ABSTRACT
PURPOSE: During the coronavirus disease 2019 (COVID-19) pandemic, intensive care units (ICUs) around the world introduced virtual visiting to mediate the psychological impact of in-person visiting restrictions. Our objective was to evaluate levels of distress, depression, anxiety, and stress among family members experiencing virtual visits. METHODS: Multi-centre prospective observational study recruiting adult family members of critically ill patients in the United Kingdom (UK) using a bespoke virtual visiting solution (aTouchAway). We recruited participants and administered validated questionnaires digitally via their aTouchAway account. Prior to first virtual visit, participants completed the Distress Thermometer (score range 0-10) and the Depression, Anxiety and Stress Scale (DASS)-21. Following first and subsequent virtual visits, participants repeated the Distress Thermometer and completed the Discrete Emotions Questionnaire. RESULTS: We recruited 2166 adult family members of ICU patients in 37 UK hospitals. Most were grown up children (33%) or spouses/partners (23%). Most (91%) were ≤ 65 years. Mean (SD) pre-virtual-visit Distress Thermometer score was 7 (2.6) with 1349/2153 (62%) reporting severe distress. Pre-visit Distress Thermometer scores were associated with relationship type (spouse/partner OR 1.65, 95% CI 1.27-2.12) but not family member age, or length of ICU stay. Mean (SD) post-visit Distress Thermometer score provided by 762 (35%) participants was 1.6 (3.2) points lower than pre-visit (P < 0.001). Of participants experiencing multiple visits, 22% continued to report severe distress. Median (IQR) pre-visit DASS-21 score was 18 (2-42) (1754 participants). Severe-to-extremely severe depression, anxiety, or stress were reported by 249 (14%), 321 (18%), and 165 (9%) participants, respectively. Participants reported a range of emotions with reassurance being the most common, anger being the least. CONCLUSION: Family members exposed to COVID-19 pandemic ICU visiting restrictions experienced severe distress. One fifth of family members reported severe-to-extremely sever anxiety or depression. Distress score magnitude and prevalence of severe distress decreased after undertaking one or more virtual visits.
Subject(s)
COVID-19 , Psychological Distress , Adult , Anxiety/epidemiology , Anxiety/psychology , Child , Critical Care , Depression/epidemiology , Depression/psychology , Humans , Intensive Care Units , Pandemics , Prevalence , Stress, Psychological/epidemiology , Stress, Psychological/psychology , Surveys and QuestionnairesABSTRACT
BACKGROUND: Person-centred care (PCC) is being internationally recognised as a critical attribute of high-quality healthcare. The International Alliance of Patients Organisations defines PCC as care that is focused and organised around people, rather than disease. Focusing on delivery, we aimed to review and evaluate the evidence from interventions that aimed to deliver PCC for people with serious physical illness and identify models of PCC interventions. METHODS: Systematic review of literature using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched AMED, CINAHL, Cochrane Library, Embase, Medline, PsycINFO, using the following key concepts: patient/person-centred care, family centred care, family based care, individualised care, holistic care, serious illness, chronic illness, long-term conditions from inception to April 2022. Due to heterogeneity of interventions and populations studied, narrative synthesis was conducted. Study quality was appraised using the Joanna Briggs checklist. RESULTS: We screened n=6156 papers. Seventy-two papers (reporting n=55 different studies) were retained in the review. Most of these studies (n=47) were randomised controlled trials. Our search yielded two main types of interventions: (1) studies with self-management components and (2) technology-based interventions. We synthesised findings across these two models:Self-management component: the interventions consisted of training of patients and/or caregivers or staff. Some studies reported that interventions had effect in reduction hospital admissions, improving quality of life and reducing costs of care.Technology-based interventions: consisted of mobile phone, mobile app, tablet/computer and video. Although some interventions showed improvements for self-efficacy, hospitalisations and length of stay, quality of life did not improve across most studies. DISCUSSION: PCC interventions using self-management have some effects in reducing costs of care and improving quality of life. Technology-based interventions improves self-efficacy but has no effect on quality of life. However, very few studies used self-management and technology approaches. Further work is needed to identify how self-management and technology approaches can be used to manage serious illness. PROSPERO REGISTRATION NUMBER: CRD42018108302.
