Endothelial peroxiredoxin-4 is indispensable for blood-brain barrier integrity and long-term functional recovery after ischemic stroke.

The endothelial lining of cerebral microvessels is damaged relatively early after cerebral ischemia/reperfusion (I/R) injury and mediates blood-brain barrier (BBB) disruption, neurovascular injury, and long-term neurological deficits. I/R induces BBB leakage within 1 h due to subtle structural alterations in endothelial cells (ECs), including reorganization of the actin cytoskeleton and subcellular redistribution of junctional proteins. Herein, we show that the protein peroxiredoxin-4 (Prx4) is an endogenous protectant against endothelial dysfunction and BBB damage in a murine I/R model. We observed a transient upregulation of Prx4 in brain ECs 6 h after I/R in wild-type (WT) mice, whereas tamoxifen-induced, selective knockout of Prx4 from endothelial cells (eKO) mice dramatically raised vulnerability to I/R. Specifically, eKO mice displayed more BBB damage than WT mice within 1 to 24 h after I/R and worse long-term neurological deficits and focal brain atrophy by 35 d. Conversely, endothelium-targeted transgenic (eTG) mice overexpressing Prx4 were resistant to I/R-induced early BBB damage and had better long-term functional outcomes. As demonstrated in cultures of human brain endothelial cells and in animal models of I/R, Prx4 suppresses actin polymerization and stress fiber formation in brain ECs, at least in part by inhibiting phosphorylation/activation of myosin light chain. The latter cascade prevents redistribution of junctional proteins and BBB leakage under conditions of Prx4 repletion. Prx4 also tempers microvascular inflammation and infiltration of destructive neutrophils and proinflammatory macrophages into the brain parenchyma after I/R. Thus, the evidence supports an indispensable role for endothelial Prx4 in safeguarding the BBB and promoting functional recovery after I/R brain injury.

Long-term open-label vebicorvir for chronic HBV infection: Safety and off-treatment responses.

Background & Aims: The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs). Methods: Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for ≥52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at 24 weeks off treatment. Results: Ninety-two patients entered the extension study and received VBR + NrtI. Long-term VBR + NrtI treatment led to continued suppression of HBV nucleic acids and, to a lesser extent, HBV antigens. Forty-three patients met criteria to discontinue VBR + NrtI, with no patients achieving the primary endpoint; the majority of virologic rebound occurred ≥4 weeks off treatment. Treatment was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no deaths. Most AEs and laboratory abnormalities were related to elevations in alanine aminotransferase and occurred during the off-treatment or NrtI-restart phases. No drug-drug interactions between VBR + NrtI and no cases of treatment-emergent resistance among patients who adhered to treatment were observed. Conclusions: Long-term VBR + NrtI was safe and resulted in continued reductions in HBV nucleic acids following completion of the 24-week parent studies. Following treatment discontinuation, virologic relapse was observed in all patients. This first-generation core inhibitor administered with NrtI for at least 52 weeks was not sufficient for HBV cure. Clinical trial number: NCT03780543. Impact and implications: Approved treatments for chronic hepatitis B virus infection (cHBV) suppress viral replication, but viral rebound is almost always observed after treatment discontinuation, highlighting an unmet need for improved therapies with finite treatment duration producing greater therapeutic responses that can be sustained off treatment. First-generation core inhibitors, such as vebicorvir, have mechanisms of action orthogonal to standard-of-care therapies that deeply suppress HBV viral replication during treatment; however, to date, durable virologic responses have not been observed after treatment discontinuation. The results reported here will help researchers with the design and interpretation of future studies investigating core inhibitors as possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir.

Establishing consensus recommendations for long-term osteoporosis care for patients who have attended an Australian fracture liaison service: a Delphi study.

