Human skin-resident CD8+ T cells require RUNX2 and RUNX3 for induction of cytotoxicity and expression of the integrin CD49a.

The integrin CD49a marks highly cytotoxic epidermal-tissue-resident memory (TRM) cells, but their differentiation from circulating populations remains poorly defined. We demonstrate enrichment of RUNT family transcription-factor-binding motifs in human epidermal CD8+CD103+CD49a+ TRM cells, paralleled by high RUNX2 and RUNX3 protein expression. Sequencing of paired skin and blood samples revealed clonal overlap between epidermal CD8+CD103+CD49a+ TRM cells and circulating memory CD8+CD45RA-CD62L+ T cells. In vitro stimulation of circulating CD8+CD45RA-CD62L+ T cells with IL-15 and TGF-ß induced CD49a expression and cytotoxic transcriptional profiles in a RUNX2- and RUNX3-dependent manner. We therefore identified a reservoir of circulating cells with cytotoxic TRM potential. In melanoma patients, high RUNX2, but not RUNX3, transcription correlated with a cytotoxic CD8+CD103+CD49a+ TRM cell signature and improved patient survival. Together, our results indicate that combined RUNX2 and RUNX3 activity promotes the differentiation of cytotoxic CD8+CD103+CD49a+ TRM cells, providing immunosurveillance of infected and malignant cells.

Tissue-Specific Features of Innate Lymphoid Cells.

Although the function of the circulating immune cell compartment has been studied in detail for decades, limitations in terms of access and cell yields from peripheral tissues have restricted our understanding of tissue-based immunity, particularly in humans. Recent advances in high-throughput protein analyses, transcriptional profiling, and epigenetics have partially overcome these obstacles. Innate lymphoid cells (ILCs) are predominantly tissue-resident, and accumulating data indicate that they have significant tissue-specific functions. We summarize current knowledge of ILC phenotypes in various tissues in mice and humans, aiming to clarify ILC immunity in distinct anatomical locations.

End-of-life wishes and care planning for patients with advanced skin cancer.

BACKGROUND: Patients with advanced or metastatic skin cancer have a limited life expectancy and the majority die as a result of the tumor despite modern treatment options. The preferences of these patients concerning care during their last phase of life are currently unknown. PATIENTS AND METHODS: 150 patients with advanced skin cancer (AJCC/UICC stage III or IV) were interviewed using a structured questionnaire. RESULTS: 75% of the respondents wished to die in their domestic environment, although a more advanced tumor stage and increased reflection upon end-of-life care lead away from this wish. However, only 42% reported having communicated this wish to someone else. 55% of the respondents had completed advance directives, while younger patients did this significantly less often (95% CI: 0.11-0.56; p  =  0.001). The majority of patients (62%) would like to have discussions about possibilities for end-of-life care with the attending dermato-oncologist. CONCLUSIONS: Although the moment of death is unpredictable, early initiation of end-of-life advance care planning appears prudent. The attending dermato-oncologists should take the initiative to raise the subject with their patients during routine control visits. In this context, it may be useful to present available care options to patients and relatives and to design strategies for the event of deteriorating health.

Palliative care of older glioblastoma patients in neurosurgery.

PURPOSE: The care of older neurosurgical patients at the end life is a particularly demanding challenge. Especially, the specific needs of very old patients with glioblastoma at the end of life are at risk of being deprived of adequate care. METHODS: Based on a narrative literature review, this article aims to explore key issues of the thematic intersection of geriatric glioblastoma patients, palliative care and neurosurgery. RESULTS AND DISCUSSION: Four key issues were identified: patient-centeredness (need orientation and decision making), early palliative care, advance care planning, and multi-professionalism. Possible benefits and barriers are highlighted with regard to integrating these concepts into neurosurgery. CONCLUSIONS: Palliative care complements neurosurgical care of geriatric glioblastoma multiforme patients to optimise care for this highly vulnerable category of patients.

