Effectiveness of integrated person-centered interventions for older people's care: Review of Swedish experiences and experts' perspective.

Older adults have multiple medical and social care needs, requiring a shift toward an integrated person-centered model of care. Our objective was to describe and summarize Swedish experiences of integrated person-centered care by reviewing studies published between 2000 and 2023, and to identify the main challenges and scientific gaps through expert discussions. Seventy-three publications were identified by searching MEDLINE and contacting experts. Interventions were categorized using two World Health Organization frameworks: (1) Integrated Care for Older People (ICOPE), and (2) Integrated People-Centered Health Services (IPCHS). The included 73 publications were derived from 31 unique and heterogeneous interventions pertaining mainly to the micro- and meso-levels. Among publications measuring mortality, 15% were effective. Subjective health outcomes showed improvement in 24% of publications, morbidity outcomes in 42%, disability outcomes in 48%, and service utilization outcomes in 58%. Workshop discussions in Stockholm (Sweden), March 2023, were recorded, transcribed, and summarized. Experts emphasized: (1) lack of rigorous evaluation methods, (2) need for participatory designs, (3) scarcity of macro-level interventions, and (4) importance of transitioning from person- to people-centered integrated care. These challenges could explain the unexpected weak beneficial effects of the interventions on health outcomes, whereas service utilization outcomes were more positively impacted. Finally, we derived a list of recommendations, including the need to engage care organizations in interventions from their inception and to leverage researchers' scientific expertise. Although this review provides a comprehensive snapshot of interventions in the context of Sweden, the findings offer transferable perspectives on the real-world challenges encountered in this field.

Epidemiology of mastocytosis: a population-based study (Sweden).

BACKGROUND: Mastocytosis is a disease characterized by accumulation of aberrant mast cells and mediator-related symptoms and is divided into systemic mastocytosis (SM) and cutaneous mastocytosis (CM). The epidemiology of mastocytosis remains incompletely understood. OBJECTIVE: To estimate the incidence, prevalence, overall survival (OS) and burden of comorbidities in adult mastocytosis patients identified in Swedish population-based registries. METHODS: Individuals (≥ 20 years of age) with a mastocytosis diagnosis in the National Patient Register (NPR) and/or the Swedish Cancer Register (SCR) between 2001 and 2018, were identified. In a matched cohort design, for each case five randomly selected mastocytosis-free comparators matched on age, sex, and county of residence were chosen from the Population Register. The Kaplan-Meier method was used to compare OS between individuals with mastocytosis and comparators. Information on concomitant disease at baseline was assessed by use of the Charlson Comorbidity Index (CCI). RESULTS: We identified 2,040 adults with a mastocytosis diagnosis yielding an annual incidence of 1.56 per 100,000 (95% CI 1.29-1.87) and a prevalence of 23.9 per 100,000 (95% CI 22.8-25.0). The comorbidity burden was higher, and the OS lower, in patients with mastocytosis compared to comparators. INTERPRETATION: We found a higher incidence and prevalence of mastocytosis compared to assessments in other settings and confirmed that the prognosis generally is favorable. Of special note was evidence of a higher comorbidity burden in mastocytosis patients compared to the background population. LIMITATIONS: Underreporting and inconsistencies in the use of diagnostic codes.

A comparative trial of blood pressure monitoring in a self-care kiosk, in office, and with ambulatory blood pressure monitoring.

