Implement social prescribing successfully towards embedding: what works, for whom and in which context? A rapid realist review.

BACKGROUND: Some clients who access healthcare services experience problems due to the wider determinants of health which cannot be addressed (solely) by the medical sector. Social Prescribing (SP) addresses clients ' wider health needs and is based on linkworkers who support primary care clients in accessing social, community and voluntary care services that support their needs. Previous literature has provided valuable insights about what works (or not) in an early stage of implementing SP. However, there is limited insight into what works for the implementation of SP towards embedding. This study provides guiding principles by which SP can be successfully implemented towards the embedding stage and identifies which contextual factors and mechanisms influence these guiding principles. METHODS: A Rapid Realist Review was conducted to examine what works, for whom, why, and in which contexts. A local Dutch reference panel consisting of health and care organisations helped to inform the research questions. Additionally, a workshop was held with the panel, to discuss what the international insights mean for their local contexts. This input helped to further refine the literature review's findings. RESULTS: Five guiding principles were identified for successful implementation of SP at the embedding stage: • Create awareness for addressing the wider determinants of health and the role SP services can play; • Ensure health and care professionals build trusting relationships with all involved stakeholders to create a cyclical referral process; • Invest in linkworkers' skills and capacity so that they can act as a bridge between the sectors; • Ensure clients receive appropriate support to improve their self-reliance and increase their community participation; • Invest in the aligning of structures, processes and resources between involved sectors to support the use of SP services. CONCLUSION: To embed SP, structural changes on a system level as well as cultural changes are needed. This will require a shift in attitude amongst health and care professionals as well as clients towards the use, role and benefit of SP services in addressing the wider determinants of health. It will also require policymakers and researchers to involve communities and include their perspectives.

A case report of a blueberry muffin baby caused by congenital self-healing indeterminate cell histiocytosis.

BACKGROUND: Blueberry muffin is a descriptive term for a neonate with multiple purpuric skin lesions. Many causes are known, amongst them life-threatening diseases like congenital infections or leukemia. Indeterminate cell histiocytosis (ICH) is an exceptionally rare cause of blueberry muffin rash. ICH is a histiocytic disorder which can be limited to the skin or can present with systemic involvement. A mutation that has been described in histiocytic disorders is a MAP2K1 mutation. In ICH, this mutation has previously been described in merely one case. CASE PRESENTATION: A term male neonate was admitted to the neonatology ward directly after birth because of a blueberry muffin rash. ICH was diagnosed on skin biopsy. The lesions resolved spontaneously. The patient is currently 3 years old and has had no cutaneous lesions or systemic involvement so far. This disease course is similar to that of the Hashimoto-Pritzker variant of LCH. CONCLUSIONS: ICH can manifest in neonates as resolving skin lesions. It is limited to the skin in most cases, but systemic development is possible. Therefore, it is essential to confirm the diagnosis with a biopsy before the lesions resolve and to monitor these patients closely with routine follow-up.

Update about Oralair® as a treatment for grass pollen allergic rhinitis.

Sublingual immunotherapy (SLIT) is a well-tolerated, safe, and effective approach to treating allergic rhinitis (AR). Oralair® is a five-grass pollen SLIT tablet containing natural pollen allergens from five of the major grass species responsible for seasonal AR due to grass pollen allergy. Recommended use is in a pre-coseasonal regimen, starting daily treatment approximately 4 months before the start of the pollen season, with treatment then continued daily throughout the season; treatment should continue for 3-5 y. Clinical efficacy and safety of Oralair® in patients with grass pollen-induced AR has been demonstrated in a comprehensive clinical development program of randomized controlled trials. Effectiveness has been substantiated in subsequent observational studies with sustained efficacy following treatment cessation and a favorable level of adherence, quality of life, benefit, and satisfaction for the patients. Supportive evidence for a benefit in reducing the risk or delaying the development of allergic asthma is emerging.

