Physicians' experience of and collaboration with return-to-work coordinators in healthcare: a cross-sectional study in Sweden.

PURPOSE: Return-to-work coordinators (RTWCs) give people on sick leave individualized support and coordinate between different stakeholders, including physicians. The aim of this study was to explore physicians' experience of RTWCs and investigate factors that influence how much physicians collaborate with RTWCs, or refer patients to them, in primary, orthopaedic, and psychiatric care clinics. MATERIALS AND METHODS: Of the 1229 physicians responding to a questionnaire, 629 physicians who had access to a RTWC in their clinic answered to questions about collaborating with RTWCs. RESULTS: Among physicians who had access to a RTWC, 29.0% collaborated with a RTWC at least once a week. Physicians with a more favourable experience of RTWCs reported more frequent collaboration (adjusted OR 2.92, 95% CI 2.06-4.15). Physicians also collaborated more often with RTWCs if they reported to often deal with problematic sick-leave cases, patients with multiple diagnoses affecting work ability, and conflicts with patients over sickness certification. CONCLUSIONS: Physicians who had more problematic sick-leave cases to handle and a favourable experience of RTWCs, also reported collaborating more often with RTWCs. The results indicate that RTWCs' facilitation of contacts with RTW stakeholders and improvements in the sickness certification process may be of importance for physicians.Implications for RehabilitationThis study of physicians' experience of collaborating with return-to-work coordinators (RTWCs) observes that physicians reported more collaboration with or referrals to coordinators if they had a favourable experience of coordinators.The results indicate that physicians report more collaboration with or referrals to RTWCs if they had more problematic sick-leave cases to handle in the clinic.These findings imply that it might be possible to increase the collaboration between physicians and RTWCs in clinical settings by managing factors of importance.

Coordinators in the return-to-work process: Mapping their work models.

PURPOSE: In recent decades, many countries have implemented return-to-work coordinators to combat high rates of sickness absence and insufficient collaboration in the return-to-work process. The coordinators should improve communication and collaboration between stakeholders in the return-to-work process for people on sickness absence. How they perform their daily work remains unexplored, and we know little about to what extent they collaborate and perform other work tasks to support people on sickness absence. This study examines which work models return-to-work coordinators use in primary healthcare, psychiatry and orthopaedics in Sweden. METHODS: A questionnaire was sent to all 82 coordinators in one region (89% response rate) with questions about the selection of patients, individual patient support, healthcare collaboration, and external collaboration. Random forest classification analysis was used to identify the models. RESULTS: Three work models were identified. In model A, coordinators were more likely to select certain groups of patients, spend more time in telephone than in face-to-face meetings, and collaborate fairly much. In Model B there was less patient selection and much collaboration and face-to-face meetings. Model C involved little patient selection, much telephone contact and very little collaboration. Model A was more common in primary healthcare, model C in orthopaedics, while model B was distributed equally between primary healthcare and psychiatry. CONCLUSION: The work models correspond differently to the coordinator's assignments of supporting patients and collaborating with healthcare and other stakeholders. The differences lie in how much they actively select patients, how much they collaborate, and with whom. Their different distribution across clinical contexts indicates that organisational demands influence how work models evolve in practice.

Siplizumab combination therapy with belatacept or abatacept broadly inhibits human T cell alloreactivity in vitro.

Combined antigen-specific T cell receptor stimulation and costimulation are needed for complete T cell activation. Belatacept and abatacept are nondepleting fusion proteins blocking CD28/B7 costimulation, whereas siplizumab is a depleting antiCD2 immunoglobulin G1 monoclonal antibody targeting CD2/CD58 costimulation. Herein, the effect of siplizumab combination therapy with abatacept or belatacept on T cell alloreactivity in mixed lymphocyte reactions was investigated. In contrast to monotherapy, the combination of siplizumab with belatacept or abatacept induced near-complete suppression of T cell proliferation and increased the potency of siplizumab-mediated T cell inhibition. Furthermore, dual targeting of CD2 and CD28 costimulation enhanced the selective depletion of memory T cells compared with monotherapy. Although siplizumab monotherapy leads to significant regulatory T cell enrichment, high doses of cytotoxic T-lymphocyte-associated antigen 4 and a human IgG1 Fc fragment in the combination therapy reduced this effect. These results support the clinical evaluation of dual costimulation blockade, combining siplizumab with abatacept or belatacept, for the prophylaxis of organ transplant rejection and improvement of long-term outcomes following transplantation. Ongoing investigative research will elucidate when other forms of siplizumab-based dual costimulatory blockade may be able to induce similarly strong inhibition of T cell activation although still allowing for enrichment of regulatory T cells.