Subject(s)
Cell Phone , Mobile Applications , Hospitalization , Humans , Quality of Life , Self CareABSTRACT
OBJECTIVE: To understand the experiences and perceived benefits of virtual visiting from the perspectives of intensive care unit (ICU)-experienced clinicians and non-ICU-experienced family liaison team members. DESIGN: Qualitative descriptive study. SETTING: Adult intensive care setting across 14 hospitals within the UK National Health Service. PARTICIPANTS: ICU-experienced clinicians and non-ICU-experienced family liaison team members deployed during the first wave of the COVID-19 pandemic. METHODS: Semistructured telephone/video interviews were conducted with ICU clinicians. Analytical themes were developed inductively following a standard thematic approach, using 'family-centred care' and 'sensemaking' as sensitising concepts. RESULTS: We completed 36 interviews, with 17 ICU-experienced clinicians and 19 non-ICU-experienced family liaison team members. In the context of inperson visiting restrictions, virtual visiting offered an alternative conduit to (1) restoring the family unit, (2) facilitating family involvement, and (3) enabling sensemaking for the family. Virtual visits with multiple family members concurrently and with those living in distant geographical locations restored a sense of family unit. Family involvement in rehabilitation, communication and orientation activities, as well as presence at the end of life, highlighted how virtual visiting could contribute to family-centred care. Virtual visits were emotionally challenging for many family members, but also cathartic in helping make sense of their own emotions and experience by visualising their relatives in the ICU. Being able to see and interact with loved ones and their immediate care providers afforded important cues to enable family sensemaking of the ICU experience. CONCLUSIONS: In this UK qualitative study of clinicians using virtual ICU visiting, in the absence of inperson visiting, virtual visiting was perceived positively as an alternative that promoted family-centred care through virtual presence. We anticipate the perceived benefits of virtual visiting may extend to non-pandemic conditions through improved equity and timeliness of family access to the ICU by offering an alternative option alongside inperson visiting.
Subject(s)
COVID-19 , Adult , Critical Care/psychology , Humans , Intensive Care Units , Pandemics , State MedicineABSTRACT
INTRODUCTION: Health and social care services worldwide need to support ageing populations to live well with advanced progressive conditions while adapting to functional decline and finitude. We aimed to identify and map common elements of effective geriatric and palliative care services and consider their scalability and generalisability to high, middle and low-income countries. METHODS: Tertiary systematic review (Cochrane Database of Systematic Reviews, CINAHL, Embase, January 2000-October 2019) of studies in geriatric or palliative care that demonstrated improved quality of life and/or health service use outcomes among older people with advanced progressive conditions. Using frameworks for health system analysis, service elements were identified. We used a staged, iterative process to develop a 'common components' logic model and consulted experts in geriatric or palliative care from high, middle and low-income countries on its scalability. RESULTS: 78 studies (59 geriatric and 19 palliative) spanning all WHO regions were included. Data were available from 17 739 participants. Nearly half the studies recruited patients with heart failure (n=36) and one-third recruited patients with mixed diagnoses (n=26). Common service elements (≥80% of studies) included collaborative working, ongoing assessment, active patient participation, patient/family education and patient self-management. Effective services incorporated patient engagement, patient goal-driven care and the centrality of patient needs. Stakeholders (n=20) emphasised that wider implementation of such services would require access to skilled, multidisciplinary teams with sufficient resource to meet patients' needs. Identified barriers to scalability included the political and societal will to invest in and prioritise palliative and geriatric care for older people, alongside geographical and socioeconomic factors. CONCLUSION: Our logic model combines elements of effective services to achieve optimal quality of life and health service use among older people with advanced progressive conditions. The model transcends current best practice in geriatric and palliative care and applies across the care continuum, from prevention of functional decline to end-of-life care. PROSPERO REGISTRATION NUMBER: CRD42020150252.