Coordinating healthcare activities between fracture liaison services (FLS) and primary care is challenging. Using a Delphi technique, we developed 34 consensus statements to support improved care coordination across this healthcare transition. PURPOSE: Evidence supporting an optimal coordination strategy between fracture liaison services (FLS) and primary care is lacking. This study aimed to develop consensus statements to support consistency and benchmarking of clinical practice to improve coordination of care for patients transitioning from FLS to primary care following an osteoporotic fracture. METHODS: A Delphi technique was used to develop consensus among a panel of experts, including FLS clinicians (medical and non-medical), general practitioners (GPs), and consumers. RESULTS: Results of a preparatory questionnaire (n = 33) informed the development of 34 statements for review by expert panellists over two Delphi rounds (n = 25 and n = 19, respectively). The majority of participants were from New South Wales (82%), employed as FLS clinicians (78.8%) and working in metropolitan centres (60.6%). Consensus was achieved for 24/34 statements in round one and 8/10 statements in round two. All statements concerning patient education, communication, and the GP-patient relationship achieved consensus. Expert opinions diverged in some areas of clinician roles and responsibilities and long-term monitoring and management recommendations. CONCLUSION: We found clear consensus among experts in many key areas of FLS integration with primary care. While experts agreed that primary care is the most appropriate setting for long-term osteoporosis care, overall confidence in primary care systems to achieve this was low. The role of (and responsibility for) adherence monitoring in a resource-limited setting remains to be defined.

Synaptic Zn2+ contributes to deleterious consequences of spreading depolarizations.

Spreading depolarizations (SDs) are profound waves of neuroglial depolarization that can propagate repetitively through injured brain. Recent clinical work has established SD as an important contributor to expansion of acute brain injuries and have begun to extend SD studies into other neurological disorders. A critical challenge is to determine how to selectively prevent deleterious consequences of SD. In the present study, we determined whether a wave of profound Zn2+ release is a key contributor to deleterious consequences of SD, and whether this can be targeted pharmacologically. Focal KCl microinjection was used to initiate SD in the CA1 region of the hippocampus in murine brain slices. An extracellular Zn2+ chelator with rapid kinetics (ZX1) increased SD propagation rates and improved recovery of extracellular DC potential shifts. Under conditions of metabolic compromise, tissues showed sustained impairment of functional and structural recovery following a single SD. ZX1 effectively improved recovery of synaptic potentials and intrinsic optical signals in these vulnerable conditions. Fluorescence imaging and genetic deletion of a presynaptic Zn2+ transporter confirmed synaptic release as the primary contributor to extracellular accumulation and deleterious consequences of Zn2+ during SD. These results demonstrate a role for synaptic Zn2+ release in deleterious consequences of SD and show that targeted extracellular chelation could be useful for disorders where repetitive SD enlarges infarcts in injured tissues.

Reflux Symptoms Increase Following Sleeve Gastrectomy Despite Triage of Symptomatic Patients to Roux-en-Y Gastric Bypass.

BACKGROUND AND AIMS: Bariatric surgical options in obese patients include sleeve gastrectomy (SG) and roux-en-Y gastric bypass (RYGB), which may not be equivalent in risk of postoperative reflux symptoms. We evaluated risk and predictive factors for postbariatric surgery reflux symptoms. METHODS: Patients with obesity evaluated for bariatric surgery over a 15-month period were prospectively followed with validated symptom questionnaires (GERDQ, dominant symptom index: product of symptom frequency and intensity from 5-point Likert scores) administered before and after SG and RYGB. Esophageal testing included high-resolution manometry in all patients, and ambulatory reflux monitoring off therapy in those with abnormal GERDQ or prior reflux history. Univariate comparisons and multivariable analysis were performed to determine if preoperative factors predicted postoperative reflux symptoms. RESULTS: Sixty-four patients (median age 49.0 years, 84% female, median BMI 46.5 kg/m 2 ) fulfilled inclusion criteria and underwent follow-up assessment 4.4 years after bariatric surgery. Baseline GERDQ and dominant symptom index for heartburn were significantly higher in RYGB patients ( P ≤0.04). Despite this, median GERDQ increased by 2 (0.0 to 4.8) following SG and decreased by 0.5 (-1.0 to 5.0) following RYGB ( P =0.02). GERDQ became abnormal in 43.8% after SG and 18.8% after RYGB ( P =0.058); abnormal GERDQ improved in 12.5% and 37.5%, respectively ( P =0.041). In a model that included age, gender, BMI, acid exposure time, and type of surgery, multivariable analysis identified SG as an independent predictor of postoperative heartburn (odds ratio 16.61, P =0.024). CONCLUSIONS: Despite preferential RYGB when preoperative GERD was identified, SG independently predicted worsening heartburn symptoms after bariatric surgery.