Factors associated with hospitalisations of patients with chronic heart failure approaching the end of life: A systematic review.

BACKGROUND: Heart failure has high mortality and is linked to substantial burden for patients, carers and health care systems. Patients with chronic heart failure frequently experience recurrent hospitalisations peaking at the end of life, but most prefer to avoid hospital. The drivers of hospitalisations are not well understood. AIM: We aimed to synthesise the evidence on factors associated with all-cause and heart failure hospitalisations of patients with advanced chronic heart failure. DESIGN: Systematic review of studies quantitatively evaluating factors associated with all-cause or heart failure hospitalisations in adult patients with advanced chronic heart failure. DATA SOURCES: Five electronic databases were searched from inception to September 2020. Additionally, searches for grey literature, citation searching and hand-searching were performed. We assessed the quality of individual studies using the QualSyst tool. Strength of evidence was determined weighing number, quality and consistency of studies. Findings are reported narratively as pooling was not deemed feasible. RESULTS: In 54 articles, 68 individual, illness-level, service-level and environmental factors were identified. We found high/moderate strength evidence for specialist palliative or hospice care being associated with reduced risk of all-cause and heart failure hospitalisations, respectively. Based on high strength evidence, we further identified black/non-white ethnicity as a risk factor for all-cause hospitalisations. CONCLUSION: Efforts to integrate hospice and specialist palliative services into care may reduce avoidable hospitalisations in advanced heart failure. Inequalities in end-of-life care in terms of race/ethnicity should be addressed. Further research should investigate the causality of the relationships identified here.

Developing a care pathway for hospital-based advance care planning for cancer patients: A modified Delphi study.

OBJECTIVES: The objective of this study is to develop a care pathway for a hospital-based advance care planning service for cancer patients. METHODS: A web-based modified Delphi study consulted an expert panel consisting of a convenience sample of stakeholders including professionals with a special interest in advance care planning as well as a 'public and patient involvement group'. After generating ideas for core elements of a care pathway in the first round, numerical ratings and rankings informed the multi-professional research steering group's decision process eventually resulting in a final pathway. RESULTS: The 41 participants in the Delphi study identified 177 potential core elements of the pathway in the first round. In two further rounds, consensus was reached on a final version of the pathway with 148 elements covering the 10 domains: prerequisites, organisation and coordination, identification and referral, provision of information, information sources, family involvement, advance care planning discussion, documentation, update and quality assurance. CONCLUSION: We propose a care pathway for advance care planning for hospital patients with cancer based on the results of a Delphi study that reached consensus on an implementation strategy. Our study pioneers the standardisation of the process and provides input for further policy and research with the aim of aligning cancer patients' care with their preferences and values.

'It was like taking an inner bath': A qualitative evaluation of a collaborative advance care planning-approach.

BACKGROUND: Impaired readiness may hinder purposeful advance care planning in cancer patients. To reduce barriers to participation in end-of-life decision-making, a collaborative intervention was developed combining a psycho-oncological approach of dignity-based and cognitive-behavioural interventions, followed by a standardised advance care planning-process. AIM: To evaluate the novel collaborative advance care planning-approach by synthetising cancer patient and carer perspectives on communicational and relational effects. DESIGN: As a sub-project of a mixed-methods evaluation study, we conducted an inductive content analysis of qualitative interviews with advanced cancer patients and caregivers to deeply explore the focused impact of a collaborative advance care planning-approach on communication and relationship dynamics. SETTING/PARTICIPANTS: Twelve patients with advanced cancer and 13 carers who participated in a collaborative advance care planning-intervention. RESULTS: The collaborative advance care planning-approach was consistently evaluated positively by participants. Transcriptions of the semi-structured interviews were coded, analysed and merged under three main themes concerning communicational and relationship dynamics: action readiness, content readiness and impact on future communication and relationship. CONCLUSIONS: The novel intervention served to foster individual readiness - including action and content readiness - for advance care planning-discussions by addressing highly individualised barriers to participation, as well as specific end-of-life issues. In addition, societal readiness could be promoted. Although the brief psycho-oncological intervention could not fully meet the needs of all participants, it can be used to develop individual psychotherapeutic strategies to improve different facets of readiness. The collaborative advance care planning-approach might require more time and human resources, but could pioneer successful advance care planning.