Subject(s)
Quality of Life , Terminal Care , Aged , Humans , Palliative Care , Patient Acceptance of Health CareABSTRACT
Rationale: Restriction or prohibition of family visiting intensive care units (ICUs) during the coronavirus disease (COVID-19) pandemic poses substantial barriers to communication and family- and patient-centered care. Objectives: To understand how communication among families, patients, and the ICU team was enabled during the pandemic. The secondary objectives were to understand strategies used to facilitate virtual visiting and associated benefits and barriers. Methods: A multicenter, cross-sectional, and self-administered electronic survey was sent (June 2020) to all 217 UK hospitals with at least one ICU. Results: The survey response rate was 54%; 117 of 217 hospitals (182 ICUs) responded. All hospitals imposed visiting restrictions, with visits not permitted under any circumstance in 16% of hospitals (28 ICUs); 63% (112 ICUs) of hospitals permitted family presence at the end of life. The responsibility for communicating with families shifted with decreased bedside nurse involvement. A dedicated ICU family-liaison team was established in 50% (106 ICUs) of hospitals. All but three hospitals instituted virtual visiting, although there was substantial heterogeneity in the videoconferencing platform used. Unconscious or sedated ICU patients were deemed ineligible for virtual visits in 23% of ICUs. Patients at the end of life were deemed ineligible for virtual visits in 7% of ICUs. Commonly reported benefits of virtual visiting were reducing patient psychological distress (78%), improving staff morale (68%), and reorientation of patients with delirium (47%). Common barriers to virtual visiting were related to insufficient staff time, rapid implementation of videoconferencing technology, and challenges associated with family members' ability to use videoconferencing technology or access a device. Conclusions: Virtual visiting and dedicated communication teams were common COVID-19 pandemic innovations addressing the restrictions to family ICU visiting, and they resulted in valuable benefits in terms of patient recovery and staff morale. Enhancing access and developing a more consistent approach to family virtual ICU visits could improve the quality of care, both during and outside of pandemic conditions.
Subject(s)
COVID-19 , Pandemics , Communication , Critical Care , Cross-Sectional Studies , Family , Humans , Intensive Care Units , SARS-CoV-2 , United KingdomABSTRACT
We identify an intronic deletion in VANGL1 that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop nephritis, yet the predisposing mechanisms to kidney damage remain poorly understood. There is limited evidence of genetic contribution to specific organ involvement in SLE.1,2 We identify a large deletion in intron 7 of Van Gogh Like 1 (VANGL1), which associates with nephritis in SLE patients. The same deletion occurs at increased frequency in an indigenous population (Tiwi Islanders) with 10-fold higher rates of kidney disease compared with non-indigenous populations. Vangl1 hemizygosity in mice results in spontaneous IgA and IgG deposition within the glomerular mesangium in the absence of autoimmune nephritis. Serum transfer into B cell-deficient Vangl1+/- mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of Vangl1. These results suggest that Vangl1 acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE.
Subject(s)
Antibodies/adverse effects , Carrier Proteins/genetics , Gene Deletion , Kidney Diseases/pathology , Membrane Proteins/genetics , Adult , Aged , Animals , Biopsy , Cohort Studies , DNA Copy Number Variations/genetics , Homozygote , Humans , Introns/genetics , Kidney/metabolism , Kidney/pathology , Lupus Nephritis/genetics , Membrane Proteins/deficiency , Membrane Proteins/metabolism , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Risk FactorsABSTRACT
Genetic primary immunodeficiency diseases are increasingly recognized, with pathogenic mutations changing the composition of circulating leukocyte subsets measured by flow cytometry (FCM). Discerning changes in multiple subpopulations is challenging, and subtle trends might be missed if traditional reference ranges derived from a control population are applied. We developed an algorithm where centiles were allocated using non-parametric comparison to controls, generating multiparameter heat maps to simultaneously represent all leukocyte subpopulations for inspection of trends within a cohort or segregation with a putative genetic mutation. To illustrate this method, we analyzed patients with Primary Antibody Deficiency (PAD) and kindreds harboring mutations in TNFRSF13B (encoding TACI), CTLA4, and CARD11. In PAD, loss of switched memory B cells (B-SM) was readily demonstrated, but as a continuous, not dichotomous, variable. Expansion of CXCR5+/CD45RA- CD4+ T cells (X5-Th cells) was a prominent feature in PAD, particularly in TACI mutants, and patients with expansion in CD21-lo B cells or transitional B cells were readily apparent. We observed differences between unaffected and affected TACI mutants (increased B cells and CD8+ T-effector memory cells, loss of B-SM cells and non-classical monocytes), cellular signatures that distinguished CTLA4 haploinsufficiency itself (expansion of plasmablasts, activated CD4+ T cells, regulatory T cells, and X5-Th cells) from its clinical expression (B-cell depletion), and those that were associated with CARD11 gain-of-function mutation (decreased CD8+ T effector memory cells, B cells, CD21-lo B cells, B-SM cells, and NK cells). Co-efficients of variation exceeded 30% for 36/54 FCM parameters, but by comparing inter-assay variation with disease-related variation, we ranked each parameter in terms of laboratory precision vs. disease variability, identifying X5-Th cells (and derivatives), naïve, activated, and central memory CD8+ T cells, transitional B cells, memory and SM-B cells, plasmablasts, activated CD4 cells, and total T cells as the 10 most useful cellular parameters. Applying these to cluster analysis of our PAD cohort, we could detect subgroups with the potential to reflect underlying genotypes. Heat mapping of normalized FCM data reveals cellular trends missed by standard reference ranges, identifies changes associating with a phenotype or genotype, and could inform hypotheses regarding pathogenesis of genetic immunodeficiency.
