Process of Withdrawal of Mechanical Ventilation at End of Life in the ICU: Clinician Perceptions.

BACKGROUND: Nearly one-quarter of all Americans die in the ICU. Many of their deaths are anticipated and occur following the withdrawal of mechanical ventilation (WMV). However, there are few data on which to base best practices for interdisciplinary ICU teams to conduct WMV. RESEARCH QUESTION: What are the perceptions of current WMV practices among ICU clinicians, and what are their opinions of processes that might improve the practice of WMV at end of life in the ICU? STUDY DESIGN AND METHODS: This prospective two-center observational study conducted in Boston, Massachusetts, the Observational Study of the Withdrawal of Mechanical Ventilation (OBSERVE-WMV) was designed to better understand the perspectives of clinicians and experience of patients undergoing WMV. This report focuses on analyses of qualitative data obtained from in-person surveys administered to the ICU clinicians (nurses, respiratory therapists, and physicians) caring for these patients. Surveys assessed a broad range of clinician perspectives on planning, as well as the key processes required for WMV. This analysis used independent open, inductive coding of responses to open-ended questions. Initial codes were reconciled iteratively and then organized and interpreted using a thematic analysis approach. Opinions were assessed on how WMV could be improved for individual patients and the ICU as a whole. RESULTS: Among 456 eligible clinicians, 312 in-person surveys were completed by clinicians caring for 152 patients who underwent WMV. Qualitative analyses identified two main themes characterizing high-quality WMV processes: (1) good communication (eg, mutual understanding of family preferences) between the ICU team and family; and (2) medical management (eg, planning, availability of ICU team) that minimizes patient distress. Team member support was identified as an essential process component in both themes. INTERPRETATION: Clinician perceptions of the appropriateness or success of WMV prioritize the quality of team and family communication and patient symptom management. Both are modifiable targets of interventions aimed at optimizing overall WMV.

Repeat tracheal aspirate cultures in pediatric intensive care patients: Frequency, resistance, and antimicrobial use.

OBJECTIVE: To evaluate the clinical impact and features associated with repeat tracheal aspirate (TA) cultures in children admitted to the intensive care unit. DESIGN: Retrospective cohort study. SETTING: A 338-bed freestanding, tertiary pediatric academic medical center with pediatric medical intensive care unit (PICU) and cardiac intensive care units (CICU). PATIENTS: Children ≤18 years of age who were admitted to either the PICU or CICU who had ≥2 TA cultures in a single intensive care admission. METHODS: Patients with ≥2 TA cultures between 2018 and 2019 were included in this study. The following information was collected: patient demographics, clinical data summarizing patient condition at the time of culture collection, number of TA cultures per patient, antibiotic usage, and microbiologic data. Descriptive statistics established the frequency of TA collection, time between culturing, clinical reasoning for collection, antibiotic exposure, and development of multidrug-resistant organisms (MDRO). RESULTS: Sixty-three patients had repeat TA cultures and accounted for 252 TA cultures during the study period. Most patients with repeat TA cultures were admitted to the PICU (71%) and were male (65%). A median of 3 TA cultures per patient were obtained with 50% of repeat cultures occurring within 7 days from the previous culture. Sixty-six percent of patients had the same organism cultured on ≥2 TA cultures. Most antibiotics were not modified or continued to treat the results of the TA culture. CONCLUSIONS: Repeat TA cultures frequently show the same pathogens, and results do not often influence antibiotic selection or usage. Repeat TA cultures did demonstrate the development of MDROs.

Dyspnoea in acutely ill mechanically ventilated adult patients: an ERS/ESICM statement.

This statement outlines a review of the literature and current practice concerning the prevalence, clinical significance, diagnosis and management of dyspnoea in critically ill, mechanically ventilated adult patients. It covers the definition, pathophysiology, epidemiology, short- and middle-term impact, detection and quantification, and prevention and treatment of dyspnoea. It represents a collaboration of the European Respiratory Society and the European Society of Intensive Care Medicine. Dyspnoea ranks among the most distressing experiences that human beings can endure. Approximately 40% of patients undergoing invasive mechanical ventilation in the intensive care unit (ICU) report dyspnoea, with an average intensity of 45 mm on a visual analogue scale from 0 to 100 mm. Although it shares many similarities with pain, dyspnoea can be far worse than pain in that it summons a primal fear response. As such, it merits universal and specific consideration. Dyspnoea must be identified, prevented and relieved in every patient. In the ICU, mechanically ventilated patients are at high risk of experiencing breathing difficulties because of their physiological status and, in some instances, because of mechanical ventilation itself. At the same time, mechanically ventilated patients have barriers to signalling their distress. Addressing this major clinical challenge mandates teaching and training, and involves ICU caregivers and patients. This is even more important because, as opposed to pain which has become a universal healthcare concern, very little attention has been paid to the identification and management of respiratory suffering in mechanically ventilated ICU patients.