End-of-Life Care Preferences of Patients with Advanced Urological Malignancies: An Explorative Survey Study at a Tertiary Referral Center.

Background: Many people want to die at home, but it is often not possible because they do not share their wishes with family members. This study was conducted to find out the extent to which patients with advanced urological malignancies had wishes regarding their final stage of life, made arrangements accordingly, and communicated their wishes to relatives and health care professionals. Methods: We conducted a survey among advanced urological tumor patients during their clinic visit at a German university hospital using a 31-item questionnaire. Inclusion criteria were metastatic or irresectable prostate cancer, urothelial carcinoma, or renal cell carcinoma. Results: In total, 88 patients (76 male, 12 female) completed the questionnaire, and 62 of those respondents (70%) had received their tumor diagnosis within the past 5 years. Symptoms were reported by 80%, and 18% described five or more symptoms. The majority (88%) stated that they had thought about their preferred place of death but 58% had not informed anyone about it. The preference for a hospice as the place of death correlated statistically significantly with the absence of a domestic partnership (p = 0.001) or marriage (p < 0.001) and with a high number of symptoms (≥5; p = 0.009). However, 73% had not talked with their urological oncologist about care options in case their health deteriorated though 36% of those were interested in having a conversation about it. Conclusions: Our results showed that 9 out of 10 patients reflected on their preferred place of death but only a few discussed it with anyone. Based on this finding, physicians and healthcare staff should initiate discussions about early care planning so that patients in incurable situations can express their wishes regarding their preferred place of death.

How Safe Do Dying People Feel at Home? Patients' Perception of Safety While Receiving Specialist Community Palliative Care.

BACKGROUND: There is a research gap regarding safety concerns of patients at the end of life. The aim of this study was, therefore, to explore whether patients under specialist community palliative care feel safe at home and which factors affect the perceived safety. Furthermore, we investigated if perception of safety is associated with different aspects of subsequent care. METHODS: Using a standardized questionnaire, a cross-sectional survey was conducted among 100 specialist community palliative care patients. Logistic regression was used to examine the strength of the association between clinical and socio-demographic variables and the perception of safety. After a 6-month follow-up period, we analyzed differences in various care-related outcomes between patients with unaffected and impaired perceptions of safety. RESULTS: In our study, one in five patients receiving specialist community palliative care expressed safety concerns. Subdomains of safety that were reported most frequently were physical disability (60%), physical symptoms (30%), psychological symptoms (26%), and side effects/complications of drug therapy (19%). Of the participants surveyed after the initial COVID-19 lockdown, 35.1% reported that they felt their safety had been adversely affected by the pandemic. Compromised safety perception was associated with higher levels of palliative care-related problems, and proximity to death. CONCLUSIONS: Our study uncovered relevant safety concerns of palliative care patients receiving specialist community palliative care. The insights gained into patient-reported problems may help healthcare professionals to identify situations where patients feel unsafe. Further research should address primary and secondary prevention measures to improve the quality of end-of-life care in the home environment.

Cancer advance care planning: development of a screening tool.