Subject(s)
Flow Cytometry , Genetic Diseases, Inborn/immunology , Hot Temperature , Immunologic Deficiency Syndromes/immunology , Mutation , Adult , Aged , B-Lymphocytes/immunology , B-Lymphocytes/pathology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Female , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/pathology , Humans , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/pathology , Immunologic Memory , Male , Middle Aged , T-Lymphocytes, Helper-Inducer/immunology , T-Lymphocytes, Helper-Inducer/pathologyABSTRACT
OBJECTIVE: Impaired awareness of hypoglycemia (IAH) and recurrent severe hypoglycemia (RSH) remain problematic for people with type 1 diabetes (T1D), despite major therapeutic advances. We explored beliefs around hypo- and hyperglycemia in adults with T1D with, and without, IAH and RSH. RESEARCH DESIGN AND METHODS: A cross-sectional U.S. multicenter survey included Attitudes to Awareness of Hypoglycemia (A2A; a 19-item questionnaire concerning beliefs about hypoglycemia), the Gold score (single item: awareness of hypoglycemia), and a question about severe hypoglycemia over the preceding year. The survey was emailed to 6,200 adult participants of the annual T1D Exchange clinic registry data collection. A2A data were subjected to principal component analysis with varimax rotation. RESULTS: Among 1,978 respondents (response rate 32%), 61.7% were women, mean ± SD age was 39.6 ± 16.3 years, and T1D duration was 23.1 ± 13.8 years. Thirty-seven percent reported IAH, 16% RSH, and 9% both. A2A items segregated into three factors, differently distributed by hypoglycemia experience. Respondents with IAH or RSH expressed appropriate concern about hypoglycemia, but those with IAH were more likely to prioritize hyperglycemia concerns than those with intact awareness (P = 0.002). Those with RSH showed greater normalization of asymptomatic hypoglycemia than those without (P = 0.019) and trended toward prioritizing hyperglycemia concerns (P = 0.097), driven by those with both IAH and RSH. CONCLUSIONS: Adults with T1D with IAH and RSH report specific cognitions about hypoglycemia and hyperglycemia, which may act as barriers to hypoglycemia avoidance and recovery of awareness. These may be modifiable and present a target for enhancing engagement of vulnerable people with strategies to avoid future hypoglycemia.
Subject(s)
Attitude to Health , Cognition , Diabetes Mellitus, Type 1/psychology , Hyperglycemia/psychology , Hypoglycemia/psychology , Adult , Awareness , Cross-Sectional Studies , Diabetes Mellitus, Type 1/complications , Female , Humans , Hyperglycemia/etiology , Hypoglycemia/etiology , Male , Middle Aged , Principal Component Analysis , Surveys and Questionnaires , United StatesABSTRACT
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Genetic Predisposition to Disease , Lupus Erythematosus, Systemic/genetics , Membrane Proteins/genetics , src-Family Kinases/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adolescent , Adult , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Case-Control Studies , Cell Line , Cell Nucleus/immunology , Cell Nucleus/metabolism , Child , Disease Models, Animal , Female , Gene Frequency , HEK293 Cells , Healthy Volunteers , Humans , Interferon Regulatory Factors/immunology , Interferon Regulatory Factors/metabolism , Interferon Type I/immunology , Interferon Type I/metabolism , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/immunology , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation, Missense , Exome Sequencing , src-Family Kinases/metabolismABSTRACT
BACKGROUND: Increasingly the population is eating meals and snacks prepared outside the home, especially younger adults. Takeaway foods can be energy-dense, high in saturated fat and sodium, and deleterious to health. Extending studies examining the barriers to healthy eating, this paper explores strategies employed by young adults who report reducing consumption of unhealthy takeaway foods. METHODS: Young adults aged 18 to 35 years in paid employment were recruited to participate in eight semi-structured focus groups. In response to initial findings, recruitment for the final four groups refocused on participants who either wanted, were in the process of, or had changed their takeaway food habits. Focus group recordings were transcribed verbatim and coded by two researchers for recurrent themes using an inductive method. RESULTS: Forty-eight participants with a mean BMI of 23.4 kg/m2 and mean age of 25 years took part, of which 34 were female, and 27 were born outside Australia. Four broad strategies emerged: altering cognitions about consumption/reduction of takeaway food; practical changes to behaviours; finding external support; and, reconfiguring social events. In detail, participants cognitively recast takeaway food consumption as negative (expensive and unhealthy) and reducing consumption of such foods or consuming healthy alternatives as a (positive) self-care action. Setting goals and making personal rules around consumption, and consciously making practical changes, such as planning for food shopping, were other strategies. Externally derived support including supportive food environments and friends and family passively reduced exposure to unhealthy takeaway food. Finally, some participants actively created social environments supportive of healthy choices. CONCLUSIONS: Our participants reported strategies they believed led to them successfully reduce their takeaway food consumption by matching the attractions (e.g., convenience) and countering apparent disincentives for reducing consumption (e.g., losing a reward) of takeaway food. They reported eschewing more short-term rewards and costs, to prioritise their health, believing that avoiding these foods would benefit them personally and financially. The identified strategies are consistent with documented techniques for successful behaviour change and corresponded to all levels in the social-ecological model from intrapersonal factors to public policy. The findings could underpin health promotion strategies to support this at-risk group.