Dyspnoea in acutely ill mechanically ventilated adult patients: an ERS/ESICM statement.

This statement outlines a review of the literature and current practice concerning the prevalence, clinical significance, diagnosis and management of dyspnoea in critically ill, mechanically ventilated adult patients. It covers the definition, pathophysiology, epidemiology, short- and middle-term impact, detection and quantification, and prevention and treatment of dyspnoea. It represents a collaboration of the European Respiratory Society (ERS) and the European Society of Intensive Care Medicine (ESICM). Dyspnoea ranks among the most distressing experiences that human beings can endure. Approximately 40% of patients undergoing invasive mechanical ventilation in the intensive care unit (ICU) report dyspnoea, with an average intensity of 45 mm on a visual analogue scale from 0 to 100 mm. Although it shares many similarities with pain, dyspnoea can be far worse than pain in that it summons a primal fear response. As such, it merits universal and specific consideration. Dyspnoea must be identified, prevented and relieved in every patient. In the ICU, mechanically ventilated patients are at high risk of experiencing breathing difficulties because of their physiological status and, in some instances, because of mechanical ventilation itself. At the same time, mechanically ventilated patients have barriers to signalling their distress. Addressing this major clinical challenge mandates teaching and training, and involves ICU caregivers and patients. This is even more important because, as opposed to pain which has become a universal healthcare concern, very little attention has been paid to the identification and management of respiratory suffering in mechanically ventilated ICU patients.

Effectiveness of an Algorithmic Approach to Ventilator Withdrawal at the End of Life: A Stepped Wedge Cluster Randomized Trial.

Background: The transition to spontaneous breathing puts patients who are undergoing ventilator withdrawal at high risk for developing respiratory distress. A patient-centered algorithmic approach could standardize this process and meet unique patient needs because a single approach (weaning vs. one-step extubation) does not capture the needs of a heterogenous population undergoing this palliative procedure. Objectives: (1) Demonstrate that the algorithmic approach can be effective to ensure greater patient respiratory comfort compared to usual care; (2) determine differences in opioid or benzodiazepine use; (3) predict factors associated with duration of survival. Design/Settings/Measures: A stepped-wedge cluster randomized design at five sites was used. Sites crossed over to the algorithm in random order after usual care data were obtained. Patient comfort was measured with the Respiratory Distress Observation Scale© (RDOS) at baseline, at ventilator off, and every 15-minutes for an hour. Parenteral morphine and lorazepam equivalents from the onset of the process until patient death were calculated. Results: Usual care data n = 120, algorithm data n = 48. Gender and race were evenly distributed. All patients in the usual care arm underwent a one-step ventilator cessation; 58% of patients in the algorithm arm were weaned over an average of 18 ± 27 minutes as prescribed in the algorithm. Patients had significantly less respiratory distress in the intervention arm (F = 10.41, p = 0.0013, effective size [es] = 0.49). More opioids (t = -2.30, p = 0.023) and benzodiazepines (t = -2.08, p = 0.040) were given in the control arm. Conclusions: The algorithm was effective in ensuring patient respiratory comfort. Surprisingly, more medication was given in the usual care arm; however, less may be needed when distress is objectively measured (RDOS), and treatment is initiated as soon as distress develops as in the algorithm. Clinical Trial Registration number: NCT03121391.

Psychometric Properties of the Piper Fatigue Scale-12.