Applied imagination.

Imagination is a fundamental human capacity, and to navigate our current global challenges, we need to define and encourage the practice of imagination, or what we term "applied imagination." In this study, we convened a series of focus groups or "virtual salons" to address three guiding questions: (1) How might we define imagination? (2) How might we (or should we) measure imagination? And (3) How might we foster imagination? Our efforts to define applied imagination highlight the crucial role imagination plays in human survival and thriving, the role of social forces in fostering or discouraging imagination, the connection between imagination and faith, and the "dark side" or maladaptive aspects of imagination. The discussions on measuring imagination were quite divided, with some salon participants arguing for the potential of indirect modes for measuring imaginative capacity while others argued that measuring imagination was functionally impossible and morally suspect. Finally, our results around fostering imagination suggest the importance of using play and humor, separating imaginative activities from the everyday, and employing constraints to prompt imaginative responses. We end with a discussion of possible directions for future research and a call to create a transdisciplinary field of imagination studies.

External Validation of a Urinary Biomarker Risk Score for the Prediction of Steroid Responsiveness in Adults With Nephrotic Syndrome.

Introduction: In idiopathic nephrotic syndrome, response to corticosteroids remains the best indicator of prognosis. Noninvasive markers to predict a patient's response to steroids would allow improved prognostication and a more personalized approach to management. We have previously derived a urinary biomarker risk score which can differentiate steroid sensitive nephrotic syndrome (SSNS) from steroid resistant nephrotic syndrome (SRNS) in children. The goal of this study was to validate this previously derived biomarker risk score in a cohort of steroid-naïve adult patients, to determine whether the panel could be used to predict steroid responsiveness at the time of initial diagnosis. Methods: In this external validation study, clinical data, and urinary specimens (obtained before initiation of steroid treatment) from adult patients were used in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. A panel of 5 previously identified and validated urinary biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), vitamin D binding protein (VDBP), Fetuin-A (FetA), Transthyretin (TTR), and alpha-1 acid glycoprotein 2 (AGP2) was measured. A summary risk score for steroid resistance was calculated based on biomarker concentrations. Receiver operating characteristic curves were created for each log-transformed biomarker concentration and for the individual and combined biomarker risk score. Results: The urine biomarker risk score predicted development of steroid resistance, with optimal sensitivity and specificity of 0.74, and area under the receiver operating characteristic curve (AUC) of 0.79 using both absolute and creatinine-corrected concentrations. Conclusion: This study validates the previously derived urinary biomarker risk score to predict steroid resistance in adult patients with nephrotic syndrome at initial diagnosis.

Synaptic Zn2+ contributes to deleterious consequences of spreading depolarizations.

Spreading depolarizations (SDs) are profound waves of neuroglial depolarization that can propagate repetitively through injured brain. Recent clinical work has established SD as an important contributor to expansion of acute brain injuries and have begun to extend SD studies into other neurological disorders. A critical challenge is to determine how to selectively prevent deleterious consequences of SD. In the present study, we determined whether a wave of profound Zn2+ release is a key contributor to deleterious consequences of SD, and whether this can be targeted pharmacologically. Focal KCl microinjection was used to initiate SD in the CA1 region of the hippocampus in murine brain slices. An extracellular Zn2+ chelator with rapid kinetics (ZX-1) increased SD propagation rates and improved recovery of extracellular DC potential shifts. Under conditions of metabolic compromise, tissues showed sustained impairment of functional and structural recovery following a single SD. ZX-1 effectively improved recovery of synaptic potentials and intrinsic optical signals in these vulnerable conditions. Fluorescence imaging and genetic deletion of a presynaptic Zn2+ transporter confirmed synaptic release as the primary contributor to extracellular accumulation and deleterious consequences of Zn2+ during SD. These results demonstrate a role for synaptic Zn2+ release in deleterious consequences of SD and show that targeted extracellular chelation could be useful for disorders where repetitive SD enlarges infarcts in injured tissues.