OBJECTIVES: Advance care discussions are a useful communication tools for medical preferences and beneficial for shared decision-making processes in hospital settings. The present study developed the first screening tool for need for advance care planning (ACP). METHODS: In phase 1 (n=92), items were evaluated using feasibility analysis and item reduction. In phase 2 (n=201), reduced screening items were analysed for predictive value of need for ACP. Statistical analysis included receiver-operating characteristics analysis (area under the curve>0.80), optimal cut-off based on sensitivity and specificity, interpretation of OR and construct validity using correlation with death anxiety, communication avoidance within families and trust based on the relationship with the treating physician. RESULTS: Participants in both phases were approximately 60 years old with non-curative prognosis. After item reduction, predictive values of four possible items with good item difficulty and discrimination were compared for mild, moderate and great levels of death anxiety. A two-item combination of I am burdened by thoughts of an unfavourable course of the disease and I am burdened by the feeling of being ill-prepared for the end of life showed best prediction of death anxiety and communication avoidance. Clinical cut-off at sum-score ≥6 was of high sensitivity (95%) and specificity (81%). Previous use of social support and readiness for ACP was related to higher chance of interest in ACP. CONCLUSION: Screening for need of ACP is possible with two objective items and one subjective item. Positive screening therefore indicates when to offer ACP discussions and provides routine estimation of ACP need in clinical practice.

The electronic health record Risk of Alzheimer's and Dementia Assessment Rule (eRADAR) Brain Health Trial: Protocol for an embedded, pragmatic clinical trial of a low-cost dementia detection algorithm.

BACKGROUND: About half of people living with dementia have not received a diagnosis, delaying access to treatment, education, and support. We previously developed a tool, eRADAR, which uses information in the electronic health record (EHR) to identify patients who may have undiagnosed dementia. This paper provides the protocol for an embedded, pragmatic clinical trial (ePCT) implementing eRADAR in two healthcare systems to determine whether an intervention using eRADAR increases dementia diagnosis rates and to examine the benefits and harms experienced by patients and other stakeholders. METHODS: We will conduct an ePCT within an integrated healthcare system and replicate it in an urban academic medical center. At primary care clinics serving about 27,000 patients age 65 and above, we will randomize primary care providers (PCPs) to have their patients with high eRADAR scores receive targeted outreach (intervention) or usual care. Intervention patients will be offered a "brain health" assessment visit with a clinical research interventionist mirroring existing roles within the healthcare systems. The interventionist will make follow-up recommendations to PCPs and offer support to newly-diagnosed patients. Patients with high eRADAR scores in both study arms will be followed to identify new diagnoses of dementia in the EHR (primary outcome). Secondary outcomes include healthcare utilization from the EHR and patient, family member and clinician satisfaction assessed through surveys and interviews. CONCLUSION: If this pragmatic trial is successful, the eRADAR tool and intervention could be adopted by other healthcare systems, potentially improving dementia detection, patient care and quality of life.

The single-cell transcriptional landscape of innate and adaptive lymphocytes in pediatric-onset colitis.

Innate lymphoid cells (ILCs) are considered innate counterparts of adaptive T cells; however, their common and unique transcriptional signatures in pediatric inflammatory bowel disease (pIBD) are largely unknown. Here, we report a dysregulated colonic ILC composition in pIBD colitis that correlates with inflammatory activity, including accumulation of naive-like CD45RA+CD62L- ILCs. Weighted gene co-expression network analysis (WGCNA) reveals modules of genes that are shared or unique across innate and adaptive lymphocytes. Shared modules include genes associated with activation/tissue residency, naivety/quiescence, and antigen presentation. Lastly, nearest-neighbor-based analysis facilitates the identification of "most inflamed" and "least inflamed" lymphocytes in pIBD colon with unique transcriptional signatures. Our study reveals shared and unique transcriptional signatures of colonic ILCs and T cells in pIBD. We also provide insight into the transcriptional regulation of colonic inflammation, deepening our understanding of the potential mechanisms involved in pIBD.

Is a gluten-free diet necessary in Marsh I intestinal lesions in patients with HLADQ2, DQ8 genotype and without gastrointestinal symptoms?