A cross-sectional study of health and well-being among newly settled refugee migrants in Sweden-The role of health literacy, social support and self-efficacy.

Structural barriers such as inadequate housing, lack of employment opportunities, and discrimination are known to adversely affect the health of newly settled refugee migrants. However, these barriers remain largely unresolved and unaddressed. Thus, there is a need to better understand how other factors, such as individual-level health resources, may influence health and mitigate ill health in the early post-migration phase. In this study, we aimed to explore the relationship between health outcomes and individual health resources including health literacy, social support, and self-efficacy in newly settled refugee migrants. Survey data was collected from 787 refugee migrants in Sweden. Logistical regression analysis showed that limited health literacy, lack of emotional support, and low self-efficacy were consistently associated with poor health outcomes. Demographic variables such as gender, education, and type of residence permit were not as imperative. Individual-level health resources may play an important role in the general and psychological well-being of newly settled migrants. Promoting health literacy and facilitating the attainment of social support may buffer for structural challenges in the establishment phase and enhance the prospects of later health and social integration.

Understanding and assessing gamification in digital healthcare interventions for patients with cardiovascular disease.

Gamification is defined as the use of game design elements in contexts other than gaming to increase user engagement and experience. Gamification in cardiovascular care can contribute to positively change health behaviour with possible effects and benefits on physical health and mental well-being. Based on previous literature, in this article we describe: the conceptualization of gamification, the five gamification principles for gamified digital health programmes or applications, the six most common game elements used to impact health behaviour applied in gamified digital health interventions and finally scientifically validated instruments to use for assessment of gamification in terms of self-reported psychological outcomes.

Inward and outward currents of native and cloned K(ATP) channels (Kir6.2/SUR1) share single-channel kinetic properties.

Background: The ATP-sensitive K+ (K(ATP)) channel is found in a variety of tissues extending from the heart and vascular smooth muscles to the endocrine pancreas and brain. Common to all K(ATP) channels is the pore-forming subunit Kir6.x, a member of the family of small inwardly rectifying K+ channels, and the regulatory subunit sulfonylurea receptor (SURx). In insulin secreting ß-cells in the endocrine part of the pancreas, where the channel is best studied, the K(ATP) channel consists of Kir6.2 and SUR1. Under physiological conditions, the K(ATP) channel current flow is outward at membrane potentials more positive than the K+ equilibrium potential around -80 mV. However, K(ATP) channel kinetics have been extensively investigated for inward currents and the single-channel kinetic model is based on this type of recording, whereas only a limited amount of work has focused on outward current kinetics. Methods: We have estimated the kinetic properties of both native and cloned K(ATP) channels under varying ionic gradients and membrane potentials using the patch-clamp technique. Results: Analyses of outward currents in K(ATP) and cloned Kir6.2ΔC26 channels, alone or co-expressed with SUR1, show openings that are not grouped in bursts as seen for inward currents. Burst duration for inward current corresponds well to open time for outward current. Conclusions: Outward K(ATP) channel currents are not grouped in bursts regardless of membrane potential, and channel open time for outward currents corresponds to burst duration for inward currents.

Coordination and Perceived Support for Return to Work: A Cross-Sectional Study among Patients in Swedish Healthcare.