Investigation into the effect of hyperbaric hyperoxia on serum cardiac Troponin T levels as a biomarker of cardiac injury.

Introduction: There is clinical equipoise as to whether hyperoxia is injurious to the myocardium, both in the setting of acute ischaemic insults and on the stable myocardium. This study examined the effect of extreme hyperoxia - in the form of hyperbaric oxygen treatment - on the myocardium through measurement of high-sensitivity cardiac troponin. Methods: Forty-eight individuals were enrolled to undergo a series of 30 exposures to hyperbaric oxygen for treatment of non-cardiac pathologies. High-sensitivity troponin T was measured before and after each session. Results: There was no clinically significant difference in troponin measurements following acute or recurrent sequential exposures to extreme hyperoxia, despite the studied patient population having a high rate of previous ischaemic heart disease or cardiovascular risk factors. Conclusions: This study demonstrates that profound hyperoxaemia does not induce any measurable cardiac injury at a biochemical level. Neither is there a reduction in cardiac troponin to suggest a cardioprotective effect of hyperbaric hyperoxia. This provides some reassurance as to the cardiac safety of the routine use of hyperbaric oxygen treatment in management of non-cardiac pathology.

Differential effects of SARS-CoV-2 variants on central nervous system cells and blood-brain barrier functions.

BACKGROUND: Although mainly causing a respiratory syndrome, numerous neurological symptoms have been identified following of SARS-CoV-2 infection. However, how the virus affects the brain and how the mutations carried by the different variants modulate those neurological symptoms remain unclear. METHODS: We used primary human pericytes, foetal astrocytes, endothelial cells and a microglial cell line to investigate the effect of several SARS-CoV-2 variants of concern or interest on their functional activities. Cells and a 3D blood-brain barrier model were infected with the wild-type form of SARS-CoV-2, Alpha, Beta, Delta, Eta, or Omicron (BA.1) variants at various MOI. Cells and supernatant were used to evaluate cell susceptibility to the virus using a microscopic assay as well as effects of infection on (i) cell metabolic activity using a colorimetric MTS assay; (ii) viral cytopathogenicity using the xCELLigence system; (iii) extracellular glutamate concentration by fluorometric assay; and (iv) modulation of blood-brain barrier permeability. RESULTS: We demonstrate that productive infection of brain cells is SARS-CoV-2 variant dependent and that all the variants induce stress to CNS cells. The wild-type virus was cytopathic to all cell types except astrocytes, whilst Alpha and Beta variants were only cytopathic for pericytes, and the Omicron variant cytopathic for endothelial cells and pericytes. Lastly wild-type virus increases blood-brain barrier permeability and all variants, except Beta, modulate extracellular glutamate concentration, which can lead to excitotoxicity or altered neurotransmission. CONCLUSIONS: These results suggest that SARS-CoV-2 is neurotropic, with deleterious consequences for the blood-brain barrier integrity and central nervous system cells, which could underlie neurological disorders following SARS-CoV-2 infection.

Hyperbaric oxygen therapy for late radiation tissue injury.