Background and Purpose: The Piper Fatigue Scale (PFS)-12 is a recently shortened version of the original PFS that has 40 items. Psychometric evidence for PFS-12 from a small sample of individuals on hemodialysis is presented. Methods: The psychometric analysis with pilot data was done using a detailed item analysis, including Bland-Altman plots, exploratory factor analysis of pre- and post-item scores, and item change scores. Additional measures were used to investigate the validity including the Patient-Reported Outcomes Measurement Information System-Fatigue Scale and the 6-minute walk test. Results: The sample consisted of 86 hemodialysis individuals. The internal consistency reliability of the PFS-12 total scale was 0.91 (pre), 0.95 (post), and subscale alphas were 0.79-0.94. Convergent, concurrent, and predictive validity of PFS-12 were supported. Construct validity of PFS-12 was confirmed predialysis and partially supported in the change score analysis. Conclusion: The brief 12-item PFS is a good alternative to the longer version of this scale to reduce the respondent burden and measure the overall fatigue; further validation in test-retest situations and subscale validity is needed.

Evidence Guiding Withdrawal of Mechanical Ventilation at the End of Life: A Review.

OBJECTIVE: Distress at the end of life in the intensive care unit (ICU) is common. We reviewed the evidence guiding symptom assessment, withdrawal of mechanical ventilation (WMV) process, support for the ICU team, and symptom management among adults, and specifically older adults, at end of life in the ICU. SETTING AND DESIGN: Systematic search of published literature (January 1990-December 2021) pertaining to WMV at end of life among adults in the ICU setting using PubMed, Embase, and Web of Science. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. PARTICIPANTS: Adults (age 18 and over) undergoing WMV in the ICU. MEASUREMENTS: Study quality was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Out of 574 articles screened, 130 underwent full text review, and 74 were reviewed and assessed for quality. The highest quality studies pertained to use of validated symptom scales during WMV. Studies of the WMV process itself were generally lower quality. Support for the ICU team best occurs via structured communication and social supports. Dyspnea is the most distressing symptom, and while high quality evidence supports the use of opiates, there is limited evidence to guide implementation of their use for specific patients. CONCLUSION: High quality studies support some practices in palliative WMV, while gaps in evidence remain for the WMV process, supporting the ICU team, and medical management of distress. Future studies should rigorously compare WMV processes and symptom management to reduce distress at end of life.

Intravenous injection of adipose-derived mesenchymal stromal cells benefits gait and inflammation in a spontaneous osteoarthritis model.

Osteoarthritis (OA) is a leading cause of morbidity among aging populations, yet symptom and/or disease-modification remains elusive. Adipose-derived mesenchymal stromal cells (adMSCs) have demonstrated immunomodulatory and anti-inflammatory properties that may alleviate clinical signs and interrupt disease onset and progression. Indeed, multiple manuscripts have evaluated intra-articular administration of adMSCs as a therapeutic; however, comparatively few evaluations of systemic delivery methods have been published. Therefore, the aim of this study was to evaluate the short-term impact of intravenous (IV) delivery of allogeneic adMSCs in an established model of spontaneous OA, the Hartley guinea pig. Animals with moderate OA received once weekly injections of 2 × 106 adMSCs or vehicle control for 4 weeks in peripheral veins; harvest occurred 2 weeks after the final injection. Systemic administration of adMSCs resulted in no adverse effects and was efficacious in reducing clinical signs of OA (as assessed by computer-aided gait analysis) compared to control injected animals. Further, there were significant decreases in key inflammatory mediators (including monocyte chemoattractant protein-1, tumor necrosis factor, and prostaglandin E2 ) both systemically (liver, kidney, and serum) and locally in the knee (joint tissues and synovial fluid) in animals treated with IV adMSCs relative to controls (as per enzyme-linked immunosorbent assay and/or immunohistochemistry, dictated by tissue sample). Thus, systemic administration of adMSCs by IV injection significantly improved gait parameters and reduced both systemic and intra-articular inflammatory mediators in animals with OA. These findings demonstrate the potential utility of alternative delivery approaches for cellular therapy of OA, particularly for patients with multiple affected joints.

Phytochemical compound PB125 attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a model of musculoskeletal decline.