Subject(s)
Diet, Healthy , Fast Foods , Adolescent , Adult , Australia , Cross-Sectional Studies , Diet , Feeding Behavior , Female , Focus Groups , Humans , Male , Qualitative Research , Social Environment , Young AdultABSTRACT
OBJECTIVE: Friedreich's ataxia is an incurable inherited neurological disease caused by frataxin deficiency. Here, we report the neuroreparative effects of myeloablative allogeneic bone marrow transplantation in a humanized murine model of the disease. METHODS: Mice received a transplant of fluorescently tagged sex-mismatched bone marrow cells expressing wild-type frataxin and were assessed at monthly intervals using a range of behavioral motor performance tests. At 6 months post-transplant, mice were euthanized for protein and histological analysis. In an attempt to augment numbers of bone marrow-derived cells integrating within the nervous system and improve therapeutic efficacy, a subgroup of transplanted mice also received monthly subcutaneous infusions of the cytokines granulocyte-colony stimulating factor and stem cell factor. RESULTS: Transplantation caused improvements in several indicators of motor coordination and locomotor activity. Elevations in frataxin levels and antioxidant defenses were detected. Abrogation of disease pathology throughout the nervous system was apparent, together with extensive integration of bone marrow-derived cells in areas of nervous tissue injury that contributed genetic material to mature neurons, satellite-like cells, and myelinating Schwann cells by processes including cell fusion. Elevations in circulating bone marrow-derived cell numbers were detected after cytokine administration and were associated with increased frequencies of Purkinje cell fusion and bone marrow-derived dorsal root ganglion satellite-like cells. Further improvements in motor coordination and activity were evident. INTERPRETATION: Our data provide proof of concept of gene replacement therapy, via allogeneic bone marrow transplantation, that reverses neurological features of Friedreich's ataxia with the potential for rapid clinical translation. Ann Neurol 2018;83:779-793.
Subject(s)
Bone Marrow Transplantation/methods , Friedreich Ataxia/surgery , Animals , Body Weight/physiology , Cytokines/metabolism , Disease Models, Animal , Exploratory Behavior/physiology , Friedreich Ataxia/genetics , Ganglia, Spinal/pathology , Granulocyte Colony-Stimulating Factor/metabolism , Granulocyte Colony-Stimulating Factor/therapeutic use , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Iron-Binding Proteins/genetics , Leukocytes, Mononuclear/pathology , Mice , Mice, Inbred C57BL , Muscle Strength/physiology , Mutation/genetics , Nerve Tissue Proteins/metabolism , Neurons/pathology , FrataxinABSTRACT
Physical activity and diet are major modifiable risk factors for chronic disease and have been shown to be associated with neighborhood built environment. Systematic review evidence from longitudinal studies on the impact of changing the built environment on physical activity and diet is currently lacking. A systematic review of natural experiments of neighborhood built environment was conducted. The aims of this systematic review were to summarize study characteristics, study quality, and impact of changes in neighborhood built environment on physical activity and diet outcomes among residents. Natural experiments of neighborhood built environment change, exploring longitudinal impacts on physical activity and/or diet in residents, were included. From five electronic databases, 2084 references were identified. A narrative synthesis was conducted, considering results in relation to study quality. Nineteen papers, reporting on 15 different exposures met inclusion criteria. Four studies included a comparison group and 11 were pre-post/longitudinal studies without a comparison group. Studies reported on the impact of redeveloping or introducing cycle and/or walking trails (n = 5), rail stops/lines (n = 4), supermarkets and farmers' markets (n = 4) and park and green space (n = 2). Eight/15 studies reported at least one beneficial change in physical activity, diet or another associated health outcome. Due to limitations in study design and reporting, as well as the wide array of outcome measures reported, drawing conclusions to inform policy was challenging. Future research should consider a consistent approach to measure the same outcomes (e.g., using measurement methods that collect comparable physical activity and diet outcome data), to allow for pooled analyses. Additionally, including comparison groups wherever possible and ensuring high quality reporting is essential.