BACKGROUND: This is the third update of the original Cochrane Review published in July 2005 and updated previously in 2012 and 2016. Cancer is a significant global health issue. Radiotherapy is a treatment modality for many malignancies, and about 50% of people having radiotherapy will be long-term survivors. Some will experience late radiation tissue injury (LRTI), developing months or years following radiotherapy. Hyperbaric oxygen therapy (HBOT) has been suggested as a treatment for LRTI based on the ability to improve the blood supply to these tissues. It is postulated that HBOT may result in both healing of tissues and the prevention of complications following surgery and radiotherapy. OBJECTIVES: To evaluate the benefits and harms of hyperbaric oxygen therapy (HBOT) for treating or preventing late radiation tissue injury (LRTI) compared to regimens that excluded HBOT. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 24 January 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing the effect of HBOT versus no HBOT on LRTI prevention or healing. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. survival from time of randomisation to death from any cause; 2. complete or substantial resolution of clinical problem; 3. site-specific outcomes; and 4. ADVERSE EVENTS: Our secondary outcomes were 5. resolution of pain; 6. improvement in quality of life, function, or both; and 7. site-specific outcomes. We used GRADE to assess certainty of evidence. MAIN RESULTS: Eighteen studies contributed to this review (1071 participants) with publications ranging from 1985 to 2022. We added four new studies to this updated review and evidence for the treatment of radiation proctitis, radiation cystitis, and the prevention and treatment of osteoradionecrosis (ORN). HBOT may not prevent death at one year (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.47 to 1.83; I2 = 0%; 3 RCTs, 166 participants; low-certainty evidence). There is some evidence that HBOT may result in complete resolution or provide significant improvement of LRTI (RR 1.39, 95% CI 1.02 to 1.89; I2 = 64%; 5 RCTs, 468 participants; low-certainty evidence) and HBOT may result in a large reduction in wound dehiscence following head and neck soft tissue surgery (RR 0.24, 95% CI 0.06 to 0.94; I2 = 70%; 2 RCTs, 264 participants; low-certainty evidence). In addition, pain scores in ORN improve slightly after HBOT at 12 months (mean difference (MD) -10.72, 95% CI -18.97 to -2.47; I2 = 40%; 2 RCTs, 157 participants; moderate-certainty evidence). Regarding adverse events, HBOT results in a higher risk of a reduction in visual acuity (RR 4.03, 95% CI 1.65 to 9.84; 5 RCTs, 438 participants; high-certainty evidence). There was a risk of ear barotrauma in people receiving HBOT when no sham pressurisation was used for the control group (RR 9.08, 95% CI 2.21 to 37.26; I2 = 0%; 4 RCTs, 357 participants; high-certainty evidence), but no such increase when a sham pressurisation was employed (RR 1.07, 95% CI 0.52 to 2.21; I2 = 74%; 2 RCTs, 158 participants; high-certainty evidence). AUTHORS' CONCLUSIONS: These small studies suggest that for people with LRTI affecting tissues of the head, neck, bladder and rectum, HBOT may be associated with improved outcomes (low- to moderate-certainty evidence). HBOT may also result in a reduced risk of wound dehiscence and a modest reduction in pain following head and neck irradiation. However, HBOT is unlikely to influence the risk of death in the short term. HBOT also carries a risk of adverse events, including an increased risk of a reduction in visual acuity (usually temporary) and of ear barotrauma on compression. Hence, the application of HBOT to selected participants may be justified. The small number of studies and participants, and the methodological and reporting inadequacies of some of the primary studies included in this review demand a cautious interpretation. More information is required on the subset of disease severity and tissue type affected that is most likely to benefit from this therapy, the time for which we can expect any benefits to persist and the most appropriate oxygen dose. Further research is required to establish the optimum participant selection and timing of any therapy. An economic evaluation should also be undertaken.

The Plant DNA C-Values Database: A One-Stop Shop for Plant Genome Size Data.

Genome size is a plant character with far-reaching implications, ranging from impacts on the financial and computing feasibility of sequencing and assembling genomes all the way to influencing the very ecology and evolution of species. The increasing recognition of the role of genome size in plant science has led to a rising demand for comprehensive and easily accessible sources of genome size data. The Plant DNA C-values database has established itself as a trusted and widely used central hub for users needing to access available plant genome size data, complemented with related cytogenetic (ploidy level) and karyological (chromosome number) information where available. Since its inception in 2001, the database has undergone six major updates to incorporate newly available genome size information, leading to the most recent release (Release 7.1), which comprises data for 12,273 species across all the major land plant and some algal lineages. Here we describe how to use the database efficiently, making use of its different query and filtering settings.

Experiences of pain and pain management in advanced disease and serious illness for people from South Asian communities in Leeds and Bradford: a qualitative interview study.