BACKGROUND: Automated measurement of blood pressure (BP) in designated BP kiosks have in recent years been introduced in primary care. If kiosk blood pressure (BP) monitoring provides results equivalent to in-office BP or daytime ambulatory BP monitoring (ABPM), follow-up of adult patients could be managed primarily by self-checks. We therefore designed a comparative trial and evaluated the diagnostic performance of kiosk- and office-based BP (nurse- versus physician-measured) compared with daytime ABPM. METHODS: A trial of automated BP monitoring in three settings: a designated BP kiosk, by nurses and physicians in clinic, and by ABPM. The primary outcome was systolic and diastolic BP, with respective diagnostic thresholds of ≥135 mmHg and/or ≥ 85 mmHg for daytime ABPM and kiosk BP and ≥ 140 mmHg and/or ≥ 90 mmHg for office BP (nurse- and physician-measured). RESULTS: Compared with daytime ABPM, mean systolic kiosk BP was higher by 6.2 mmHg (95% confidence interval [CI] 3.8-8.6) and diastolic by 7.9 mmHg (95% CI 6.2-9.6; p < 0.001). Mean systolic BP taken by nurses was similar to daytime ABPM values (+ 2.0 mmHg; 95% CI - 0.2-4.2; p = 0.071), but nurse-measured diastolic values were higher, by 7.2 mmHg (95% CI 5.9-9.6; p < 0.001). Mean systolic and diastolic physician-measured BPs were higher compared with daytime ABPM (systolic, by 7.6 mmHg [95% CI 4.5-10.2] and diastolic by 5.8 mmHg [95% CI 4.1-7.6]; p < 0.001). Receiver operating characteristic curves of BP monitoring across pairs of systolic/diastolic cut-off levels among the three settings, with daytime ABPM as reference, demonstrated overall similar diagnostic performance between kiosk and nurse-measured values and over the curve performance for physician-measured BP. Accuracy with nurse-measured BP was 69.2% (95% CI 60.0-77.4%), compared with 65.8% (95% CI 56.5-74.3%) for kiosk BP. CONCLUSIONS: In this study kiosk BP monitoring was not comparable to daytime ABPM but could be an alternative to in-office BP monitoring by trained nurses. The diagnostic performance of kiosk and nurse-measured BP monitoring was similar and better than that of physician-measured BP. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04488289) 27/07/2020.

Long-term outcomes after surgery for subaxial cervical spine injuries in octogenarians, a matched population-based cohort study.

PURPOSE: We aimed to investigate surgical outcomes in octogenarians with subaxial cervical spine injuries and determine the predictors of complications and mortality. METHODS: Eligible for inclusion were all patients surgically treated between 2006 and 2018, with either anterior or posterior fixation for subaxial spine injuries. A cohort of octogenarians was identified and matched 1:1 to a corresponding cohort of younger adults. Primary outcomes were perioperative complications and mortality. RESULTS: Fifty-four patients were included in each of the octogenarian and younger groups (median age: 84.0 vs. 38.5). While the risks for surgical complications, including dural tears and wound infections, were similar between groups, the risks of postoperative medical complications, including respiratory or urinary tract infections, were significantly higher among the elderly (p < 0.05). Additionally, there were no differences in operative time (p = 0.625) or estimated blood loss (p = 0.403) between groups. The 30 and 90-day mortality rates were significantly higher among the elderly (p = 0.004 and p < 0.001). These differences were due to comorbidities in the octogenarian cohort as they were revoked when propensity score matching was performed to account for the differences in American Society of Anesthesiology (ASA) grade. Multivariable logistic regression revealed age and ASA score to be independent predictors of complications and the 90-day mortality, respectively. CONCLUSIONS: Octogenarians with comorbidities were more susceptible to postoperative complications, explaining the increased short-term mortality in this group. However, octogenarians without comorbidities had similar outcomes compared to the younger patients, indicating that overall health, including comorbidities, rather than chronological age should be considered in surgical decision-making.

Predictors of failure after primary anterior cervical discectomy and fusion for subaxial traumatic spine injuries.