Impaired mitochondrial function and disrupted proteostasis contribute to musculoskeletal dysfunction. However, few interventions simultaneously target these two drivers to prevent musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) activates a transcriptional programme promoting cytoprotection, metabolism, and proteostasis. We hypothesized daily treatment with a purported Nrf2 activator, PB125, in Hartley guinea pigs, a model of musculoskeletal decline, would attenuate the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis and preserve musculoskeletal function. We treated 2- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical compound PB125. Longitudinal assessments of voluntary mobility were measured using Any-MazeTM open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in soleus muscles was measured using high resolution respirometry. In both sexes, PB125 (1) increased electron transfer system capacity; (2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and (3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial and cytosolic subfractions of the soleus. These effects were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, treatment with PB125 contributed to maintenance of skeletal muscle mitochondrial respiration and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these documented effects of PB125 are also accompanied by slowed progression of other aspects of musculoskeletal dysfunction. KEY POINTS: Aside from exercise, there are no effective interventions for musculoskeletal decline, which begins in the fifth decade of life and contributes to disability and cardiometabolic diseases. Targeting both mitochondrial dysfunction and impaired protein homeostasis (proteostasis), which contribute to the age and disease process, may mitigate the progressive decline in overall musculoskeletal function (e.g. gait, strength). A potential intervention to target disease drivers is to stimulate nuclear factor erythroid 2-related factor 2 (Nrf2) activation, which leads to the transcription of genes responsible for redox homeostasis, proteome maintenance and mitochondrial energetics. Here, we tested a purported phytochemical Nrf2 activator, PB125, to improve mitochondrial function and proteostasis in male and female Hartley guinea pigs, which are a model for musculoskeletal ageing. PB125 improved mitochondrial respiration and attenuated disease- and age-related declines in skeletal muscle protein synthesis, a component of proteostasis, in both male and female Hartley guinea pigs.

Early removal of the infrapatellar fat pad/synovium complex beneficially alters the pathogenesis of moderate stage idiopathic knee osteoarthritis in male Dunkin Hartley guinea pigs.

BACKGROUND: The infrapatellar fat pad (IFP) is the largest adipose deposit in the knee; however, its contributions to the homeostasis of this organ remain undefined. To determine the influence of the IFP and its associated synovium (IFP/synovium complex or IFP/SC) on joint health, this study evaluated the progression of osteoarthritis (OA) following excision of this unit in a rodent model of naturally-occurring disease. METHODS: Male Dunkin-Hartley guinea pigs (n=18) received surgical removal of the IFP in one knee at 3 months of age; contralateral knees received sham surgery as matched internal controls. Mobility and gait assessments were performed prior to IFP/SC removal and monthly thereafter. Animals were harvested at 7 months of age. Ten set of these knees were processed for microcomputed tomography (microCT), histopathology, transcript expression analyses, and immunohistochemistry (IHC); 8 sets of knees were dedicated to microCT and biomechanical testing (material properties of knee joints tissues and anterior drawer laxity). RESULTS: Fibrous connective tissue (FCT) developed in place of the native adipose depot. Gait demonstrated no significant differences between IFP/SC removal and contralateral hindlimbs. MicroCT OA scores were improved in knees containing the FCT. Quantitatively, IFP/SC-containing knees had more osteophyte development and increased trabecular volume bone mineral density (vBMD) in femora and tibiae. Histopathology confirmed maintenance of articular cartilage structure, proteoglycan content, and chondrocyte cellularity in FCT-containing knees. Transcript analyses revealed decreased expression of adipose-related molecules and select inflammatory mediators in FCTs compared to IFP/SCs. This was verified via IHC for two key inflammatory agents. The medial articular cartilage in knees with native IFP/SCs showed an increase in equilibrium modulus, which correlated with increased amounts of magnesium and phosphorus. DISCUSSION/CONCLUSION: Formation of the FCT resulted in reduced OA-associated changes in both bone and cartilage. This benefit may be associated with: a decrease in inflammatory mediators at transcript and protein levels; and/or improved biomechanical properties. Thus, the IFP/SC may play a role in the pathogenesis of knee OA in this strain, with removal prior to disease onset appearing to have short-term benefits.

Palliative Care Early in the Care Continuum among Patients with Serious Respiratory Illness: An Official ATS/AAHPM/HPNA/SWHPN Policy Statement.