BACKGROUND: Pain is a significant problem for many people with advanced disease or a serious illness. Culture and ethnicity can affect the experience and management of pain. However, there is limited research in South Asian communities in the UK on their experiences of pain. The aim of this study is to explore the experiences and attitudes of patients and family carers from South Asian communities about pain and its management within advanced disease or serious illness. METHODS: Qualitative thematic analysis based on descriptive phenomenology (Sundler et al. 2019). Qualitative semi-structured interviews with patients or family carers from South Asian communities (N = 15). Interviews were recorded, transcribed and analysed using an inductive approach. Public and Patient Involvement representatives from British South Asian communities were consulted for guidance. RESULTS: There were five key themes from the interviews: The importance of communication about pain with healthcare professionals; Concerns about taking pain medication; Personal resilience, privacy and self-management; Gender, culture and pain; Home pain management as struggle and frustration. CONCLUSION: To improve pain management for people from South Asian communities with advanced disease or a serious illness, there are a number of important issues for healthcare professionals from palliative and primary care services to address. These include: greater awareness around people's fears and concerns about pain medication; their potential use of alternative pain management strategies; and cultural issues such as resilience, privacy, dignity and gender roles. Effective communication between doctors, patients and family members could be improved by using a 'cultural humility' model; providing clear and accessible pain medication information; understanding and taking account of people with both low, and medium levels, of English language proficiency; and improving patient trust. Additionally, improvements to out of hours services could improve pain management for all patients managing their pain at home.

Leveraging single-cell RNA sequencing to unravel the impact of aging on stroke recovery mechanisms in mice.

Aging compromises the repair and regrowth of brain vasculature and white matter during stroke recovery, but the underlying mechanisms remain elusive. To understand how aging jeopardizes brain tissue repair after stroke, we performed single-cell transcriptomic profiling of young adult and aged mouse brains at acute (3 d) and chronic (14 d) stages after ischemic injury, focusing a priori on the expression of angiogenesis- and oligodendrogenesis-related genes. We identified unique subsets of endothelial cells (ECs) and oligodendrocyte (OL) progenitors in proangiogenesis and pro-oligodendrogenesis phenotypic states 3 d after stroke in young mice. However, this early prorepair transcriptomic reprogramming was negligible in aged stroke mice, consistent with the impairment of angiogenesis and oligodendrogenesis observed during the chronic injury stages after ischemia. In the stroke brain, microglia and macrophages (MG/MΦ) may drive angiogenesis and oligodendrogenesis through a paracrine mechanism. However, this reparative cell-cell cross talk between MG/MΦ and ECs or OLs is impeded in aged brains. In support of these findings, permanent depletion of MG/MΦ via antagonism of the colony-stimulating factor 1 receptor resulted in remarkably poor neurological recovery and loss of poststroke angiogenesis and oligodendrogenesis. Finally, transplantation of MG/MΦ from young, but not aged, mouse brains into the cerebral cortices of aged stroke mice partially restored angiogenesis and oligodendrogenesis and rejuvenated sensorimotor function and spatial learning and memory. Together, these data reveal fundamental mechanisms underlying the age-related decay in brain repair and highlight MG/MΦ as effective targets for promoting stroke recovery.

Stretching a Penny: Completing a Rapid Needs Assessment for a Nonprofit Community-Based Hospice Wellness Center in Ontario, Canada.

The literature pertaining to community-based hospice wellness centres, especially concerning program evaluation, is sparse. This article describes the development and implementation of a mixed-method, rapid needs assessment for a nonprofit community-based hospice wellness centre in Ontario, Canada. As part of the needs assessment, a survey and focus groups were performed to elicit responses from service users. Individuals registered for services and wellness centre attendees were asked about their needs, opinions, and preferences to help guide future program and service options. Findings and recommendations are presented for programming and service options, and implications for future program evaluation projects are discussed. The methodology of this time and cost-efficient evaluation provides insights that can be utilized by other hospice wellness centres facing similar challenges of time, money, and program evaluation expertise constraints. The findings and recommendations may inform program and service offerings at other Canadian hospice wellness centres.

A systematic review of subcutaneous versus intramuscular or intravenous routes of opioid administration on pain outcomes in cancer and post-surgical clinical populations - challenging current assumptions in palliative care practice.