Subject(s)
Diet/psychology , Environment Design , Exercise/psychology , Health Behavior , Health Risk Behaviors , Healthy Lifestyle , Residence Characteristics , Humans , Longitudinal StudiesABSTRACT
Chagas disease, caused by the parasite Trypanosoma cruzi, is endemic in Latin America but has become a global public health concern by migration of infected people. It has been reported that parasite persistence as well as the intensity of the inflammatory immune response are determinants of the clinical manifestations of the disease. Even though inflammation is indispensable for host defense, when deregulated, it can contribute to tissue injury and organ dysfunction. Here, we report the importance of B cells in conditioning T cell response in T. cruzi infection. Mice deficient in mature B cells (muMT mice) infected with T. cruzi exhibited an increase in plasma TNF concentration, TNF-producing CD4+ T cells, and mortality. The increase in TNF-producing CD4+ T cells was accompanied by a reduction in IFNγ+CD4+ T cells and a decrease of the frequency of regulatory Foxp3+, IL-10+, and IL17+CD4+ T cells populations. The CD4+ T cell population activated by T. cruzi infection, in absence of mature B cells, had a high frequency of Ly6C+ cells and showed a lower expression of inhibitory molecules such as CTLA-4, PD-1, and LAG3. CD4+ T cells from infected muMT mice presented a high frequency of CD62LhiCD44- cells, which is commonly associated with a naïve phenotype. Through transfer experiments we demonstrated that CD4+ T cells from infected muMT mice were able to condition the CD4+ T cells response from infected wild-type mice. Interestingly, using Blimp-flox/flox-CD23icre mice we observed that in absence of plasmablast/plasma cell T. cruzi-infected mice exhibited a higher number of TNF-producing CD4+ T cells. Our results showed that the absence of B cells during T. cruzi infection affected the T cell response at different levels and generated a favorable scenario for unconventional activation of CD4+ T cell leading to an uncontrolled effector response and inflammation. The product of B cell differentiation, the plasmablast/plasma cells, could be able to regulate TNF-producing CD4+ T cells since their absence favor the increase of the number of TNF+ CD4+ in T. cruzi-infected mice.
ABSTRACT
To systematically review studies of health promotion intervention in the police force. Four databases were searched for articles reporting on prepost single and multigroup studies in police officers and trainees. Data were extracted and bias assessed to evaluate study characteristics, intervention design and the impact of interventions on health. Database searching identified 25 articles reporting on 21 studies relevant to the aims of this review. Few studies (n=3) were of long duration (≥6 months). Nine of 21 studies evaluated structured physical activity and/or diet programmes only, 5 studies used education and behaviour change support-only interventions, 5 combined structured programmes with education and behaviour change support, and 2 studies used computer prompts to minimise sedentary behaviour. A wide array of lifestyle behaviour and health outcomes was measured, with 11/13 multigroup and 8/8 single-group studies reporting beneficial impacts on outcomes. High risk of bias was evident across most studies. In those with the lowest risk of bias (n=2), a large effect on blood pressure and small effects on diet, sleep quality, stress and tobacco use, were reported. Health promotion interventions can impact beneficially on health of the police force, particularly blood pressure, diet, sleep, stress and tobacco use. Limited reporting made comparison of findings challenging. Combined structured programmes with education and behaviour change support and programmes including peer support resulted in the most impact on health-related outcomes.