Background: Patients with serious respiratory illness and their caregivers suffer considerable burdens, and palliative care is a fundamental right for anyone who needs it. However, the overwhelming majority of patients do not receive timely palliative care before the end of life, despite robust evidence for improved outcomes. Goals: This policy statement by the American Thoracic Society (ATS) and partnering societies advocates for improved integration of high-quality palliative care early in the care continuum for patients with serious respiratory illness and their caregivers and provides clinicians and policymakers with a framework to accomplish this. Methods: An international and interprofessional expert committee, including patients and caregivers, achieved consensus across a diverse working group representing pulmonary-critical care, palliative care, bioethics, health law and policy, geriatrics, nursing, physiotherapy, social work, pharmacy, patient advocacy, psychology, and sociology. Results: The committee developed fundamental values, principles, and policy recommendations for integrating palliative care in serious respiratory illness care across seven domains: 1) delivery models, 2) comprehensive symptom assessment and management, 3) advance care planning and goals of care discussions, 4) caregiver support, 5) health disparities, 6) mass casualty events and emergency preparedness, and 7) research priorities. The recommendations encourage timely integration of palliative care, promote innovative primary and secondary or specialist palliative care delivery models, and advocate for research and policy initiatives to improve the availability and quality of palliative care for patients and their caregivers. Conclusions: This multisociety policy statement establishes a framework for early palliative care in serious respiratory illness and provides guidance for pulmonary-critical care clinicians and policymakers for its proactive integration.

The feasibility of using an autologous GM-CSF-secreting breast cancer vaccine to induce immunity in patients with stage II-III and metastatic breast cancers.

PURPOSE: The antigenic targets of immunity and the role of vaccination in breast cancer are unknown. We performed a phase I study of an autologous GM-CSF-secreting breast cancer vaccine in patients with metastatic and stage II-III breast cancer. METHODS: Tumor cells from patients with metastatic (n = 15) and stage II-III (n = 7) disease were transduced with a replication-defective adenoviral vector encoding GM-CSF, and then irradiated. Twelve and seven patients with metastatic and stage II-III disease, respectively, received weekly vaccination for three weeks, followed by every other week until disease progression or vaccine supply was exhausted (metastatic) or until six total vaccine doses were administered (stage II-III). RESULTS: Among those patients with metastatic disease who received vaccinations, eight had progressive disease at two months, three had stable disease for 4-13 months, and one has had no evidence of disease for 13 years. Of the patients with stage II-III disease, five died of metastatic disease between 1.16 and 8.49 years after the start of vaccinations (median 6.24 years) and two are alive as of September 2021. Toxicities included injection site reactions, fatigue, fever, upper respiratory symptoms, joint pain, nausea, and edema. Four of five evaluable patients with metastatic disease developed a skin reaction with immune cell infiltration after the fifth injection of unmodified, irradiated tumor cells. CONCLUSION: We conclude that tumor cells can be harvested from patients with metastatic or stage II-III breast cancer to prepare autologous GM-CSF-secreting vaccines that induce coordinated immune responses with limited toxicity. TRIAL REGISTRATION AND DATE OF REGISTRATION: clinicaltrials.gov, NCT00317603 (April 25, 2006) and NCT00880464 (April 13, 2009).

Evaluation of the Victorian Healthy Homes Program: protocol for a randomised controlled trial.

INTRODUCTION: The evaluation of the Victorian Healthy Homes Program (VHHP) will generate evidence about the efficacy and cost-effectiveness of home upgrades to improve thermal comfort, reduce energy use and produce health and economic benefits to vulnerable households in Victoria, Australia. METHODS AND ANALYSIS: The VHHP evaluation will use a staggered, parallel group clustered randomised controlled trial to test the home energy intervention in 1000 households. All households will receive the intervention either before (intervention group) or after (control group) winter (defined as 22 June to 21 September). The trial spans three winters with differing numbers of households in each cohort. The primary outcome is the mean difference in indoor average daily temperature between intervention and control households during the winter period. Secondary outcomes include household energy consumption and residential energy efficiency, self-reported respiratory symptoms, health-related quality of life, healthcare utilisation, absences from school/work and self-reported conditions within the home. Linear and logistic regression will be used to analyse the primary and secondary outcomes, controlling for clustering of households by area and the possible confounders of year and timing of intervention, to compare the treatment and control groups over the winter period. Economic evaluation will include a cost-effectiveness and cost-benefit analysis. ETHICS AND DISSEMINATION: Ethical approval was received from Victorian Department of Human Services Human Research Ethics Committee (reference number: 04/17), University of Technology Sydney Human Research Ethics Committee (reference number: ETH18-2273) and Australian Government Department of Veterans Affairs. Study results will be disseminated in a final report and peer-reviewed journals. TRIAL REGISTRATION NUMBER: ACTRN12618000160235.

Health care cost of crusted scabies in Aboriginal communities in the Northern Territory, Australia.