Objective: The objective of this review is to investigate the use of the subcutaneous route of administration of analgesics, common practice within palliative medicine. Design: Systematic review using consensus approach, direct comparison of subcutaneous route with intravenous and intramuscular routes. Results: The limited available evidence demonstrates non-inferiority of the subcutaneous route in both cancer patients and those post-surgery. Pain management is comparable to other routes. Route-related side effects are rare and systemic side effects are comparable. Conclusion: Pain management is a critical role of palliative medicine. The subcutaneous route of administration offers a viable option for the delivery of parenteral analgesia within all settings, including the community. This review supports current practice, demonstrating equivalence with more invasive routes of administration.

Exploring barriers and opportunities to improve osteoporosis care across the acute-to-primary care interface: a qualitative study.

This qualitative study interviewed general practitioners, patients, and FLS clinicians and identified key challenges facing stakeholders seeking to improve post-fracture osteoporosis care. Local policies and care pathways as an initial strategy may address information and service delivery issues across the acute-primary care divide. INTRODUCTION: Fracture liaison services (FLS) can be effective for secondary fracture prevention, but long-term adherence to therapies remains suboptimal. Few studies have explored how services manage the transition between tertiary and primary post-fracture care. This study mapped service processes and factors influencing integration of post-clinic care, identifying barriers, supports, and opportunities for seamless healthcare. METHODS: Qualitative descriptive study using semi-structured interviews with FLS stakeholders at two metropolitan hospitals in New South Wales (NSW) and surrounding general practices. RESULTS: Seven FLS clinicians, 11 general practitioners (GPs), and seven patients were interviewed. Six key themes emerged on the transition of patient care from tertiary to primary care (PC). Interprofessional communication issues and role ambiguity posed threats to seamless care. Delayed, absent, inaccessible, or poor-quality communication frustrated GPs, while FLS clinicians lacked confidence in existing communication systems and desired bidirectional communication with PC. GPs were confident managing osteoporosis, but FLS clinicians had limited confidence that patients would discuss osteoporosis with their GP and that GPs would action recommendations. Effective PC follow-up required a positive GP-patient relationship and that patients perceived a need to engage with PC. Patient understanding of osteoporosis (influenced by patient education, knowledge, beliefs, and health behaviours) affected PC attendance. Limited public awareness of osteoporosis and healthcare policy deficits contributed to care gaps. CONCLUSION: Key challenges were identified facing stakeholders seeking to improving post-clinic osteoporosis care. Development and implementation of local, integrated acute-community policies and care pathways as an initial intervention may address information and service delivery issues across the acute-PC divide.

Characteristics of good home-based end-of-life care: analysis of 5-year data from a nationwide mortality follow-back survey in England.

BACKGROUND: Recently, there has been an emphasis on providing good-quality end-of-life care; however, little is known about it and its determinants for patients living at home. AIM: To determine what characterises good-quality end-of-life care for patients living at home. DESIGN AND SETTING: An observational study using 5-year data from the National Survey of Bereaved People (Views of Informal Carers - Evaluation of Services [VOICES]) in England. METHOD: Analysis was based on data for 63 598 decedents, who were cared for at home in the last 3 months of life. Data were drawn from 110 311 completed mortality follow-back surveys of a stratified sample of 246 763 deaths registered in England between 2011 and 2015. Logistic regression analyses were used to identify independent variables associated with overall quality of end-of-life care and other indicators of end-of-life care quality. RESULTS: Patients who received good continuity of primary care (adjusted odds ratio [AOR] 2.03; 95% confidence interval [CI] = 2.01 to 2.06) and palliative care support (AOR 1.86; 95% CI = 1.84 to 1.89) experienced better overall quality of end-of-life care than those who did not, as perceived by relatives. Decedents who died from cancer (AOR 1.05; 95% CI = 1.03 to 1.06) or outside of hospital were more likely to receive good end-of-life care, as perceived by relatives. Being older, female (AOR 1.16; 95% CI = 1.15 to 1.17), from areas with least socioeconomic deprivation, and White (AOR 1.09; 95% CI = 1.06 to 1.12) were associated with better overall end-of-life care, as perceived by relatives. CONCLUSION: Better quality of end-of-life care was associated with good continuity of primary care, specialist palliative care support, and death outside of hospital. Disparities still exist for those from minority ethnic groups and those living in areas of socioeconomic deprivation. Future commissioning and initiatives must consider these variables to provide a more-equitable service.