Subject(s)
Health Promotion/methods , Life Style , Police , Blood Pressure , Diet , Exercise , Humans , Sleep , Smoking , Stress, PsychologicalABSTRACT
Defects in motor protein-mediated neuronal transport mechanisms have been implicated in a number of neurodegenerative disorders but remain relatively little studied in Alzheimer's disease (AD). Our aim in the present study was to assess the expression of the anterograde kinesin superfamily motor proteins KIF5A, KIF1B, and KIF21B, and to examine their relationship to levels of hyperphosphorylated tau, amyloid-ß protein precursor (AßPP), and amyloid-ß (Aß) in human brain tissue. We used a combination of qPCR, immunoblotting, and ELISA to perform these analyses in midfrontal cortex from 49 AD and 46 control brains. Expression of KIF5A, KIF1B, and KIF21B at gene and protein level was significantly increased in AD. KIF5A protein expression correlated inversely with the levels of AßPP and soluble Aß in AD brains. Upregulation of KIFs may be an adaptive response to impaired axonal transport in AD.
Subject(s)
Alzheimer Disease/metabolism , Frontal Lobe/metabolism , Kinesins/metabolism , Aged , Aged, 80 and over , Amyloid beta-Protein Precursor/metabolism , Blotting, Western , Cohort Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Phosphorylation , RNA, Messenger/metabolism , Real-Time Polymerase Chain Reaction , Up-Regulation , tau Proteins/metabolismABSTRACT
Friedreich's ataxia is an inherited neurological disorder characterised by mitochondrial dysfunction and increased susceptibility to oxidative stress. At present, no therapy has been shown to reduce disease progression. Strategies being trialled to treat Friedreich's ataxia include drugs that improve mitochondrial function and reduce oxidative injury. In addition, stem cells have been investigated as a potential therapeutic approach. We have used siRNA-induced knockdown of frataxin in SH-SY5Y cells as an in vitro cellular model for Friedreich's ataxia. Knockdown of frataxin protein expression to levels detected in patients with the disorder was achieved, leading to decreased cellular viability, increased susceptibility to hydrogen peroxide-induced oxidative stress, dysregulation of key anti-oxidant molecules and deficiencies in both cell proliferation and differentiation. Bone marrow stem cells are being investigated extensively as potential treatments for a wide range of neurological disorders, including Friedreich's ataxia. The potential neuroprotective effects of bone marrow-derived mesenchymal stem cells were therefore studied using our frataxin-deficient cell model. Soluble factors secreted by mesenchymal stem cells protected against cellular changes induced by frataxin deficiency, leading to restoration in frataxin levels and anti-oxidant defences, improved survival against oxidative stress and stimulated both cell proliferation and differentiation down the Schwann cell lineage. The demonstration that mesenchymal stem cell-derived factors can restore cellular homeostasis and function to frataxin-deficient cells further suggests that they may have potential therapeutic benefits for patients with Friedreich's ataxia.
Subject(s)
Friedreich Ataxia/metabolism , Iron-Binding Proteins/metabolism , Mesenchymal Stem Cells/metabolism , Cell Differentiation/physiology , Cell Line, Tumor , Cell Proliferation/physiology , Cell Survival/physiology , Femur , Gene Knockdown Techniques , Homeostasis/physiology , Humans , Hydrogen Peroxide/metabolism , Iron-Binding Proteins/genetics , Nitric Oxide/metabolism , Oxidative Stress/physiology , RNA, Small Interfering , Schwann Cells/metabolism , FrataxinABSTRACT
OBJECTIVES: Friedreich's ataxia is a devastating neurological disease currently lacking any proven treatment. We studied the neuroprotective effects of the cytokines, granulocyte-colony stimulating factor (G-CSF) and stem cell factor (SCF) in a humanized murine model of Friedreich's ataxia. METHODS: Mice received monthly subcutaneous infusions of cytokines while also being assessed at monthly time points using an extensive range of behavioral motor performance tests. After 6 months of treatment, neurophysiological evaluation of both sensory and motor nerve conduction was performed. Subsequently, mice were sacrificed for messenger RNA, protein, and histological analysis of the dorsal root ganglia, spinal cord, and cerebellum. RESULTS: Cytokine administration resulted in significant reversal of biochemical, neuropathological, neurophysiological, and behavioural deficits associated with Friedreich's ataxia. Both G-CSF and SCF had pronounced effects on frataxin levels (the primary molecular defect in the pathogenesis of the disease) and a regulators of frataxin expression. Sustained improvements in motor coordination and locomotor activity were observed, even after onset of neurological symptoms. Treatment also restored the duration of sensory nerve compound potentials. Improvements in peripheral nerve conduction positively correlated with cytokine-induced increases in frataxin expression, providing a link between increases in frataxin and neurophysiological function. Abrogation of disease-related pathology was also evident, with reductions in inflammation/gliosis and increased neural stem cell numbers in areas of tissue injury. INTERPRETATION: These experiments show that cytokines already clinically used in other conditions offer the prospect of a novel, rapidly translatable, disease-modifying, and neuroprotective treatment for Friedreich's ataxia. Ann Neurol 2017;81:212-226.