PURPOSE OF REVIEW: To describe whether a gluten-free diet (GFD) is indicated in Marsh I gluten-sensitive enteropathy where gastrointestinal symptoms are not present. Arguments are provided to prescribe a GFD to manage extraintestinal symptoms. By contrast, there are not enough reasons to prescribe a GFD to prevent long-term complications. RECENT FINDINGS: Population-based and prospective observational studies have found that lymphocytic duodenosis may be due to not just gluten-sensitive enteropathy but also due to other aetiologic factors. Marsh I type lesions may be the cause of iron-deficiency anaemia of unknown aetiology which is reverted by a GFD. A similar effect seems to occur with bone mineralization and hypertransaminasemia. The beneficial influence of a GFD reducing lymphoma and coeliac disease-related mortality remains controversial. SUMMARY: An appropriate differential diagnosis of the lymphocytic duodenosis is essential before a GFD is indicated. As a third of patients remained undiagnosed, in spite of genetic study and specific coeliac serology, flow cytometry and transglutaminase antibodies in duodenal tissue may be helpful in establishing gluten-sensitive enteropathy diagnosis. Future studies should assess whether lymphoma risk is reduced by a GFD in Marsh I patients. Also a more precise benefit in bone mineralization in this setting is needed.

Measuring Quality of Life in Parkinson's Disease-A Call to Rethink Conceptualizations and Assessments.

Parkinson's disease (PD) is a chronic condition that considerably impacts the perception of quality of life (QoL) in both patients and their caregivers. Modern therapeutic approaches and social efforts strive at maintaining and promoting QoL. It has emerged as a fundamental parameter for clinical follow-up and poses one of the most important endpoints in scientific and economic evaluations of new care models. It is therefore of utmost importance to grasp concepts of QoL in a meaningful way. However, when taking a look at the origin of our modern understanding of QoL and existing methods for its measurement in PD patients, some aspects seem to lack sufficient appreciation. This article elaborates on how the perception of health and QoL have changed over time and discuss whether current understandings of both are reflected in the most commonly applied assessment methods for people with PD.

Risk Factors Associated With Alzheimer Disease and Related Dementias by Sex and Race and Ethnicity in the US.

Importance: Previous estimates suggested that 1 in 3 cases of Alzheimer disease and related dementia (ADRDs) in the US are associated with modifiable risk factors, the most prominent being physical inactivity, depression, and smoking. However, these estimates do not account for changes in risk factor prevalence over the past decade and do not consider potential differences by sex or race and ethnicity. Objective: To update estimates of the proportion of ADRDs in the US that are associated with modifiable risk factors and to assess for differences by sex and race and ethnicity. Design, Setting, and Participants: For this cross-sectional study, risk factor prevalence and communality were obtained from the nationally representative US Behavioral Risk Factor Surveillance Survey data from January 2018 to December 2018, and relative risks for each risk factor were extracted from meta-analyses. Data were analyzed from December 2020 to August 2021. Respondents included 378 615 noninstitutionalized adults older than 18 years. The number before exclusion was 402 410. Approximately 23 795 (~6%) had missing values on at least 1 of the variables of interest. Exposures: Physical inactivity, current smoking, depression, low education, diabetes, midlife obesity, midlife hypertension, and hearing loss. Main Outcomes and Measures: Individual and combined population-attributable risks (PARs) associated with ADRDs, accounting for nonindependence between risk factors. Results: Among 378 615 individuals, 171 161 (weighted 48.7%) were male, and 134 693 (weighted 21.1%) were 65 years and older. Race and ethnicity data were self-reported and defined by the US Behavioral Risk Factor Surveillance System Data; 6671 participants (weighted 0.9%) were American Indian and Alaska Native, 8043 (weighted 5.1%) were Asian, 29 956 (weighted 11.7%) were Black, 28 042 (weighted 16.0%) were Hispanic (any race), and 294 394 (weighted 64.3%) were White. Approximately 1 in 3 of ADRD cases (36.9%) in the US were associated with 8 modifiable risk factors, the most prominent of which were midlife obesity (17.7%; 95% CI, 17.5-18.0), physical inactivity (11.8%; 95% CI, 11.7-11.9), and low educational attainment (11.7%; 95% CI, 11.5-12.0). Combined PARs were higher in men (35.9%) than women (30.1%) and differed by race and ethnicity: American Indian and Alaska Native individuals, 39%; Asian individuals, 16%; Black individuals, 40%; Hispanic individuals (any race), 34%; and White individuals, 29%. The most prominent modifiable risk factors regardless of sex were midlife obesity for American Indian and Alaska Native individuals, Black individuals, and White individuals; low education for Hispanic individuals; and physical inactivity for Asian individuals. Conclusions and Relevance: The findings suggest that risk factors associated with ADRDs have changed over the past decade and differ based on sex and race and ethnicity. Alzheimer risk reduction strategies may be more effective if they target higher-risk groups and consider current risk factor profiles.

