination of in-hospital death or need for intensive care unit (ICU) admission. RESULTS: The sample included 166 COVID-19 patients; median age was 74 years and 109 (66%) were men. Overall, 111 (67%) patients were taking an ACEI or ARB. Twenty-nine (17%) patients died during the hospital stay, and 51 (31%) met the combined end-point. After adjustment for comorbidities, age and degree of severity at the presentation, ACEI or ARB treatment was an independent predictor neither of in-hospital death nor of the combination of in-hospital death/need for ICU. No differences were documented between treatment with ACEI compared to ARB. CONCLUSIONS: Among hypertensive patients hospitalised for COVID-19, treatment with ACEI or ARB is not associated with an increased risk of in-hospital death.

Palliative care provision in long-term care facilities differs across Europe: Results of a cross-sectional study in six European countries (PACE).

BACKGROUND: While the need for palliative care in long-term care facilities is growing, it is unknown whether palliative care in this setting is sufficiently developed. AIM: To describe and compare in six European countries palliative care provision in long-term care facilities and to assess associations between patient, facility and advance care planning factors and receipt and timing of palliative care. DESIGN: Cross-sectional after-death survey regarding care provided to long-term care residents in Belgium, England, Finland, Italy, the Netherlands and Poland. Generalized estimating equations were used for analyses. SETTING/PARTICIPANTS: Nurses or care assistants who are most involved in care for the resident. RESULTS: We included 1298 residents in 300 facilities, of whom a majority received palliative care in most countries (England: 72.6%-Belgium: 77.9%), except in Poland (14.0%) and Italy (32.1%). Palliative care typically started within 2 weeks before death and was often provided by the treating physician (England: 75%-the Netherlands: 98.8%). A palliative care specialist was frequently involved in Belgium and Poland (57.1% and 86.7%). Residents with cancer, dementia or a contact person in their record more often received palliative care, and it started earlier for residents with whom the nurse had spoken about treatments or the preferred course of care at the end of life. CONCLUSION: The late initiation of palliative care (especially when advance care planning is lacking) and palliative care for residents without cancer, dementia or closely involved relatives deserve attention in all countries. Diversity in palliative care organization might be related to different levels of its development.

Dying in long-term care facilities in Europe: the PACE epidemiological study of deceased residents in six countries.

BACKGROUND: By 2030, 30% of the European population will be aged 60 or over and those aged 80 and above will be the fastest growing cohort. An increasing number of people will die at an advanced age with multiple chronic diseases. In Europe at present, between 12 and 38% of the oldest people die in a long-term care facility. The lack of nationally representative empirical data, either demographic or clinical, about people who die in long-term care facilities makes appropriate policy responses more difficult. Additionally, there is a lack of comparable cross-country data; the opportunity to compare and contrast data internationally would allow for a better understanding of both common issues and country-specific challenges and could help generate hypotheses about different options regarding policy, health care organization and provision. The objectives of this study are to describe the demographic, facility stay and clinical characteristics of residents dying in long-term care facilities and the differences between countries. METHODS: Epidemiological study (2015) in a proportionally stratified random sample of 322 facilities in Belgium, Finland, Italy, the Netherlands, Poland and England. The final sample included 1384 deceased residents. The sampled facilities received a letter introducing the project and asking for voluntary participation. Facility manager, nursing staff member and treating physician completed structured questionnaires for all deaths in the preceding 3 months. RESULTS: Of 1384 residents the average age at death ranged from 81 (Poland) to 87 (Belgium, England) (p < 0.001) and length of stay from 6 months (Poland, Italy) to 2 years (Belgium) (p < 0.05); 47% (the Netherlands) to 74% (Italy) had more than two morbidities and 60% (England) to 83% (Finland) dementia, with a significant difference between countries (p < 0.001). Italy and Poland had the highest percentages with poor functional and cognitive status 1 month before death (BANS-S score of 21.8 and 21.9 respectively). Clinical complications occurred often during the final month (51.9% England, 66.4% Finland and Poland). CONCLUSIONS: The population dying in long-term care facilities is complex, displaying multiple diseases with cognitive and functional impairment and high levels of dementia. We recommend future policy should include integration of high-quality palliative and dementia care.