INTRODUCTION: Traumatic subaxial fractures account for more than half of all cervical spine injuries. The optimal surgical approach is a matter of debate and may include anterior, posterior or a combined anteroposterior (360º) approach. Analyzing a cohort of patients initially treated with anterior cervical discectomy and fusion (ACDF) for traumatic subaxial injuries, the study aimed to identify predictors for treatment failure and the subsequent need for supplementary posterior fusion (PF). METHODS: A retrospective, single center, consecutive cohort study of all adult patients undergoing primary ACDF for traumatic subaxial cervical spine fractures between 2006 and 2018 was undertaken and 341 patients were included. Baseline clinical and radiological data for all included patients were analyzed and 11 cases of supplementary posterior fixation were identified. RESULTS: Patients were operated at a median of 2.0 days from the trauma, undergoing 1-level (78%), 2-levels (16%) and ≥ 3-levels (6.2%) ACDF. A delayed supplementary PF was performed in 11 cases, due to ACDF failure. On univariable regression analysis, older age (p = 0.017), shorter stature (p = 0.031), posterior longitudinal ligament (PLL) injury (p = 0.004), injury to ligamentum flavum (p = 0.005), bilateral facet joint dislocation (p < 0.001) and traumatic cervical spondylolisthesis (p = 0.003) predicted ACDF failure. On the multivariable regression model, older age (p = 0.015), PLL injury (p = 0.048), and bilateral facet joint dislocation (p = 0.010) remained as independent predictors of ACDF failure. CONCLUSIONS: ACDF is safe and effective for the treatment of subaxial cervical spine fractures. High age, bilateral facet joint dislocation and traumatic PLL disruption are independent predictors of failure. We suggest increased vigilance regarding these cases.

Safety of anterior cervical corpectomy and fusion (ACCF) for the treatment of subaxial cervical spine injuries, a single center comparative matched analysis.

INTRODUCTION: Anterior Cervical Discectomy and Fusion (ACDF) and Anterior Cervical Corpectomy and Fusion (ACCF) are both common surgical procedures in the management of pathologies of the subaxial cervical spine. While recent reviews have demonstrated ACCF to provide better decompression results compared to ACDF, the procedure has been associated with increased surgical risks. Nonetheless, the use of ACCF in a traumatic context has been poorly described. The aim of this study was to assess the safety of ACCF as compared to the more commonly performed ACDF. METHODS: All patients undergoing ACCF or ACDF for subaxial cervical spine injuries spanning over 2 disc-spaces and 3 vertebral-levels, between 2006 and 2018, at the study center, were eligible for inclusion. Patients were matched based on age and preoperative ASIA score. RESULTS: After matching, 60 patients were included in the matched analysis, where 30 underwent ACDF and ACCF, respectively. Vertebral body injury was significantly more common in the ACCF group (p = 0.002), while traumatic disc rupture was more frequent in the ACDF group (p = 0.032). There were no statistically significant differences in the rates of surgical complications, including implant failure, wound infection, dysphagia, CSF leakage between the groups (p ≥ 0.05). The rates of revision surgeries (p > 0.999), mortality (p = 0.222), and long-term ASIA scores (p = 0.081) were also similar. CONCLUSION: Results of both unmatched and matched analyses indicate that ACCF has comparable outcomes and no additional risks compared to ACDF. It is thus a safe approach and should be considered for patients with extensive anterior column injury.

Dysphagia, health-related quality of life, and return to work after occipitocervical fixation.

PURPOSE: The purpose of this study was to evaluate patient-reported outcome measures (PROMS) on dysphagia, health-related quality of life (HRQoL) and return to work after occipitocervical fixation (OCF). Postoperative radiographic measurements were evaluated to identify possible predictors of dysphagia. METHODS: All individuals (≥ 18 years) who underwent an OCF at the study center or were registered in the Swedish spine registry (Swespine) between 2005 and 2019, and were still alive when the study was conducted, were eligible for inclusion. There was no overlap between the cohorts. Prospectively collected data on dysphagia (Dysphagia Short Questionnaire DSQ), HRQoL (EQ5D-3L) and return to work were used. Radiological and baseline patient data were retrospectively collected. In addition, HRQoL data of a matched sample of individuals was elicited from the Stockholm Public Health Survey 2006. RESULTS: In total, 54 individuals were included. At long-term follow-up, 26 individuals (51%) had no dysphagia, and 25 (49%) reported some degree of dysphagia: 11 (22%) had mild dysphagia, and 14 (27%) had moderate to severe dysphagia. On a group level, the OCF sample scored significantly lower EQVAS and EQ-5Dindex values compared to the general population (60.0 vs. 80.0, p = 0.016; 0.43 vs. 0.80, p < 0.001). Individuals working preoperatively returned to work after surgery. Of those responding, 88% stated that they would undergo the OCF operation if it was offered today. No predictors of dysphagia based on radiographic measurements were identified. CONCLUSION: Occipitocervical fixation results in a high frequency of long-term dysphagia. The HRQoL of OCF patients is significantly reduced compared to matched controls. However, most patients are satisfied with their surgery. No radiographic predictors of long-term dysphagia could be identified. Future prospective and systematic studies with larger samples and more objective outcome measures are needed to elucidate the causes of dysphagia in OCF.