BACKGROUND: Receiving support from a return-to-work (RTW) coordinator (RTWC) may be beneficial for people on long-term sick leave. The aim of this study was to investigate whether the number of contacts with an RTWC and their involvement in designing rehabilitation plans for the patients were associated with perceiving support for RTW, emotional response to the RTWC, and healthcare utilization. METHODS: In this cross-sectional study, 274 patients who had recently been in contact with an RTWC in Swedish primary or psychiatric care answered questions regarding their interaction with an RTWC, perceived support for RTW, and emotional response to the RTWC. RESULTS: Having more contact with an RTWC was associated with perceiving more support in the RTW process (adjusted OR 4.14, 95% CI 1.49-11.47). RTWC involvement in designing a rehabilitation plan for the patient was associated with perceiving more support in the RTW process from an RTWC and having a more positive emotional response to the RTWC. CONCLUSIONS: From the patient's perspective, this study indicates that the involvement of an RTWC and receiving a rehabilitation plan that an RTWC has helped to design might be perceived as important in the RTW process.

Organ transplants of the future: planning for innovations including xenotransplantation.

The future clinical application of animal-to-human transplantation (xenotransplantation) is of importance to society as a whole. Favourable preclinical data relevant to cell, tissue and solid organ xenotransplants have been obtained from many animal models utilizing genetic engineering and protocols of pathogen-free husbandry. Findings have reached a tipping point, and xenotransplantation of solid organs is approaching clinical evaluation, the process of which now requires close deliberation. Such discussions include considering when there is sufficient evidence from preclinical animal studies to start first-in-human xenotransplantation trials. The present article is based on evidence and opinions formulated by members of the European Society for Organ Transplantation who are involved in the Transplantation Learning Journey project. The article includes a brief overview of preclinical concepts and biology of solid organ xenotransplantation, discusses the selection of candidates for first-in-human studies and considers requirements for study design and conduct. In addition, the paper emphasizes the need for a regulatory framework for xenotransplantation of solid organs and the essential requirement for input from public and patient stakeholders.

Evaluation of Spin Columns for Human Plasma Depletion to Facilitate MS-Based Proteomics Analysis of Plasma.

High abundant protein depletion is a common strategy applied to increase analytical depth in global plasma proteomics experiment setups. The standard strategies for depletion of the highest abundant proteins currently rely on multiple-use HPLC columns or multiple-use spin columns. Here we evaluate the performance of single-use spin columns for plasma depletion and show that the single-use spin reduces handling time by allowing parallelization and is easily adapted to a nonspecialized lab environment without reducing the high plasma proteome coverage and reproducibility. In addition, we evaluate the effect of viral heat inactivation on the plasma proteome, an additional step in the plasma preparation workflow that allows the sample preparation of SARS-Cov2-infected samples to be performed in a BSL3 laboratory, and report the advantage of performing the heat inactivation postdepletion. We further show the possibility of expanding the use of the depletion column cross-species to macaque plasma samples. In conclusion, we report that single-use spin columns for high abundant protein depletion meet the requirements for reproducibly in in-depth plasma proteomics and can be applied on a common animal model while also reducing the sample handling time.

Work-life balance predicted work ability two years later: a cohort study of employees in the Swedish energy and water sector.

BACKGROUND: Work-life balance (WLB) is the extent to which individual's multiple life roles and demands carry over between each role. WLB can be divided into work interference with personal life (WIPL) and personal life interference with work (PLIW). This study aimed to investigate longitudinal associations between WIPL, PLIW and work ability outcomes. METHODS: In this cohort study, 224 employees in the energy and water sector in Sweden were followed-up over 2 years. Three questions derived from the Work Ability Index were used for measuring work ability outcome: current work ability compared with lifetime best; work ability regarding physical; and mental demands. Logistic regression models were used to analyse longitudinal associations between work ability and WIPL and WIPL respectively, controlling for workplace (company), position at work, experience of leadership quality, demographics, and work ability. RESULTS: Work ability compared to lifetime best were associated with WIPL in the adjusted logistic regression models (odds ratio (OR) 1.77, 95% confidence interval (CI) 1.15-2.73), and PLIW (OR 3.34, 95% CI 1.66-6.74). Work ability regarding physical demands was associated with WIPL (OR 1.60, 95% CI 1.07-2.40). Work ability regarding mental demands was associated with WIPL (OR 1.59, 95% CI 1.03-2.44) and PLIW (OR 2.88, 95% CI 1.31-6.32). CONCLUSION: In this two-year longitudinal study, lower WIPL predicted good/excellent overall work ability compared with lifetime best, higher work ability regarding physical and mental demands, and lower PLIW predicted good/excellent overall work ability compared with lifetime best and higher work ability regarding and mental demands.