The impact of maintenance therapy on sleep-wake rhythms and cancer-related fatigue in pediatric acute lymphoblastic leukemia.

PURPOSE: To assess the impact of maintenance therapy and the additional impact of dexamethasone treatment on cancer-related fatigue and sleep-wake rhythms in pediatric acute lymphoblastic leukemia (ALL) patients and to determine the association between these outcomes. METHODS: A national cohort of pediatric ALL patients (≥ 2 years) was included (± 1 year post-diagnosis). Patients receiving dexamethasone were assessed twice (assessment with and without dexamethasone). Actigraphy assessments were used to calculate sleep-wake outcomes with nonparametric methods. Cancer-related fatigue was assessed with the PedsQL Multidimensional Fatigue Scale. Sleep-wake rhythms and cancer-related fatigue were compared between patients participating in the assessment without dexamethasone and healthy children (linear regression) and between assessments with and without dexamethasone (mixed models). Using linear regression, associations between sleep-wake outcomes and cancer-related fatigue were determined during assessments with and without dexamethasone. RESULTS: Responses were collected for 125 patients (113 assessments with and 81 without dexamethasone). The sleep-wake rhythm was less stable (p = 0.03) and less robust (p = 0.01), with lower physical activity levels (p < 0.001) and higher cancer-related fatigue levels (p < 0.001) in ALL patients compared to healthy children. Physical activity was lower (p = 0.001) and cancer-related fatigue more severe (p ≤ 0.001) during assessments with dexamethasone compared to without dexamethasone. Sleep-wake outcomes were significantly associated with cancer-related fatigue during periods without dexamethasone, but not during periods with dexamethasone. CONCLUSION: Sleep-wake rhythms are disturbed, physical activity levels lower, and cancer-related fatigue levels higher during maintenance therapy. Interventions aimed to enhance sleep-wake rhythms during maintenance therapy could improve cancer-related fatigue. Families should be supported in coping with the additional burden of dexamethasone treatment to improve well-being of ALL patients.

Measuring vincristine-induced peripheral neuropathy in children with cancer: validation of the Dutch pediatric-modified Total Neuropathy Score.

PURPOSE: The aims were to evaluate the construct validity and reliability of the Dutch version of the pediatric-modified Total Neuropathy Score (ped-mTNS) for assessing vincristine-induced peripheral neuropathy (VIPN) in Dutch pediatric oncology patients aged 5-18 years. METHODS: Construct validity (primary aim) of the ped-mTNS was determined by testing hypotheses about expected correlation between scores of the ped-mTNS (range: 0-32) and the Common Terminology Criteria for Adverse Events (CTCAE) (range: 0-18) for patients and healthy controls and by comparing patients and controls regarding their total ped-mTNS scores and the proportion of children identified with VIPN. Inter-rater and intra-rater reliability and measurement error (secondary aims) were assessed in a subgroup of study participants. RESULTS: Among the 112 children (56 patients and 56 age- and gender-matched healthy controls) evaluated, correlation between CTCAE and ped-mTNS scores was as expected (moderate (r = 0.60)). Moreover, as expected, patients had significantly higher ped-mTNS scores and more frequent symptoms of VIPN compared with controls (both p < .001). Reliability as measured within the intra-rater group (n = 10) (intra-class correlation coefficient (ICCagreement) = 0.64, standard error of measurement (SEMagreement) = 2.92, and smallest detectable change (SDCagreement) = 8.1) and within the inter-rater subgroup (n = 10) (ICCagreement = 0.63, SEMagreement = 3.7, and SDCagreement = 10.26) indicates insufficient reliability. CONCLUSION: The Dutch version of the ped-mTNS appears to have good construct validity for assessing VIPN in a Dutch pediatric oncology population, whereas reliability appears to be insufficient and measurement error high. To improve standardization of VIPN assessment in children, future research aimed at evaluating and further optimizing the psychometric characteristics of the ped-mTNS is needed.