Opioid, antipsychotic and hypnotic use in end of life in long-term care facilities in six European countries: results of PACE.

Background: Opioids, antipsychotics and hypnotics are recommended for comfort care in dying. We studied their prescription during the last 3 days in residents deceased in the long-term care facility (LTCF). Methods: In a retrospective, cross-sectional survey in Belgium, England, Finland, Italy, the Netherlands and Poland, LTCFs, selected by proportional stratified random sampling, reported all deaths over the previous 3 months. The nurse most involved in the residents' care reviewed the chart for opioid, antipsychotic and hypnotic prescription, cause of death and comorbidities. Multivariable logistic regression was performed to adjust for resident characteristics. Results: Response rate was 81.6%. We included 1079 deceased residents in 322 LCTFs. Opioid prescription ranged from 18.5% (95% CI: 13.0-25.8) of residents in Poland to 77.9% (95% CI: 69.5-84.5) in the Netherlands, antipsychotic prescription from 4.8% (95% CI: 2.4-9.1) in Finland to 22.4% (95% CI: 14.7-32.4) in Italy, hypnotic prescription from 7.8% (95% CI: 4.6-12.8) in Finland to 47.9% (95% CI: 38.5-57.3) in the Netherlands. Differences in opioid, antipsychotic and hypnotic prescription between countries remained significant (P < 0.001) when controlling for age, gender, length of stay, cognitive status, cause of death in multilevel, multivariable analyses. Dying from cancer showed higher odds for receiving opioids (OR 3.51; P < 0.001) and hypnotics (OR 2.10; P = 0.010). Conclusions: Opioid, antipsychotic and hypnotic prescription in the dying phase differed significantly between six European countries. Further research should determine the appropriateness of their prescription and refine guidelines especially for LTCF residents dying of non-cancer diseases.

A framework for cross-cultural development and implementation of complex interventions to improve palliative care in nursing homes: the PACE steps to success programme.

BACKGROUND: The PACE Steps to Success programme is a complex educational and development intervention to improve palliative care in nursing homes. Little research has investigated processes in the cross-cultural adaptation and implementation of interventions in palliative care across countries, taking account of differences in health and social care systems, legal and regulatory policies, and cultural norms. This paper describes a framework for the cross-cultural development and support necessary to implement such an intervention, taking the PACE Steps to Success programme as an exemplar. METHODS: The PACE Steps to Success programme was implemented as part of the PACE cluster randomised control trial in seven European countries. A three stage approach was used, a) preparation of resources; b) training in the intervention using a train-the-trainers model; and c) cascading support throughout the implementation. All stages were underpinned by cross-cultural adaptation, including recognising legal and cultural norms, sensitivities and languages. This paper draws upon collated evidence from minutes of international meetings, evaluations of training delivered, interviews with those delivering the intervention in nursing homes and providing and/or receiving support. RESULTS: Seventy eight nursing homes participated in the trial, with half randomized to receive the intervention, 3638 nurses/care assistants were identified at baseline. In each country, 1-3 trainers were selected (total n = 16) to deliver the intervention. A framework was used to guide the cross-cultural adaptation and implementation. Adaptation of three English training resources for different groups of staff consisted of simplification of content, identification of validated implementation tools, a review in 2 nursing homes in each country, and translation into local languages. The same training was provided to all country trainers who cascaded it into intervention nursing homes in local languages, and facilitated it via in-house PACE coordinators. Support was cascaded from country trainers to staff implementing the intervention. CONCLUSIONS: There is little guidance on how to adapt complex interventions developed in one country and language to international contexts. This framework for cross-cultural adaptation and implementation of a complex educational and development intervention may be useful to others seeking to transfer quality improvement initiatives in other contexts.