Hypertension management in primary health care: a survey in eight regions of Sweden.

PURPOSE: To explore hypertension management in primary healthcare (PHC). DESIGN: Structured interviews of randomly selected PHC centres (PHCCs) from December 2019 to January 2021. SETTING: Seventy-six PHCCs in eight regions of Sweden. MAIN OUTCOME MEASURES: Staffing and organization of hypertension care. Methods of measuring blood pressure (BP), laboratory tests, registration of co-morbidities and lifestyle advice at diagnosis and follow-up. RESULTS: The management of hypertension varied among PHCCs. At diagnosis, most PHCCs (75%) used the sitting position at measurements, and only 13% routinely measured standing BP. One in three (33%) PHCCs never used home BP measurements and 25% only used manual measurements. The frequencies of laboratory analyses at diagnosis were similar in the PHCCs. At follow-up, fewer analyses were performed and the tests of lipids and microalbuminuria decreased from 95% to 45% (p < 0.001) and 61% to 43% (p = 0.001), respectively. Only one out of 76 PHCCs did not measure kidney function at routine follow-ups. Lifestyle, physical activity, food habits, smoking and alcohol use were assessed in ≥96% of patients at diagnosis. At follow-up, however, there were fewer assessments. Half of the PHCCs reported dedicated teams for hypertension, 82% of which were managed by nurses. There was a great inequality in the number of patients per tenured GP in the PHCCs (median 2500; range 1300-11300) patients. CONCLUSIONS: The management of hypertension varies in many respects between PHCCs in Sweden. This might lead to inequity in the care of patients with hypertension.

Hypertension is mainly handled in primary healthcare (PHC), and this study shows important dissimilarities in organization and clinical management.Several variants in techniques and measurements of blood pressure were found between PHC centres.Lifestyle, clinical and laboratory assessments decreased at follow-ups compared to at diagnosis, specifically for lipids, microalbuminuria and electrocardiograms.Nearly half of the PHC centres reported that they had dedicated hypertension teams.

Medical students' perception of learning from patient encounters in primary health care; a qualitative interview study.

BACKGROUND: Clinical practice gives medical students opportunities to develop clinical skills and to gain insight into their future profession as a physician. Students in the medical programme at Karolinska Institutet in Sweden had clinical practice in primary health care in nine of their 11 semesters. The aim of this study was to explore medical students' perceptions of learning from patient encounters in a primary health care context. METHODS: The study was a qualitative inductive interview study. The 21 participating medical students were from their 3rd, 4th and 5th (final year) year of the study programme. A semi-structured interview guide was used. The data analysis was performed with qualitative content analysis. RESULTS: The overarching theme of the study was: The individual patient encounters are the key to learning in primary health care. The patient encounters presented both useful opportunities and challenges that could contribute to the students' professional development. The following four categories were found: 1. Patient encounters in are instructive, rewarding and challenging. Practising in primary health care provided experience in meeting and communicating with a wide variety of patients. Students described it being challenging to trust in their own clinical competence and feeling a responsibility towards the patients. 2. Encounters with patients in primary health care provide opportunities for gradual professional development. Students had the opportunity of increasing independence based on their level of clinical competence. They experienced a progression in their professional development after each period in primary health care. 3. A committed supervisor plays a significant role in learning. Committed supervisors who set aside time for supervision, offered support, and encouraged the student, played an important role in the student's learning. 4. Learning in primary health care and learning in hospitals complement one another. It could be difficult for the students to sort out exactly where they learnt different things as they perceived that learning in primary health care and in hospitals complemented one another. CONCLUSIONS: The students' encounters with authentic patients in primary health care gave them recurring opportunities to develop communication skills and to be trusted to work on their own under supervision, giving them guidance on their way to becoming future physicians.