Population Pharmacokinetics and Pharmacodynamics of Ciprofloxacin Prophylaxis in Pediatric Acute Lymphoblastic Leukemia Patients.

BACKGROUND: Ciprofloxacin is used as antimicrobial prophylaxis in pediatric acute lymphoblastic leukemia (ALL) to decrease infections with gram-negative bacteria. However, there are no clear guidelines concerning prophylactic dose. AIMS: To determine the pharmacokinetics and pharmacodynamics (PKPD) of ciprofloxacin prophylaxis in a pediatric ALL population. The effect of patient characteristics and antileukemic treatment on ciprofloxacin exposure, the area under the concentration time curve over minimal inhibitory concentration (AUC24/MIC) ratios, and emergence of resistance were studied. METHODS: A total of 615 samples from 129 children (0-18 years) with ALL were collected in a multicenter prospective study. A population pharmacokinetic model was developed. Microbiological cultures were collected prior to and during prophylaxis. An AUC24/MIC of ≥125 was defined as target ratio. RESULTS: A 1-compartment model with zero-order absorption and allometric scaling best described the data. No significant (P < .01) covariates remained after backward elimination and no effect of asparaginase or azoles were found. Ciprofloxacin AUC24 was 16.9 mg*h/L in the prednisone prophase versus 29.3 mg*h/L with concomitant chemotherapy. Overall, 100%, 81%, and 18% of patients at, respectively, MIC of 0.063, 0.125, and 0.25 mg/L achieved AUC24/MIC ≥ 125. In 13% of the patients, resistant bacteria were found during prophylactic treatment. CONCLUSION: Ciprofloxacin exposure shows an almost 2-fold change throughout the treatment of pediatric ALL. Depending on the appropriateness of 125 as target ratio, therapeutic drug monitoring or dose adjustments might be indicated for less susceptible bacteria starting from ≥ 0.125 mg/L to prevent the emergence of resistance and reach required targets for efficacy.

Assessment of 3D motion modeling performance for dose accumulation mapping on the MR-linac by simultaneous multislice MRI.

Hybrid MR-linac systems enable intrafraction motion monitoring during radiation therapy. Since time-resolved 3D MRI is still challenging, various motion models have been developed that rely on time-resolved 2D imaging. Continuous validation of these models is important for accurate dose accumulation mapping. In this study we used 2D simultaneous multislice (SMS) imaging to improve the PCA-based motion modeling method developed previously (Stemkens et al 2016 Phys. Med. Biol. 61 5335-55). From the additional simultaneously acquired slices, several independent motion models could be generated, which allowed for an assessment of the sensitivity of the motion model to the location of the time-resolved 2D slices. Additionally, the best model could be chosen at every time-point, increasing the method's robustness. Imaging experiments were performed in six healthy volunteers using three simultaneous slices, which generated three independent models per volunteer. For each model the motion traces of the liver tip and both kidneys were estimated. We found that the location of the 2D slices influenced the model's error in five volunteers significantly with a p -value <0.05, and that selecting the best model at every time-point can improve the method. This allows for more accurate and robust motion characterization in MR-guided radiotherapy.

Characterization of imaging latency for real-time MRI-guided radiotherapy.

Hybrid MR-linac systems can use fast dynamic MR sequences for tumor tracking and adapt the radiation treatment in real-time. For this the imaging latency must be as short as possible. This work describes how different acquisition parameters influence this latency. First, the latency was measured for Cartesian readouts with phase encode orderings linear, reverse-linear, and high-low. Second, the latency was measured for radial readouts with linear and golden angle profile orderings. To reduce the latency, a spatio-temporal (k-t) filter that suppresses the k-space center of earlier acquired spokes was implemented for the golden angle sequence. For Cartesian readouts a high-low ordering achieved a three times lower latency compared to a linear ordering with our sampling parameters. For radial readouts the filter was able to reduce the acquisition latency from half the acquisition time to a quarter of the acquisition time. The filter did not compromise the signal-to-noise ratio and the artifact power.