Direct interaction of the ATP-sensitive K+ channel by the tyrosine kinase inhibitors imatinib, sunitinib and nilotinib.

The ATP-regulated K+ channel (KATP) plays an essential role in the control of many physiological processes, and contains a ATP-binding site. Tyrosine kinase inhibitors (TKI) are commonly used drugs, that primarily target ATP-binding sites in tyrosine kinases. Herein, we used the patch-clamp technique to examine the effects of three clinically established TKIs on KATP channel activity in isolated membrane patches, using a pancreatic ß-cell line as a KATP channel source. In excised inside-out patches, the activity of the KATP channel was dose-dependently inhibited by imatinib with half-maximal concentration of approximately 9.4 µM. The blocking effect of imatinib was slow and reversible. No effect of imatinib was observed on either the large (KBK) or the small (KSK) conductance, Ca2+-regulated K+ channel. In the presence of ATP/ADP (ratio 1) addition of imatinib increased channel activity approximately 1.5-fold. Sunitinib and nilotinib were also found to decrease KATP channel activity. These findings are compatible with the view that TKIs, designed to interact at the ATP-binding pocket on the tyrosine receptor, also interact at the ATP-binding site on the KATP channel. Possibly, this might explain some of the side effects seen with TKIs.

Siplizumab Induces NK Cell Fratricide Through Antibody-Dependent Cell-Mediated Cytotoxicity.

The glycoprotein CD2 is expressed on T and NK cells and contributes to cell-cell conjugation, agonistic signaling and actin cytoskeleton rearrangement. CD2 has previously been shown to have an important function in natural NK cell cytotoxicity but to be expendable in antibody-mediated cytotoxicity. Siplizumab is a monoclonal anti-CD2 IgG1 antibody that is currently undergoing clinical trials in the field of transplantation. This study investigated the effect of CD2 binding and Fc γ receptor binding by siplizumab (Fc-active) and Fc-silent anti-CD2 monoclonal antibodies in allogeneic mixed lymphocyte reaction and autologous lymphocyte culture. Further, induction of NK cell fratricide and inhibition of natural cytotoxicity as well as antibody-dependent cytotoxicity by these agents were assessed. Blockade of CD2 via monoclonal antibodies in the absence of Fc γ receptor binding inhibited NK cell activation in allogeneic mixed lymphocyte reaction. In contrast, siplizumab increased NK cell activation in both mixed lymphocyte reaction and autologous lymphocyte culture due to FcγRIIIA binding. However, experiments using purified NK cells did not show an inhibitory effect of CD2 blockade on natural cytotoxicity or antibody-dependent cytotoxicity. Lastly, it was shown that siplizumab induces NK cell fratricide. Concluding, siplizumab is a promising biopharmaceutical drug candidate for depletion of T and NK cells with minimal off-target effects.

Strategies for Liver Transplantation Tolerance.

Liver transplant (LT) recipients require life-long immunosuppression (IS) therapy to preserve allograft function. The risks of chronic IS include an increased frequency of malignancy, infection, renal impairment, and other systemic toxicities. Despite advances in IS, long-term LT outcomes have not been improved over the past three decades. Standard-of-care (SoC) therapy can, in rare cases, lead to development of operational tolerance that permits safe withdrawal of maintenance IS. However, successful IS withdrawal cannot be reliably predicted and, in current prospective studies, is attempted several years after the transplant procedure, after considerable exposure to the cumulative burden of maintenance therapy. A recent pilot clinical trial in liver tolerance induction demonstrated that peri-transplant immunomodulation, using a regulatory T-cell (Treg) approach, can reduce donor-specific alloreactivity and allow early IS withdrawal. Herein we review protocols for active tolerance induction in liver transplantation, with a focus on identifying tolerogenic cell populations, as well as barriers to tolerance. In addition, we propose the use of novel IS agents to promote immunomodulatory mechanisms favoring tolerance. With numerous IS withdrawal trials underway, improved monitoring and use of novel immunomodulatory strategies will help provide the necessary knowledge to establish an active liver tolerance induction protocol for widespread use.