The Interplay between Immunity and Microbiota at Intestinal Immunological Niche: The Case of Cancer.

The gut microbiota is central to the pathogenesis of several inflammatory and autoimmune diseases. While multiple mechanisms are involved, the immune system clearly plays a special role. Indeed, the breakdown of the physiological balance in gut microbial composition leads to dysbiosis, which is then able to enhance inflammation and to influence gene expression. At the same time, there is an intense cross-talk between the microbiota and the immunological niche in the intestinal mucosa. These interactions may pave the way to the development, growth and spreading of cancer, especially in the gastro-intestinal system. Here, we review the changes in microbiota composition, how they relate to the immunological imbalance, influencing the onset of different types of cancer and the impact of these mechanisms on the efficacy of traditional and upcoming cancer treatments.

The palliative care knowledge of nursing home staff: The EU FP7 PACE cross-sectional survey in 322 nursing homes in six European countries.

BACKGROUND: The provision of high-quality palliative care in nursing homes (NHs) is a major challenge and places demands on the knowledge and skills of the staff. AIM: This study assesses the palliative care knowledge of staff in NHs in Europe. DESIGN: Cross-sectional study using structured survey Setting/participants: Nurses and care assistants working in 322 representative samples of NHs in Belgium, the Netherlands, England, Finland, Poland and Italy. Palliative care knowledge is measured with the Palliative Care Survey. Scores on the scales range between 0 and 1; higher scores indicate more knowledge. RESULTS: A total of 3392 NH-staff were given a questionnaire, and 2275 responded (67%). Knowledge of basic palliative care issues ranged between 0.20 in Poland (95% confidence interval (CI) 0.19; 0.24) and 0.61 in Belgium (95% CI 0.59; 0.63), knowledge of physical aspects that can contribute to pain ranged between 0.81 in Poland (95% CI 0.79; 0.84) and 0.91 in the Netherlands (95% CI 0.89; 0.93), and knowledge of psychological reasons that can contribute to pain ranged between 0.56 in England (95% CI 0.50; 0.62) and 0.87 in Finland (95% CI 0.83; 0.90). Factors associated with knowledge were country, professional role and having undertaken formal training in palliative care. CONCLUSIONS: Knowledge of nurses and care assistants concerning basic palliative care issues appears to be suboptimal in all participating countries, although there is substantial heterogeneity. Education of nursing staff needs to be improved across, but each country may require its own strategy to address the unique and specific knowledge gaps.

Quality of dying and quality of end-of-life care of nursing home residents in six countries: An epidemiological study.

BACKGROUND: Nursing homes are among the most common places of death in many countries. AIM: To determine the quality of dying and end-of-life care of nursing home residents in six European countries. DESIGN: Epidemiological survey in a proportionally stratified random sample of nursing homes. We identified all deaths of residents of the preceding 3-month period. Main outcomes: quality of dying in the last week of life (measured using End-of-Life in Dementia Scales - Comfort Assessment while Dying (EOLD-CAD)); quality of end-of-life care in the last month of life (measured using Quality of Dying in Long-Term Care (QoD-LTC) scale). Higher scores indicate better quality. SETTING/PARTICIPANTS: Three hundred and twenty-two nursing homes in Belgium, Finland, Italy, the Netherlands, Poland and England. Participants were staff (nurses or care assistants) most involved in each resident's care. RESULTS: Staff returned questionnaires regarding 1384 (81.6%) of 1696 deceased residents. The End-of-Life in Dementia Scales - Comfort Assessment while Dying mean score (95% confidence interval) (theoretical 14-42) ranged from 29.9 (27.6; 32.2) in Italy to 33.9 (31.5; 36.3) in England. The Quality of Dying in Long-Term Care mean score (95% confidence interval) (theoretical 11-55) ranged from 35.0 (31.8; 38.3) in Italy to 44.1 (40.7; 47.4) in England. A higher End-of-Life in Dementia Scales - Comfort Assessment while Dying score was associated with country ( p = 0.027), older age ( p = 0.012), length of stay ⩾1 year ( p = 0.034), higher functional status ( p < 0.001). A higher Quality of Dying in Long-Term Care score was associated with country ( p < 0.001), older age ( p < 0.001), length of stay ⩾1 year ( p < 0.001), higher functional status ( p = 0.002), absence of dementia ( p = 0.001), death in nursing home ( p = 0.033). CONCLUSION: The quality of dying and quality of end-of-life care in nursing homes in the countries studied are not optimal. This includes countries with high levels of palliative care development in nursing homes such as Belgium, the Netherlands and England.