Dynamic Fluorescence Microscopy of Cellular Uptake of Intercalating Model Drugs by Ultrasound-Activated Microbubbles.

PURPOSE: The combination of ultrasound and microbubbles can facilitate cellular uptake of (model) drugs via transient permeabilization of the cell membrane. By using fluorescent molecules, this process can be studied conveniently with confocal fluorescence microscopy. This study aimed to investigate the relation between cellular uptake and fluorescence intensity increase of intercalating model drugs. PROCEDURES: SYTOX Green, an intercalating fluorescent dye that displays >500-fold fluorescence enhancement upon binding to nucleic acids, was used as a model drug for ultrasound-induced cellular uptake. SYTOX Green uptake was monitored in high spatiotemporal resolution to qualitatively assess the relation between uptake and fluorescence intensity in individual cells. In addition, the kinetics of fluorescence enhancement were studied as a function of experimental parameters, in particular, laser duty cycle (DC), SYTOX Green concentration and cell line. RESULTS: Ultrasound-induced intracellular SYTOX Green uptake resulted in local fluorescence enhancement, spreading throughout the cell and ultimately accumulating in the nucleus during the 9-min acquisition. The temporal evolution of SYTOX Green fluorescence was substantially influenced by laser duty cycle: continuous laser (100 % DC) induced a 6.4-fold higher photobleaching compared to pulsed laser (3.3 % DC), thus overestimating the fluorescence kinetics. A positive correlation of fluorescence kinetics and SYTOX Green concentration was found, increasing from 0.6 × 10-3 to 2.2 × 10-3 s-1 for 1 and 20 µM, respectively. Finally, C6 cells displayed a 2.4-fold higher fluorescence rate constant than FaDu cells. CONCLUSIONS: These data show that the temporal behavior of intracellular SYTOX Green fluorescence enhancement depends substantially on nuclear accumulation and not just on cellular uptake. In addition, it is strongly influenced by the experimental conditions, such as the laser duty cycle, SYTOX Green concentration, and cell line.

Imaging of pediatric great vessel stents: Computed tomography or magnetic resonance imaging?

BACKGROUND: Complications might occur after great vessel stent implantation in children. Therefore follow-up using imaging is warranted. PURPOSE: To determine the optimal imaging modality for the assessment of stents used to treat great vessel obstructions in children. MATERIAL AND METHODS: Five different large vessel stents were evaluated in an in-vitro setting. All stents were expanded to the maximal vendor recommended diameter (20mm; n = 4 or 10mm; n = 1), placed in an anthropomorphic chest phantom and imaged with a 256-slice CT-scanner. MRI images were acquired at 1.5T using a multi-slice T2-weighted turbo spin echo, an RF-spoiled three-dimensional T1-weighted Fast Field Echo and a balanced turbo field echo 3D sequence. Two blinded observers assessed stent lumen visibility (measured diameter/true diameter *100%) in the center and at the outlets of the stent. Reproducibility of diameter measurements was evaluated using the intraclass correlation coefficient for reliability and 95% limits of agreement for agreement analysis. RESULTS: Median stent lumen visibility was 88 (IQR 86-90)% with CT for all stents at both the center and outlets. With MRI, the T2-weighted turbo spin echo sequence was preferred which resulted in 82 (78-84%) stent lumen visibility. Interobserver reliability and agreement was good for both CT (ICC 0.997, mean difference -0.51 [-1.07-0.05] mm) and MRI measurements (ICC 0.951, mean difference -0.05 [-2.52 --2.41] mm). CONCLUSION: Good in-stent lumen visibility was achievable in this in-vitro study with both CT and MRI in different great vessel stents. Overall reliability was good with clinical acceptable limits of agreement for both CT and MRI. However, common conditions such as in-stent stenosis and associated aneurysms were not tested in this in-vitro study, limiting the value of the in-vitro study.

Towards real-time thermometry using simultaneous multislice MRI.