Siplizumab, an Anti-CD2 Monoclonal Antibody, Induces a Unique Set of Immune Modulatory Effects Compared to Alemtuzumab and Rabbit Anti-Thymocyte Globulin In Vitro.

Antibodies are commonly used in organ transplant induction therapy and to treat autoimmune disorders. The effects of some biologics on the human immune system remain incompletely characterized and a deeper understanding of their mechanisms of action may provide useful insights for their clinical application. The goal of this study was to contrast the mechanistic properties of siplizumab with Alemtuzumab and rabbit Anti-Thymocyte Globulin (rATG). Mechanistic assay systems investigating antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell phagocytosis and complement-dependent cytotoxicity were used to characterize siplizumab. Further, functional effects of siplizumab, Alemuzumab, and rATG were investigated in allogeneic mixed lymphocyte reaction. Changes in T cell activation, T cell proliferation and frequency of naïve T cells, memory T cells and regulatory T cells induced by siplizumab, Alemtuzumab and rATG in allogeneic mixed lymphocyte reaction were assessed via flow cytometry. Siplizumab depleted T cells, decreased T cell activation, inhibited T cell proliferation and enriched naïve and bona fide regulatory T cells. Neither Alemtuzumab nor rATG induced the same combination of functional effects. The results presented in this study should be used for further in vitro and in vivo investigations that guide the clinical use of immune modulatory biologics.

Phase I trial evaluating safety and efficacy of intratumorally administered inflammatory allogeneic dendritic cells (ilixadencel) in advanced gastrointestinal stromal tumors.

BACKGROUND: The majority of patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Ilixadencel (allogeneic inflammatory dendritic cells) is a cell-based immune primer injected intratumorally that previously has been clinically investigated in metastatic renal cell carcinoma and hepatocellular carcinoma. METHODS: The trial was a single arm phase I trial assessing safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Three patients were progressing while on sunitinib (second line), one on regorafenib (third line), and two on pazopanib (fourth line). TKI treatment was maintained throughout, while two intratumoral injections of ilixadencel (10 × 106 viable and HLA-DR expressing cells per dose) were administered. RESULTS: No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. One patient (on third line regorafenib) had stable disease for 9 months and another patient (on second line sunitinib) had stable disease at end of study (12 months) as per RECIST 1.1. These two patients developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. The median progression-free survival (PFS) was 4.0 months. CONCLUSION: Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial registration www.clinicaltrials.gov ; NCT: 02432846; registration date: February 22, 2016.

CD2 Immunobiology.

The glycoprotein CD2 is a costimulatory receptor expressed mainly on T and NK cells that binds to LFA3, a cell surface protein expressed on e.g., antigen-presenting cells. CD2 has an important role in the formation and organization of the immunological synapse that is formed between T cells and antigen-presenting cells upon cell-cell conjugation and associated intracellular signaling. CD2 expression is upregulated on memory T cells as well as activated T cells and plays an important role in activation of memory T cells despite the coexistence of several other costimulatory pathways. Anti-CD2 monoclonal antibodies have been shown to induce immune modulatory effects in vitro and clinical studies have proven the safety and efficacy of CD2-targeting biologics. Investigators have highlighted that the lack of attention to the CD2/LFA3 costimulatory pathway is a missed opportunity. Overall, CD2 is an attractive target for monoclonal antibodies intended for treatment of pathologies characterized by undesired T cell activation and offers an avenue to more selectively target memory T cells while favoring immune regulation.

Rehabilitation coordinator intervention versus control in psychiatric specialist care for return to work and reduced sick leave: study protocol of a randomised controlled trial.