Biosynthesis of prostaglandin 15dPGJ2 -glutathione and 15dPGJ2-cysteine conjugates in macrophages and mast cells via MGST3.

Inhibition of microsomal prostaglandin E synthase-1 (mPGES-1) results in decreased production of proinflammatory PGE2 and can lead to shunting of PGH2 into the prostaglandin D2 (PGD2)/15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2) pathway. 15dPGJ2 forms Michael adducts with thiol-containing biomolecules such as GSH or cysteine residues on target proteins and is thought to promote resolution of inflammation. We aimed to elucidate the biosynthesis and metabolism of 15dPGJ2 via conjugation with GSH, to form 15dPGJ2-glutathione (15dPGJ2-GS) and 15dPGJ2-cysteine (15dPGJ2-Cys) conjugates and to characterize the effects of mPGES-1 inhibition on the PGD2/15dPGJ2 pathway in mouse and human immune cells. Our results demonstrate the formation of PGD2, 15dPGJ2, 15dPGJ2-GS, and 15dPGJ2-Cys in RAW264.7 cells after lipopolysaccharide stimulation. Moreover, 15dPGJ2-Cys was found in lipopolysaccharide-activated primary murine macrophages as well as in human mast cells following stimulation of the IgE-receptor. Our results also suggest that the microsomal glutathione S-transferase 3 is essential for the formation of 15dPGJ2 conjugates. In contrast to inhibition of cyclooxygenase, which leads to blockage of the PGD2/15dPGJ2 pathway, we found that inhibition of mPGES-1 preserves PGD2 and its metabolites. Collectively, this study highlights the formation of 15dPGJ2-GS and 15dPGJ2-Cys in mouse and human immune cells, the involvement of microsomal glutathione S-transferase 3 in their biosynthesis, and their unchanged formation following inhibition of mPGES-1. The results encourage further research on their roles as bioactive lipid mediators.

Modulating T-cell activation with antisense oligonucleotides targeting lymphocyte cytosolic protein 2.

Dysregulated T-cell activation is a hallmark of several autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS). The lymphocyte cytosolic protein 2 (LCP2), also known as SLP-76, is essential for the development and activation of T cells. Despite the critical role of LCP2 in T-cell activation and the need for developing drugs that modify T-cell activation, no LCP2 inhibitors have been developed. This can be explained by the "undruggable" nature of LCP2, lacking a structure permissive to standard small molecule inhibitor modalities. Here, we explored an alternative drug modality, developing antisense oligonucleotides (ASOs) targeting LCP2 mRNAs, and evaluated its activity in modulating T-cell activation. We identified a set of 3' UTR targeting LCP2 ASOs, which knocked down LCP2 in a human T-cell line and primary human T cells and found that these suppressed T-cell receptor mediated activation. We also found that the ASOs suppressed FcεR1-mediated mast cell activation, in line with the role of LCP2 in mast cells. Taken together, our data provide examples of how immunomodulatory ASOs that interfere with undruggable targets can be developed and propose that such drug modalities can be used to treat autoimmune diseases.

The ingenious mast cell: Contemporary insights into mast cell behavior and function.