BACKGROUND: Crusted scabies is a debilitating dermatological condition. Although still relatively rare in the urban areas of Australia, rates of crusted scabies in remote Aboriginal communities in the Northern Territory (NT) are reported to be among the highest in the world. OBJECTIVE: To estimate the health system costs associated with diagnosing, treating and managing crusted scabies. METHODS: A disease pathway model was developed to identify the major phases of managing crusted scabies. In recognition of the higher resource use required to treat more severe cases, the pathway differentiates between crusted scabies severity grades. The disease pathway model was populated with data from a clinical audit of 42 crusted scabies patients diagnosed in the Top-End of Australia's Northern Territory between July 1, 2016 and May 1, 2018. These data were combined with standard Australian unit costs to calculate the expected costs per patient over a 12-month period, as well as the overall population cost for treating crusted scabies. FINDINGS: The expected health care cost per patient diagnosed with crusted scabies is $35,418 Australian dollars (AUD) (95% CI: $27,000 to $43,800), resulting in an overall cost of $1,558,392AUD (95% CI: $1,188,000 to $1,927,200) for managing all patients diagnosed in the Northern Territory in a given year (2018). By far, the biggest component of the health care costs falls on the hospital system. DISCUSSION: This is the first cost-of-illness analysis for treating crusted scabies. Such analysis will be of value to policy makers and researchers by informing future evaluations of crusted scabies prevention programs and resource allocation decisions. Further research is needed on the wider costs of crusted scabies including non-financial impacts such as the loss in quality of life as well as the burden of care and loss of well-being for patients, families and communities.

Dyspnea in Patients with Advanced Stage Cancer: A Nurses Guide to Assessment and Treatment.

OBJECTIVE: To provide oncology nurses with education on the specific distressing symptom of dyspnea in patients with advanced cancer, including proper assessment and a hierarchical approach to both nonpharmacologic and pharmacologic dyspnea interventions. DATA SOURCES: Sources include published research findings, literature reviews, and guidelines, as well as professional opinion from practicing nurses and clinicians. CONCLUSION: Individuals with advanced cancer often experience the distressing respiratory symptom, dyspnea. Assessment tools and treatment recommendations and guidelines are available for clinicians to appropriately evaluate and treat dyspnea. Improved awareness of symptom presence and treatment options will assist nurses in advocating for their patients with advanced cancer and obtaining and delivering the necessary treatments for dyspnea relief. IMPLICATIONS FOR NURSING: Published evidence supports the many treatment options available for dyspnea relief at varying levels. Assessment, individualized treatment, education, and reassessment are key and ongoing to assist patients with advanced cancer to achieve respiratory comfort.

B-cell intrinsic and extrinsic signals that regulate central tolerance of mouse and human B cells.

The random recombination of immunoglobulin V(D)J gene segments produces unique IgM antibodies that serve as the antigen receptor for each developing B cell. Hence, the newly formed B cell repertoire is comprised of a variety of specificities that display a range of reactivity with self-antigens. Newly generated IgM+ immature B cells that are non-autoreactive or that bind self-antigen with low avidity are licensed to leave the bone marrow with their intact antigen receptor and to travel via the blood to the peripheral lymphoid tissue for further selection and maturation. In contrast, clones with medium to high avidity for self-antigen remain within the marrow and undergo central tolerance, a process that revises their antigen receptor or eliminates the autoreactive B cell altogether. Thus, central B cell tolerance is critical for reducing the autoreactive capacity and avidity for self-antigen of our circulating B cell repertoire. Bone marrow cultures and mouse models have been instrumental for understanding the mechanisms that regulate the selection of bone marrow B cells. Here, we review recent studies that have shed new light on the contribution of the ERK, PI3K, and CXCR4 signaling pathways in the selection of mouse and human immature B cells that either bind or do not bind self-antigen.

Transportation challenges for persons aging with mobility disability: Qualitative insights and policy implications.