Integrating palliative care in long-term care facilities across Europe (PACE): protocol of a cluster randomized controlled trial of the 'PACE Steps to Success' intervention in seven countries.

BACKGROUND: Several studies have highlighted the need for improvement in palliative care delivered to older people long-term care facilities. However, the available evidence on how to improve palliative care in these settings is weak, especially in Europe. We describe the protocol of the PACE trial aimed to 1) evaluate the effectiveness and cost-effectiveness of the 'PACE Steps to Success' palliative care intervention for older people in long-term care facilities, and 2) assess the implementation process and identify facilitators and barriers for implementation in different countries. METHODS: We will conduct a multi-facility cluster randomised controlled trial in Belgium, Finland, Italy, the Netherlands, Poland, Switzerland and England. In total, 72 facilities will be randomized to receive the 'Pace Steps to Success intervention' or to 'care as usual'. Primary outcome at resident level: quality of dying (CAD-EOLD); and at staff level: staff knowledge of palliative care (Palliative Care Survey). SECONDARY OUTCOMES: resident's quality of end-of-life care, staff self-efficacy, self-perceived educational needs, and opinions on palliative care. Economic outcomes: direct costs and quality-adjusted life years (QALYs). Measurements are performed at baseline and after the intervention. For the resident-level outcomes, facilities report all deaths of residents in and outside the facilities over a previous four-month period and structured questionnaires are sent to (1) the administrator, (2) staff member most involved in care (3) treating general practitioner, and (4) a relative. For the staff-level outcomes, all staff who are working in the facilities are asked to complete a structured questionnaire. A process evaluation will run alongside the effectiveness evaluation in the intervention group using the RE-AIM framework. DISCUSSION: The lack of high quality trials in palliative care has been recognized throughout the field of palliative care research. This cross-national cluster RCT designed to evaluate the impact of the palliative care intervention for long-term care facilities 'PACE Steps to Success' in seven countries, will provide important evidence concerning the effectiveness as well as the preconditions for optimal implementation of palliative care in nursing homes, and this within different health care systems. TRIAL REGISTRATION: The study is registered at www.isrctn.com - ISRCTN14741671 (FP7-HEALTH-2013-INNOVATION-1 603111) Registration date: July 30, 2015.

Pharmacotherapy Use in Older Patients With Heart Failure and Reduced Ejection Fraction After a Skilled Nursing Facility Stay.

BACKGROUND: Little is known about guideline-directed pharmacotherapy use in patients with heart failure and reduced ejection fraction (HFrEF) discharged to skilled nursing facilities (SNFs). This study aimed to describe the use of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blocker (ARBs) and evidence-based ß-blockers (EBBBs) among older patients with HFrEF within 90 days after the SNF admission and to identify factors associated with receipt of these medications. METHODS AND RESULTS: With the use of Minimum Data Set 3.0 cross-linked with Medicare data (2011-2012), we studied 35,792 Americans aged ≥65 years with HFrEF admitted to 10,333 SNFs. The median age was 82 years, 59% were women, 81% had at least moderate physical limitations, and 39% had moderate/severe cognitive impairment. Fifty-six percent received an ACEI/ARB and 53% an EBBB; one-fourth received neither. In a multivariable log-binomial model, advanced age, severe physical limitations, and greater number of comorbid conditions not associated with heart failure were inversely associated with ACEI/ARB and EBBB receipt. CONCLUSIONS: Use of standard pharmacotherapy among patients with HFrEF after an SNF stay is higher than previously reported. In the absence of evidence demonstrating the effectiveness of ACEIs/ARBs and EBBBs in this population, whether or not improvements in prescribing are warranted remains unknown.