Mast cells are (in)famous for their role in allergic diseases, but the physiological and pathophysiological roles of this ingenious cell are still not fully understood. Mast cells are important for homeostasis and surveillance of the human system, recognizing both endogenous and exogenous agents, which induce release of a variety of mediators acting on both immune and non-immune cells, including nerve cells, fibroblasts, endothelial cells, smooth muscle cells, and epithelial cells. During recent years, clinical and experimental studies on human mast cells, as well as experiments using animal models, have resulted in many discoveries that help decipher the function of mast cells in health and disease. In this review, we focus particularly on new insights into mast cell biology, with a focus on mast cell development, recruitment, heterogeneity, and reactivity. We also highlight the development in our understanding of mast cell-driven diseases and discuss the development of novel strategies to treat such conditions.

Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction.

BACKGROUND: SUCNR1 is a sensor of extracellular succinate, a Krebs cycle intermediate generated in excess during oxidative stress and has been linked to metabolic regulation and inflammation. While mast cells express SUCNR1, its role in mast cell reactivity and allergic conditions such as asthma remains to be elucidated. METHODS: Cord blood-derived mast cells and human mast cell line LAD-2 challenged by SUCNR1 ligands were analyzed for the activation and mediator release. Effects on mast cell-dependent bronchoconstriction were assessed in guinea pig trachea and isolated human small bronchi challenged with antigen and anti-IgE, respectively. RESULTS: SUCNR1 is abundantly expressed on human mast cells. Challenge with succinate, or the synthetic non-metabolite agonist cis-epoxysuccinate, renders mast cells hypersensitive to IgE-dependent activation, resulting in augmented degranulation and histamine release, de novo biosynthesis of eicosanoids and cytokine secretion. The succinate-potentiated mast cell reactivity was attenuated by SUCNR1 knockdown and selective SUCNR1 antagonists and could be tuned by pharmacologically targeting protein kinase C and extracellular signal-regulated kinase. Both succinate and cis-epoxysuccinate dose-dependently potentiated antigen-induced contraction in a mast cell-dependent guinea pig airway model, associated with increased generation of cysteinyl-leukotrienes and histamine in trachea. Similarly, cis-epoxysuccinate aggravated IgE-receptor-induced contraction of human bronchi, which was blocked by SUCNR1 antagonism. CONCLUSION: SUCNR1 amplifies IgE-receptor-induced mast cell activation and allergic bronchoconstriction, suggesting a role for this pathway in aggravation of allergic asthma, thus linking metabolic perturbations to mast cell-dependent inflammation.

Multisource feedback in medical students' workplace learning in primary health care.

BACKGROUND: In medical students' workplace learning, feedback is important for effective learning regarding communication and clinical skills. The provision of multisource feedback (MSF) in clinical practice with focus on the patient's perspective is rarely addressed in the literature. The overall objective was to explore the experience of MSF in medical students' clinical learning in primary healthcare (PHC). METHODS: In the study, patients provided feedback by use of the Patient Feedback in Clinical Practice (PFCP) questionnaire. By use of adapted PFCP questionnaire versions peers and clinical supervisors provided feedback and students performed a self-evaluation. The MSF learning activity was evaluated using surveys (4-point Likert scale/open-ended questions), (students (n = 26), peers (n = 9) and clinical supervisors (n = 7)). Data were analysed using descriptive and qualitative content analysis. RESULTS: Results (mean 4-point Likert scale) from participants evaluation of the MSF learning activity visualises the value of feedback in terms of patient-centred communication (students 3.50, peers 2.44 and clinical supervisors 3.57), guidance for further training (students 3.14, peers 2.89 and clinical supervisors 3.00) and clarification of pedagogical assignment (students 3.14, peers 2.89 and clinical supervisors 3.00). Thematic analysis of participants' free-text answers in the evaluation surveys resulted in three themes: (1) applicability of the MSF, (2) MSF - collaborative learning process and (3) MSF as a facilitator in students' clinical skills development. The participants experienced that the written MSF provided multi-facetted perspectives, which contributed to students' and peers' clinical and communication learning. MSF experience also enhanced clinical supervisors' feedback regarding communication skills, targeting the supervisors' pedagogical assignment. CONCLUSION: Our findings indicate that MSF provided directly after a patient encounter, using the PFCP questionnaire as feedback provider, could be an adequate learning activity for medical students' workplace learning. The MSF, provided through the PFCP questionnaire, was experienced to neutralise and operationalise the provision of concrete feedback, facilitating peers' learning and clinical supervisors' tuition. The results visualise the importance of patients in MSF, as a valuable resource in students' workplace learning. Our study implies that this learning activity could be an applicable tool to facilitate learning and pedagogic development in clinical education in PHC.