MR-guided thermal therapies, such as high-intensity focused ultrasound (MRgHIFU) and laser-induced thermal therapy (MRgLITT) are increasingly being applied in oncology and neurology. MRI is used for guidance since it can measure temperature noninvasively based on the proton resonance frequency shift (PRFS). For therapy guidance using PRFS thermometry, high temporal resolution and large spatial coverage are desirable. We propose to use the parallel imaging technique simultaneous multislice (SMS) in combination with controlled aliasing (CAIPIRINHA) to accelerate the acquisition. We compare this with the sensitivity encoding (SENSE) acceleration technique. Two experiments were performed to validate that SMS can be used to increase the spatial coverage or the temporal resolution. The first was performed in agar gel using LITT heating and a gradient-echo sequence with echo-planar imaging (EPI), and the second was performed in bovine muscle using HIFU heating and a gradient-echo sequence without EPI. In both experiments temperature curves from an unaccelerated scan and from SMS, SENSE, and SENSE/SMS accelerated scans were compared. The precision was quantified by a standard deviation analysis of scans without heating. Both experiments showed a good agreement between the temperature curves obtained from the unaccelerated, and SMS accelerated scans, confirming that accuracy was maintained during SMS acceleration. The standard deviations of the temperature measurements obtained with SMS were significantly smaller than when SENSE was used, implying that SMS allows for higher acceleration. In the LITT and HIFU experiments SMS factors up to 4 and 3 were reached, respectively, with a loss of precision of less than a factor of 3. Based on these results we conclude that SMS acceleration of PRFS thermometry is a valuable addition to SENSE, because it allows for a higher temporal resolution or bigger spatial coverage, with a higher precision.

Fatal hyperammonaemia due to late-onset ornithine transcarbamylase deficiency.

In this case report we describe a 67-year-old male, admitted to the ICU with pneumonia who unexpectedly developed a fatal coma due to hyperammonaemia. At postmortem the diagnosis late-onset ornithine transcarbamylase deficiency was made. The non-specific clinical presentation, the rapid deterioration and incidentally the fatal outcome all underline the importance of recognition and knowledge of this genetic disorder. Several measures to treat and prevent potentially fatal episodes of hyperammonaemia are available, if only the disorder is recognised in time. In retrospect, several clues to the diagnosis were available in this fatal case, such as voluntary protein avoidance, as well as several male family members who died at a young age of an unknown cause. After his death, two daughters were discovered to be carriers of an OTC gene mutation, as well as his infant grandson. We emphasise the importance of obtaining ammonia levels in all patients with unexplained coma, seizures or cerebral oedema, irrespective of their age, especially in patients in the ICU or in an otherwise catabolic state.

Correction for photobleaching in dynamic fluorescence microscopy: application in the assessment of pharmacokinetic parameters in ultrasound-mediated drug delivery.

We have previously demonstrated the feasibility of monitoring ultrasound-mediated uptake of a hydrophilic model drug in real time with dynamic confocal fluorescence microscopy. In this study, we evaluate and correct the impact of photobleaching to improve the accuracy of pharmacokinetic parameter estimates. To model photobleaching of the fluorescent model drug SYTOX Green, a photobleaching process was added to the current two-compartment model describing cell uptake. After collection of the uptake profile, a second acquisition was performed when SYTOX Green was equilibrated, to evaluate the photobleaching rate experimentally. Photobleaching rates up to 5.0 10(-3) s(-1) were measured when applying power densities up to 0.2 W.cm(-2). By applying the three-compartment model, the model drug uptake rate of 6.0 10(-3) s(-1) was measured independent of the applied laser power. The impact of photobleaching on uptake rate estimates measured by dynamic fluorescence microscopy was evaluated. Subsequent compensation improved the accuracy of pharmacokinetic parameter estimates in the cell population subjected to sonopermeabilization.

Primary ovarian insufficiency in children after treatment with 131I-metaiodobenzylguanidine for neuroblastoma: report of the first two cases.