BACKGROUND: Mental disorders are the most common reason for sick leave in Sweden. Knowledge about effective methods to help these individuals to return to work (RTW)/entry into work or studies is limited. Rehabilitation coordinators (RC's) have been introduced within healthcare with the purpose to promote cooperation, streamline the sick leave and rehabilitation process, and facilitate RTW for sick-listed patients. The function of RC's has shown positive results by reducing sick leave within primary healthcare. However, the function has not been evaluated in terms of specialist psychiatry. This paper describes the design of a study to evaluate effects of a RC intervention on sick leave and RTW/entry in work or studies in patients with moderate to severe affective and/or moderate to severe anxiety disorders within specialist psychiatric care. METHODS: A randomised controlled trial (RCT) comparing an intervention group receiving support from a RC with a control group receiving treatment as usual (TAU). The target group is patients on sick leave, treated for affective and/or anxiety disorder, aged 25-64, with or without employment. DISCUSSION: This study gives the possibility to evaluate a RC intervention for individuals with mental disorders. If the study has promising vocational outcomes, it may be of importance for the participants in many ways, e.g. increase participation in society, provide economic benefits and improve health and wellbeing. This would be valuable for the individual as well as for the society. TRIAL REGISTRATION: The study is registered at the Clinicaltrials.gov Register Platform (ID NCT03729050) in 2 November 2018.

Polyvinyl Alcohol Carbazate as a Polymer-Based Antitumoral Agent.

Development of treatment resistance is a major concern during treatment of cancer, and there is an unmet need for therapeutic strategies with novel modes of action. Polyvinyl alcohol carbazate (PVAC) is a polymer compound with unique biological properties. Herein, we describe the antitumoral effects of PVAC. Three well-established cell lines GIST-T1, B16.F10, and A375 were used to determine the in vitro antitumoral effects of PVAC. Assessments included light microscopy, cell viability, cell cycle, and apoptosis assays. In vivo treatment safety and efficacy were characterized in one immunocompetent (B16.F10) mouse model and one athymic nude (MDA-MB-231) mouse model. Excised tumors were measured, weighed, stained for Ki-67, CD3, and histopathologically evaluated. Intact PVAC expressed a non-linear dose-response antitumoral effect in vitro, whereas its separate components, PVA and carbazate, did not display antitumoral effects alone. In vivo, PVAC induced a significant intratumoral CD3+ T-cell recruitment in immunocompetent mice (B16.F10), which was associated with tumor growth inhibition. Although growth inhibition was not significant in athymic mice (MDA-MB-231), histopathological evaluation detected an increase in stromal tissue and leukocyte infiltration. In conclusion, we present evidence for PVAC antitumoral effects both in vitro and in vivo. The mode of action was not elucidated in vitro, but a potential mechanism of in vivo activity was observed, characterized by an increase of immune cells into both immunocompetent and athymic mice. This finding warrants further study to validate its possible role as an immunomodulatory polymeric agent.

Impact of CMV Reactivation, Treatment Approaches, and Immune Reconstitution in a Nonmyeloablative Tolerance Induction Protocol in Cynomolgus Macaques.

BACKGROUND: Cytomegalovirus (CMV) infection is a serious complication in immunosuppressed patients, specifically transplant recipients. Here, we describe the development and use of an assay to monitor the incidence and treatment of CMV viremia in a Cynomolgus macaque model of bone marrow transplantation (BMT) for tolerance induction. We address the correlation between the course of viremia and immune reconstitution. METHODS: Twenty-one animals received a nonmyeloablative conditioning regimen. Seven received cyclosporine A for 28 days and 14 received rapamycin. A CMV polymerase chain reaction assay was developed and run twice per week to monitor viremia. Nineteen recipients were CMV seropositive before BMT. Immune reconstitution was monitored through flow cytometry and CMV viremia was tracked via quantitative polymerase chain reaction. RESULTS: Recipients developed CMV viremia during the first month post-BMT. Two animals developed uncontrollable CMV disease. CMV reactivation occurred earlier in cyclosporine A-treated animals compared with those receiving rapamycin. Post-BMT, T-cell counts remained significantly lower compared with pretransplant levels until CMV reactivation, at which point they increased during the viremic phase and approached pretransplant levels 3 months post-BMT. Management of CMV required treatment before viremia reached 10 000 copies/mL; otherwise clinical symptoms were observed. High doses of ganciclovir resolved the viremia, which could subsequently be controlled with valganciclovir. CONCLUSIONS: We developed an assay to monitor CMV in Cynomolgus macaques. CMV reactivation occurred in 100% of seropositive animals in this model. Rapamycin delayed CMV reactivation and ganciclovir treatment was effective at high doses. As in humans, CD8 T cells proliferated during CMV viremia.