Distinct plasma biomarkers confirm the diagnosis of mastocytosis and identify increased risk of anaphylaxis.

BACKGROUND: Mastocytosis encompasses a heterogeneous group of disorders characterized by accumulation of clonal mast cells (MCs) in the skin and/or internal organs. Patients typically present with a broad variety of recurrent mediator-related clinical symptoms, including severe anaphylaxis. However, not all patients with mastocytosis experience anaphylactic reactions. OBJECTIVE: We sought to identify disease-specific biomarkers in plasma that could be used to predict patients with mastocytosis with increased risk of anaphylaxis. METHODS: Nineteen patients (≥18 years) and 2 control groups (11 subjects with allergic asthma and 13 healthy volunteers without history of atopy) were recruited. In total, 248 plasma proteins were analyzed by Proximity Extension Assay using Olink Proseek Multiplex panels. RESULTS: We identified 4 novel proteins, in addition to tryptase, E-selectin, adrenomedullin, T-cell immunoglobulin, and mucin domain 1, and CUB domain-containing protein 1/CD138 to be significantly increased in patients with mastocytosis compared with both patients with asthma and healthy controls. Furthermore, we investigated whether we could discriminate between patients with mastocytosis with or without anaphylaxis. In addition to tryptase, we identified 3 novel proteins, that is, allergin-1, pregnancy-associated plasma protein-A, and galectin-3, with significantly different levels in patients with mastocytosis with anaphylaxis compared with those without anaphylaxis. CONCLUSIONS: Newly identified proteomic biomarkers may be used to predict patients with mastocytosis with increased risk of anaphylaxis.

Changing the threshold-Signals and mechanisms of mast cell priming.

Mast cells play a key role in allergy and other inflammatory diseases involving engagement of multivalent antigen with IgE bound to high-affinity IgE receptors (FcεRIs). Aggregation of FcεRIs on mast cells initiates a cascade of signaling events that eventually lead to degranulation, secretion of leukotrienes and prostaglandins, and cytokine and chemokine production contributing to the inflammatory response. Exposure to pro-inflammatory cytokines, chemokines, bacterial and viral products, as well as some other biological products and drugs, induces mast cell transition from the basal state into a primed one, which leads to enhanced response to IgE-antigen complexes. Mast cell priming changes the threshold for antigen-mediated activation by various mechanisms, depending on the priming agent used, which alone usually do not induce mast cell degranulation. In this review, we describe the priming processes induced in mast cells by various cytokines (stem cell factor, interleukins-4, -6 and -33), chemokines, other agents acting through G protein-coupled receptors (adenosine, prostaglandin E2 , sphingosine-1-phosphate, and ß-2-adrenergic receptor agonists), toll-like receptors, and various drugs affecting the cytoskeleton. We will review the current knowledge about the molecular mechanisms behind priming of mast cells leading to degranulation and cytokine production and discuss the biological effects of mast cell priming induced by several cytokines.

Selective inhibition of prostaglandin D2 biosynthesis in human mast cells to overcome need for multiple receptor antagonists: Biochemical consequences.