The Intricate Link among Gut "Immunological Niche," Microbiota, and Xenobiotics in Intestinal Pathology.

Inflammatory bowel diseases (IBDs) are diseases characterized by various degrees of inflammation involving the gastrointestinal tract. Ulcerative colitis and Crohn's disease are characterized by a dysregulated immune response leading to structural gut alterations in genetically predisposed individuals. Diverticular disease is characterized by abnormal immune response to normal gut microbiota. IBDs are linked to a lack of physiological tolerance of the mucosal immune system to resident gut microbiota and pathogens. The disruption of immune tolerance involves inflammatory pathways characterized by an unbalance between the anti-inflammatory regulatory T cells and the proinflammatory Th1/Th17 cells. The interaction among T cell subpopulations and their related cytokines, mediators of inflammation, gut microbiota, and the intestinal mucosa constitute the gut "immunological niche." Several evidences have shown that xenobiotics, such as rifaximin, can positively modulate the inflammatory pathways at the site of gut immunological niche, acting as anti-inflammatory agents. Xenobiotics may interfere with components of the immunological niche, leading to activation of anti-inflammatory pathways and inhibition of several mediators of inflammation. In summary, xenobiotics may reduce disease-related gut mucosal alterations and clinical symptoms. Studying the complex interplay between gut immunological niche and xenobiotics will certainly open new horizons in the knowledge and therapy of intestinal pathologies.

Changes in the prescribing pattern of antidepressant drugs in elderly patients: an Italian, nationwide, population-based study.

BACKGROUND: Despite the high use of antidepressants (ADs) among the elderly, there is limited information about the prescribing pattern of these drugs in the Italian elderly population. The aim of this study was to analyze the trend in the use of ADs in the Italian elderly patients in the years 2003-2009, and specifically, to evaluate rates and predictors of AD treatment discontinuation in depressed older patients. METHODS: The nationwide general practice Health Search Database (HSD) was used to identify AD users aged 65 years old and over from 2003 to 2009. ADs were categorized as (1) selective serotonin reuptake inhibitors (SSRIs); (2) serotonin-norepinephrine reuptake inhibitors (SNRIs); (3) tricyclic antidepressants (TCAs); (4) noradrenergic and specific serotonergic antidepressants (NaSSAs); and (5) other ADs. Incidence and prevalence of AD use per 1,000 inhabitants was calculated by drug class and single compound. We also measured rates and predictors of AD discontinuation (i.e., treatment gap ≥ 60 days) during the first year of therapy. RESULTS: Overall, 39,557 AD users ≥65 years (17 % of the total HSD elderly population) were included in the study. SSRIs were increasingly and most frequently prescribed ADs (102.7-195.3 per 1,000 over seven years). The most common indications for AD use were depression and anxiety. Overall, 14 % of AD users continued their AD medication without treatment gaps, 27 % were intermittent AD users and 58 % discontinued their ADs during the first year of follow-up. Specific AD classes such as TCAs and 'other ADs were found to be predictors of discontinuation. In depressed patients, the use of NaSSas, TCAs and 'other ADs as well the concomitant use of >5 drugs (other than ADs) and living in Southern Italy were more likely to predict discontinuation. CONCLUSION: ADs, especially SSRIs, are widely and increasingly prescribed in elderly Italian patients in recent years. The observed high AD discontinuation rates are likely to impact the achievement of a therapeutic endpoint in depressed patients. Patients who are at high risk of AD discontinuation such as those receiving multi-drug therapy or living in Southern Italy should be monitored more closely to improve benefits of AD treatments.