BACKGROUND: Persons aging with mobility disability (PAwMD) experience transportation barriers, which can hinder their ability to fully participate in society. Despite a vast infrastructure of federal laws and programs designed to ensure access to transportation, PAwMD remain a transportation-disadvantaged population. OBJECTIVES: This paper presents detailed insights on transportation challenges experienced by PAwMD along with recent Federal programmatic initiatives designed to enhance access and mobility for transportation for older adults and people with disabilities. To identify policy gaps and opportunities to improve transportation services, we compared individual-level challenges from PAwMD to national survey data about barriers associated with delivering transportation services at state and local levels. METHODS: To assess individual-level transportation challenges, we conducted in-depth, structured interviews with sixty older adult participants with self-identified mobility disabilities for at least 10 years. We also conducted a content analysis of end-user transportation challenges and agency-level transportation coordination barriers to identify correspondences. RESULTS: Participants reported challenges utilizing public and private modes of transportation, related to availability; accessibility; safety; advanced planning; as well as societal attitudes. Barriers to the availability, delivery, and coordination of access and mobility services are linked directly or indirectly to the PAwMD reports of experiencing a shortage of accessible transportation options. CONCLUSIONS: Findings highlight the complexity of federal transportation policies and programmatic initiatives designed to support older adults and people with disabilities, which contribute to implementation barriers and transportation challenges. Results highlight the importance of integrating end-user and state and local provider input into transportation policy development and program implementation.

Factors influencing participation among adults aging with long-term physical disability.

BACKGROUND: People aging with long-term physical disability (AwPD) experience barriers to participation and independent living. There are currently limited evidence-based interventions that address issues regarding participation for people AwPD. OBJECTIVE: This study examined factors influencing participation in personal and life activities among people AwPD to inform future interventions. METHODS: A cross-sectional study within an ongoing, community-based cohort study of participation was conducted. A purposive sample of people AwPD aged 45-65, living with a physical disability for at least five years, and who speak English was recruited through disability organizations, aging organizations, and social media. Participants answered open-ended questions about what supports they needed to successfully participate in nine activity categories derived from the Health and Retirement Study participation items (e.g., employment, community leisure). A content analysis was conducted using NVivo to categorize responses, and member checking occurred with four additional people AwPD. RESULTS: A total of 215 participants completed the survey. Eight categories of factors emerged from the data: physical environment factors, social factors, symptoms, economic factors, policy factors, body structure and functions, mental and emotional state, and temporal factors. Participant responses illuminated a combination of environmental and individual factors. Physical effects of disability and accelerated aging, such as pain and fatigue, paired with environmental factors, such as accessibility of transportation, were reported as influencing participation. CONCLUSIONS: People AwPD experience a range of factors that substantially impact their ability to remain independent and participate in society. By identifying barriers to participation, new interventions addressing these barriers may be developed, resulting in more effective service provision, enhanced participation in personal and life activities, and improved health and well-being.

Systemic administration of a pharmacologic iron chelator reduces cartilage lesion development in the Dunkin-Hartley model of primary osteoarthritis.

Iron has been emerging as a key contributor to aging-associated, chronic disorders due to the propensity for generating reactive oxygen species. To date, there are a limited number of publications exploring the role of iron in the pathogenesis of primary/age-related osteoarthritis (OA). The objective of this study was to determine whether reduced iron via pharmacologic iron chelation with deferoxamine (DFO) affected the development and/or severity of cartilage lesions in a primary OA model. At 12-weeks-of-age, 15 male Dunkin-Hartley guinea pigs received either 46 mg/kg DFO (n = 8) or vehicle control (n = 7) injected subcutaneously twice daily for five days each week. Movement changes, captured via overhead enclosure monitoring, were also determined. Termination occurred at 30-weeks-of-age. Iron was quantified in serum, urine, liver, and femoral head articular cartilage. Left knees were evaluated for: structural changes using histopathology guidelines; and immunohistochemistry. Gene expression analysis was conducted on right knee articular cartilage. DFO reduced iron levels in femoral head articular cartilage (p = 0.0006) and liver (p = 0.02), and increased iron within urine (p = 0.04) and serum (p = 0.0009). Mobility of control animals declined, while the DFO group maintained activity levels similar to the first month of treatment (p = 0.05). OA-associated cartilage lesions were reduced in knees of DFO animals (p = 0.0001), with chondrocyte hypocellularity a key histologic difference between groups (p < 0.0001). DFO-receiving animals had increased immunostaining for phosphorylated adenosine monophosphate activated protein kinase alpha within knee articular cartilage; lower transcript counts of several proapoptotic genes (p = 0.04-0.0004) and matrix-degrading enzymes (p = 0.02-<0.0001), and increased expression of the anti-apoptotic gene Bcl-2 (p < 0.0001) and a tissue inhibitor of matrix-metalloproteinases (p = 0.03) were also observed. These results suggest that iron chelation delayed the progression of primary OA in an animal model and could hold potential as a translational intervention. These findings provide expanded insight into factors that may contribute to the pathogenesis of primary OA.