BACKGROUND: The major mast cell prostanoid PGD2 is targeted for therapy of asthma and other diseases, because the biological actions include bronchoconstriction, vasodilation and regulation of immune cells mediated by three different receptors. It is not known if the alternative to selectively inhibit the biosynthesis of PGD2 affects release of other prostanoids in human mast cells. OBJECTIVES: To determine the biochemical consequences of inhibition of the hematopoietic prostaglandin D synthase (hPGDS) PGD2 in human mast cells. METHODS: Four human mast cell models, LAD2, cord blood derived mast cells (CBMC), peripheral blood derived mast cells (PBMC) and human lung mast cells (HLMC), were activated by anti-IgE or ionophore A23187. Prostanoids were measured by UPLC-MS/MS. RESULTS: All mast cells almost exclusively released PGD2 when activated by anti-IgE or A23187. The biosynthesis was in all four cell types entirely initiated by COX-1. When pharmacologic inhibition of hPGDS abolished formation of PGD2 , PGE2 was detected and release of TXA2 increased. Conversely, when the thromboxane synthase was inhibited, levels of PGD2 increased. Adding exogenous PGH2 confirmed predominant conversion to PGD2 under control conditions, and increased levels of TXB2 and PGE2 when hPGDS was inhibited. However, PGE2 was formed by non-enzymatic degradation. CONCLUSIONS: Inhibition of hPGDS effectively blocks mast cell dependent PGD2 formation. The inhibition was associated with redirected use of the intermediate PGH2 and shunting into biosynthesis of TXA2 . However, the levels of TXA2 did not reach those of PGD2 in naïve cells. It remains to determine if this diversion occurs in vivo and has clinical relevance.

Graft-versus-mastocytosis effect after donor lymphocyte infusion: Proof of principle.

Advanced systemic mastocytosis is a relatively rare entity where allogeneic stem cell transplantation can lead to the cure of the disease in selected patients. Delayed incomplete responses with graft-versus-mastocytosis effect were published in a few cases. In this particular patient's report, we describe the direct evidence and potency of graft-versus-mastocytosis effect of donor lymphocyte infusions in a patient with systemic mastocytosis with associated hematological neoplasm (SM-AHN). In a 53-year-old female patient, an allogeneic stem cell transplantation after conventional induction treatment was performed for transformed acute myeloid leukemia (AML) during the course of polycythemia vera. After 6 years of remission period of AML and PV, the patient developed aleukemic mast cell leukemia and JAK2-positive myeloproliferative neoplasm (SM-AHN). We were able to achieve a sustained complete remission of SM-AHN lasting for 6 years with only donor lymphocyte infusions in a status of mixed chimerism. The patient is in a good clinical condition and remission. The potent graft-versus-mastocytosis effect in this patient resembles the favorable effect of donor lymphocyte infusions in relapsing chronic myeloid leukemia patients after transplantation. This patient is, to our knowledge, the first case showing the proof of principle of graft-versus-mastocytosis effect.

Migrant physicians' choice of employment and the medical specialty general practice: a mixed-methods study.

OBJECTIVE: In many countries, migrant physicians (MP) tend to fill staff shortages in medical specialties perceived as low status. The aim of this study was to explore aspects that influence MPs', with a medical degree from outside EU/EEA, choice of employment and medical specialty in Sweden, and to explore and understand a potential over-representation in general practice (family medicine), a specialty suffering from staff shortages in Sweden. METHODS: A mixed-methods approach was applied. This included questionnaire data from 101 MPs training and working as medical specialists in Sweden and semi-structured interview data from four MPs specializing in general practice. RESULTS: Regardless of specialty, the most influential aspects when choosing employment were the ability to combine work with family, to develop one´s competence, and to have highly competent colleagues. Women scored higher on some aspects related to private life and the surroundings. More than half (55%) of the respondents specialized in general practice, and more women than men. The MPs in general practice scored higher on the aspect 'ability to have the same patients for a longer period' than MPs specializing in other specialties. No significant difference between MP general practitioner respondents and MPs in other medical specialties was found in relation to the item 'Was the specialty your first choice?'. Aspects identified in the interviews that influenced the choice to specialize in general practice related to job opportunities, positive experiences of primary health care, working conditions, and family conditions. CONCLUSION: Labour market conditions such as high competition, and the time-consuming recertification process, can influence the choice to specialize in general practice as this reduces the time to become a medical specialist. We however did not find any results indicating that MPs' decision to specialize in general practice and to work as general practitioners was any less voluntary than that of MPs who chose other specialties.