Changes in patient activation in people starting dialysis: A prospective longitudinal, observational study.

INTRODUCTION: Increased patient activation is associated with improved health outcomes; however, little is known about patient activation in people with end-stage kidney disease at the start of their dialysis journey. This study aimed to measure activation status changes over the first 4 months of dialysis. METHODS: Prospective, longitudinal, and observational study. Incident patients initiating dialysis at 25 in-center hemodialysis and 17 home dialysis programs across three US states managed by the same dialysis provider completed the 13-item Patient Activation Measure (PAM-13) survey at baseline (month 1 after commencement of dialysis) and follow-up (month 4). The survey yields a score (0-100) that corresponds to four levels (1-4), with higher scores or levels indicating higher activation. FINDINGS: One hundred eighty-two participants (139 center, 43 home) completed both baseline and follow-up surveys. Mean age was 60 ± 15 years, 40% female. Mean PAM-13 scores were 65.1 ± 16.8 and 64.8 ± 17.8 at baseline and follow-up, respectively; mean intraindividual change: -0.3 ± 17.3. The proportions of patients at levels 1-4 at baseline were 11%, 23%, 35%, and 31% respectively. At follow-up, 50%, 64%, 52%, and 37% of participants at levels 1-4, respectively, changed to a different PAM level (Spearman correlation = 0.47; p < 0.001). Home dialysis was associated with higher PAM scores when compared to in-center hemodialysis in multivariable analyses, adjusted for sociodemographic variables, comorbidities, and predialysis nephrology care (ß = 5.74, 95% confidence intervals [CI]: 0.11-11.37 and 9.02, 95% CI: 3.03-15.02, at baseline and follow-up, respectively). DISCUSSION: Although aggregated group scores and levels remained stable, intra-individual patient activation changed significantly during the first 4 months of dialysis. This novel finding is foundational to future projects aiming to design interventions to improve patient activation.

[Before the diagnosis was established A retrospective analysis of bereavement care in Germany]. / Bevor die Diagnose kam Eine Retrospektive der Trauerversorgung in Deutschland.

INTRODUCTION: In Germany, many health care providers work in bereavement care. An epidemiological study of this field of work has not yet been conducted. METHODS: In the initial survey of this three-phase trend study the situation of grief-specific health care in Germany in 2009/2010 is examined, i. e., at the time before the introduction of the new ICD-11 diagnosis of Prolonged Grief Disorder. For this purpose, bereavement care providers at different organizational levels participated in an online survey. RESULTS: 410 questionnaires were included in the study. Data analysis was descriptive. The most frequent reason for using grief-specific support services was the loss of a partner. In more than half of all cases of bereavement, people experienced a loss that was preceded by an illness and suffering. More than half of those providing bereavement care do not follow a concept of intervention. DISCUSSION: There is considerable need for further development in German bereavement care, in particular with regard to qualification and the degree of professionalization, designation of the respective interventions, diagnostics, and intervention. CONCLUSION: This three-phase trend study enables health care providers to derive bereavement care service standards that aim to treat people according to their needs. Whether the diagnosis of Prolonged Grief Disorder has led to changes in bereavement care is currently analyzed in the second survey phase of the study.