Factors influencing sustainable employment of persons with acquired brain injury (ABI) or spinal cord injury (SCI): A qualitative study evaluating the perspective of health and work professionals

BackgroundThe number of persons with acquired brain injury (ABI) or spinal cord injury (SCI) who leave the labor market early despite successfully return to work post-injury, demonstrates the challenge for them to remain employed. Evidence on how enabling and hindering factors influence daily work across the lifespan and how they affect employment-related services is scarce. Professionals directly involved in work integration can add to this evidence through their experiential knowledge.PurposeTo identify and explore the factors that enable or hinder sustainable employment for persons with ABI or SCI from the perspective of health and work professionals.MethodsWe conducted 23 semi-structured interviews with professionals in Switzerland, directly involved in work reintegration and retention of persons with ABI or SCI. Interviews were transcribed verbatim and thematically analyzed.ResultsParticipants identified three main themes related to the concept of “sustainable employment”. First, the value and impact of initial work integration; an early, multidisciplinary, person-centered work integration, with the early involvement of employers is ideal. A good match between the worker and the workplace is sought. Second, critical factors for long-term sustainable work: the main risks for persons with ABI are changing supervisors, workplace restructuring and the introduction of new technologies, while deteriorating health and the occurrence of secondary health problems are the greatest risk for persons with SCI. Third, the relevance of knowledge, experience and attitudes of professionals; Knowledge of the consequences of an ABI or SCI, the legal basis and the social security process, and the attitude of professionals towards the injured worker were considered important.ConclusionsFrom the professional's perspective, enabling and hindering factors for sustainable employment in the long-term are fundamentally very similar for persons with ABI and SCI. But different physical, mental and neuropsychological effects call for individually adapted measures. While persons with SCI primarily require ongoing medical care, conscious management of changes in the workplace is critical for persons with ABI. For both groups, an easily accessible counseling and support service should be established for work-threatening problems in the long-term. Furthermore, diagnosis-specific training programs for professionals of employment-related services and disability management should be developed

Facilitators and Barriers to Sustainable Employment After Spinal Cord Injury or Acquired Brain Injury: The Person's Perspective

BackgroundSustaining employment after initial return to work represents a major challenge for people with a disability. While individuals with spinal cord injury (SCI) and acquired brain injury (ABI) make a prime example for this challenge, their view on factors supporting and hindering sustainable employment have rarely been investigated in depth so far.PurposeTo examine facilitators and barriers to sustainable employment, as perceived by persons with SCI or ABI.MethodsFourteen focus groups and four individual interviews were conducted and thematically analyzed.ResultsPerceived facilitators and barriers to sustainable employment reflected the three biopsychosocial areas of personal, impairment-related and environmental factors. For both condition groups, key facilitators included environmental factors (i.e., aspects of the work organization, the workplace, supportive private and work environment) and personal factors (i.e., the ability to self-advocate, to communicate and to learn how to live with one's own disability). Major barriers comprised injury-related impairments, including decreased mobility and pain for people with SCI and fatigue and limited cognitive resources for persons with ABI, as well as environmental factors related to insurance procedures and the social security system for both conditions.ConclusionsThe biopsychosocial factors identified in our study as well as their interplay should receive particular attention to optimally support sustainable employment in vocational integration and work retention practice. Interventions should particularly focus on the empowerment of those affected as well as on the creation of supportive work environments that match their abilities and needs

Clinical impact of PD-L1 and PD-1 expression in squamous cell cancer of the vulva