Subject(s)
Behavior, Animal/drug effects , Friedreich Ataxia/drug therapy , Granulocyte Colony-Stimulating Factor/pharmacology , Iron-Binding Proteins/metabolism , Neural Conduction/drug effects , Neuroprotective Agents/pharmacology , Peripheral Nerves/drug effects , Stem Cell Factor/pharmacology , Animals , Disease Models, Animal , Friedreich Ataxia/metabolism , Friedreich Ataxia/physiopathology , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neuroprotective Agents/administration & dosage , Stem Cell Factor/administration & dosage , FrataxinABSTRACT
A single question (SQ) and a twenty-eight-item FFQ to measure takeaway meal intake were compared with two 7-d estimated food records (EFR; reference method). Test methods were completed after the reference period and repeated 6-8 d later for repeatability. The SQ asked about intake of high-SFA takeaway meals. FFQ items included low- and high-SFA meals. Test methods were compared with EFR for sensitivity, specificity, and positive and negative predictive values, using a goal of ≤1 high-SFA weekly takeaway meals. Bland-Altman analyses were used to check agreement between measurement approaches, the κ coefficient was used to summarise the observed level of agreement, and Spearman's correlation was used to assess the degree to which instruments ranked individuals. Young adults were recruited from two universities, and 109 participants (61 % female) completed the study. The mean age was 24·4 (sd 4·9) years, and the mean BMI was 23·5 (sd 3·7) kg/m2. The SQ and the FFQ had a sensitivity of 97 and 83 % and a specificity of 46 and 92 %, respectively. Both methods exhibited moderate correlation for measuring total and high-SFA takeaway meal intakes (r s ranging from 0·64 to 0·80). Neither instrument could measure precise, absolute intake at the group or individual level. Test methods ranged from fair (κ w =0·24) to moderate agreement (κ w =0·59). The repeatability for all was acceptable. The FFQ identified excessive high-SFA takeaway meal intake and measured individuals' category for total and high-SFA takeaway intakes. Both methods are suitable for ranking individuals for total or high-SFA takeaway meal intakes.
Subject(s)
Diet, High-Fat/adverse effects , Fast Foods/adverse effects , Feeding Behavior , Meals , Perception , Portion Size , Restaurants , Adolescent , Adult , Body Mass Index , Diet Records , Energy Intake , Female , Humans , Male , New South Wales/epidemiology , Obesity/epidemiology , Obesity/etiology , Overweight/epidemiology , Overweight/etiology , Prevalence , Reproducibility of Results , Self Report , Surveys and Questionnaires , Young AdultABSTRACT
Purkinje cell pathology is a common finding in a range of inherited and acquired cerebellar disorders, with the degree of Purkinje cell injury dependent on the underlying aetiology. Purkinje cells have an unparalleled resistance to insult and display unique regenerative capabilities within the central nervous system. Their response to cell injury is not typical of most neurons and likely represents both degenerative, compensatory and regenerative mechanisms. Here we present a pathological study showing novel and fundamental insights into Purkinje cell injury, remodelling and repair in Friedreich's ataxia; the most common inherited ataxia. Analysing post-mortem cerebellum tissue from patients who had Friedreich's ataxia, we provide evidence of significant injury to the Purkinje cell axonal compartment with relative preservation of both the perikaryon and its extensive dendritic arborisation. Axonal remodelling of Purkinje cells was clearly elevated in the disease. For the first time in a genetic condition, we have also shown a disease-related increase in the frequency of Purkinje cell fusion and heterokaryon formation in Friedreich's ataxia cases; with evidence that underlying levels of cerebellar inflammation influence heterokaryon formation. Our results together further demonstrate the Purkinje cell's unique plasticity and regenerative potential. Elucidating the biological mechanisms behind these phenomena could have significant clinical implications for manipulating neuronal repair in response to neurological injury.