Interleukin-4 mitigates anxiety-like behavior and loss of neurons and fiber tracts in limbic structures in a microglial PPARγ-dependent manner after traumatic brain injury.

Traumatic brain injury (TBI) is commonly followed by intractable psychiatric disorders and long-term changes in affect, such as anxiety. The present study sought to investigate the effect of repetitive intranasal delivery of interleukin-4 (IL-4) nanoparticles on affective symptoms after TBI in mice. Adult male C57BL/6 J mice (10-12 weeks of age) were subjected to controlled cortical impact (CCI) and assessed by a battery of neurobehavioral tests up to 35 days after CCI. Neuron numbers were counted in multiple limbic structures, and the integrity of limbic white matter tracts was evaluated using ex vivo diffusion tensor imaging (DTI). As STAT6 is a critical mediator of IL-4-specific transcriptional activation, STAT6 knockout mice were used to explore the role of endogenous IL-4/STAT6 signaling axis in TBI-induced affective disorders. We also employed microglia/macrophage (Mi/Mϕ)-specific PPARγ conditional knockout (mKO) mice to test if Mi/Mϕ PPARγ critically contributes to IL-4-afforded beneficial effects. We observed anxiety-like behaviors up to 35 days after CCI, and these measures were exacerbated in STAT6 KO mice but mitigated by repetitive IL-4 delivery. We discovered that IL-4 protected against neuronal loss in limbic structures, such as the hippocampus and the amygdala, and improved the structural integrity of fiber tracts connecting the hippocampus and amygdala. We also observed that IL-4 boosted a beneficial Mi/Mϕ phenotype (CD206+/Arginase 1+/PPARγ+ triple-positive) in the subacute injury phase, and that the numbers of Mi/Mϕ appositions with neurons were robustly correlated with long-term behavioral performances. Remarkably, PPARγ-mKO completely abolished IL-4-afforded protection. Thus, CCI induces long-term anxiety-like behaviors in mice, but these changes in affect can be attenuated by transnasal IL-4 delivery. IL-4 prevents the long-term loss of neuronal somata and fiber tracts in key limbic structures, perhaps due to a shift in Mi/Mϕ phenotype. Exogenous IL-4 therefore holds promise for future clinical management of mood disturbances following TBI.

Libyan Healthcare Professionals', Patients' and Caregivers' Perceptions and Religious Beliefs about Cancer Pain and its Management: A Descriptive Qualitative Study.

Cancer pain remains a significant problem worldwide. It is often undertreated and presents in about half of cancer patients. Although several guidelines and pharmacological interventions for cancer pain management (CPM) exist, inadequate assessment and undertreatment of cancer pain are well-documented globally, especially in developing countries, including Libya. Perceptions, cultural and religious beliefs of healthcare professionals (HCP), patients, and caregivers about cancer pain and opioids are reported as barriers to CPM globally. This qualitative descriptive study aimed to explore Libyan HCPs', patients', and caregivers' views and religious beliefs about CPM and involved semi-structured interviews with 36 participants: 18 Libyan cancer patients, 6 caregivers, and 12 Libyan HCPs. Thematic analysis was used to analyse the data. Patients, caregivers, and newly qualified HCPs were concerned about poor tolerance and drug addiction. HCPs perceived a lack of policies and guidelines, pain rating scales, and professional education and training as CPM barriers. Some patients were unable to pay for medicines if they faced financial difficulties. Instead, patients and caregivers emphasised religious and cultural beliefs for managing cancer pain, including the use of the Qur'an and cautery. Our results suggest that religious and cultural beliefs, lack of knowledge and training in CPM among HCPs, and economic and Libyan healthcare system-related factors negatively affect CPM in Libya.