PurposeSquamous cell carcinoma of the vulva (SQCV) is the fifth most common cancer in women and accounts for about 5% of all genital cancers in women. The PD-L1 signaling pathway is activated in many malignant neoplasms and its blockade enhances anti-cancer immunity. The aim of our study was to examine the protein expression of PD-L1 and PD-1 in squamous cell cancer of the vulva, its correlations with clinicopathologic features and prognostic value.MethodsPatients with SQCV treated in one institution were used for the analyses. PD-L1 immunohistochemistry was performed on 4 mu m-thick section of the respective FFPE tissue blocks using the 28-8 antibody. PD-L1 scoring was performed separately for tumour cells (TC) and tumour associated immune cells. DNA was extracted to determine HPV status. Kaplan-Meier estimates for disease-free-survival and overall-survival were calculated and compared by log-rank test.ResultsPD-L1 expression in tumour cells could be observed in 32.9% of the patients. The expression of PD-L1 in peritumoural immune cells was confirmed in 91.4% of the patients. A significant correlation between PD-L1 expression in tumour cells and tumour stage was detected (p=0.007). PD-L1 expression was independent from HPV status. Using the log-rank test we could not prove any significant differences in disease-free survival (p=0.434) and overall survival (p=0.858). Regression analysis showed that nodal status is a predictive factor of survival (p<0.001).ConclusionThe present study showed that a relevant amount of patients with squamous cell cancer of the vulva express PD-L1 in both, tumour cells and tumour-associated immune cells. Furthermore, the significant correlation of PD-L1 expression in TCs with tumour stage indicated the clinical impact of PD-L1 expression during tumour development. These data indicate that SQCV might be amenable to immune checkpoint-inhibition and constitute a rational for the future clinical trials

Characterizing the Effect of Multivalent Conjugates Composed of Aβ-Specific Ligands and Metal Nanoparticles on Neurotoxic Fibrillar Aggregation

Therapeutically active small molecules represent promising nonimmunogenic alternatives to antibodies for specifically targeting disease-relevant receptors. However, a potential drawback compared to antibody–antigen interactions may be the lower affinity of small molecules toward receptors. Here, we overcome this low-affinity problem by coating the surface of nanoparticles (NPs) with multiple ligands. Specifically, we explored the use of gold and platinum nanoparticles to increase the binding affinity of Aβ-specific small molecules to inhibit Aβ peptide aggregation into fibrils in vitro. The interactions of bare NPs, free ligands, and NP-bound ligands with Aβ are comprehensively studied via physicochemical methods (spectroscopy, microscopy, immunologic tests) and cell assays. Reduction of thioflavin T fluorescence, as an indicator for β-sheet content, and inhibition of cellular Aβ excretion are even more effective with NP-bound ligands than with the free ligands. The results from this study may have implications in the development of therapeutics for treating Alzheimer’s disease

Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction

The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled "Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease-specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes

Esterified eicosanoids are acutely generated by 5-lipoxygenase in primary human neutrophils and in human and murine infection

5-Lipoxygenase (5-LOX) plays key roles in infection and allergic responses. Herein, four 5-LOX–derived lipids comprising 5-hydroxyeicosatetraenoic acid (HETE) attached to phospholipids (PLs), either phosphatidylethanolamine (PE) or phosphatidylcholine (18:0p/5-HETE-PE, 18:1p/5-HETE-PE, 16:0p/5-HETE-PE, and 16:0a/5-HETE-PC), were identified in primary human neutrophils. They formed within 2 minutes in response to serum-opsonized Staphylococcus epidermidis or f-methionine-leucine-phenylalanine, with priming by lipopolysaccharide, granulocyte macrophage colony-stimulating factor, or cytochalasin D. Levels generated were similar to free 5-HETE (0.37 ± 0.14 ng vs 0.55 ± 0.18 ng/106 cells, esterified vs free 5-HETE, respectively). They remained cell associated, localizing to nuclear and extranuclear membrane, and were formed by fast esterification of newly synthesized free 5-HETE. Generation also required Ca2+, phospholipase C, cytosolic and secretory phospholipase A2, 5-LOX activating protein, and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1. 5-HETE-PLs were detected in murine S epidermidis peritonitis, paralleling neutrophil influx, and in effluent from Gram-positive human bacterial peritonitis. Formation of neutrophil extracellular traps was significantly enhanced by 5-LOX inhibition but attenuated by HETE-PE, whereas 5-HETE-PE enhanced superoxide and interleukin-8 generation. Thus, new molecular species of oxidized PL formed by human neutrophils during bacterial infection are identified and characterized