BACKGROUND: Primary ovarian insufficiency (POI) is a noted late effect in childhood cancer survivors treated with alkylating agents or after radiation to a field that includes the ovaries. Gonadal failure in children with neuroblastoma (NBL) who were exposed to 131I- metaiodobenzylguanidine (MIBG) has only been reported in those who were also treated with chemotherapy. In these cases, the cause of gonadal failure was assumed to be the cytotoxic therapy. Here, we present the first two cases of POI after 131I-MIBG treatment only for NBL, indicating that 131I-MIBG treatment may have a causative role. PATIENTS: During follow-up after treatment for NBL in childhood, elevated gonadotropins were found in a 12-year-old girl and an 11-year-old girl (FSH values, 105 and 161 U/L, respectively), indicating POI. The first patient had been diagnosed at the age of 17 months with sacrally located (intraspinal) NBL. Treatment consisted of five courses of 131I-MIBG and local resection. The second patient had been diagnosed at the age of 8 months with an abdominal (intraspinal) NBL. She had been treated with acute (neuro) surgery for decompression of her intraspinal tumor causing neurological symptoms, followed by two courses of 131I-MIBG therapy. Both girls had normal karyotypes (46, XX). No other cause for the ovarian failure was found. Estrogen suppletion was started, and patients and parents were counseled regarding fertility options. CONCLUSION: These two cases suggest that exposure to 131I-MIBG may damage the female gonads. Clinicians caring for childhood cancer survivors should be aware of the risk of POI after 131I-MIBG treatment. Prospective studies are warranted to confirm our observations.

Psychiatric symptoms causing delay in diagnosing childhood cancer: two case reports and literature review.

INTRODUCTION: A somatic disorder may initially be overlooked when a child presents with psychiatric symptoms. We report two children with anorexia nervosa as initial diagnosis and in whom there was a delay in the final diagnosis of the underlying malignancy. A literature survey was performed including patients under 18 years of age with psychiatric symptoms in whom later on an oncological diagnosis became evident as an explanation. RESULTS: We have found 30 additional cases, with a median delay of 12 months until the diagnosis of the tumour. Overall, 16 boys and 16 girls had a solid tumour: 26 central nervous system tumours, 3 tumours of the gastrointestinal tract and 3 others. In 25 out of 32 patients anorexia nervosa was assumed, although it always appeared to be atypical. Patients younger than 7 years had a significantly longer delay until final diagnosis, while no other patient characteristics correlated with such delay. DISCUSSION: In addition to careful physical (including full neurological) examination, we advise additional neuroimaging especially in each case of atypical presentation of anorexia nervosa, in order to avoid a delay in diagnosis of a possible malignancy. Furthermore, it is desirable to perform a re-examination when a psychiatric disorder does not respond to therapy, in order not to overlook an underlying oncological disease.

Energy restriction only slightly influences protein metabolism in obese rats, whatever the level of protein and its source in the diet.

BACKGROUND: High protein (HP) diets during energy restriction have been studied extensively regarding their ability to reduce body fat and preserve lean body mass, but little is known about their effects on protein metabolism in lean tissues. OBJECTIVE: To determine the effects of energy restriction and protein intake on protein anabolism and catabolism in rats. METHODS: For 5 weeks, 56 male Wistar rats were fed an obesity induction (OI) diet . They were then subjected to a 40% energy restriction using the OI diet or a balanced HP diet for 3 weeks, whereas a control group was fed the OI diet ad libitum (n=8 per group). HP-restricted rats were divided into five groups differing only in terms of their protein source: total milk proteins, casein (C), whey (W), a mix of 50% C and W, and soy (n=8). The animals were then killed in the postprandial state and their body composition was determined. Protein synthesis rates were determined in the liver, gastrocnemius and kidney using a subcutaneous (13)C valine flooding dose. mRNA levels were measured for key enzymes involved in the three proteolysis pathways. RESULTS: Energy restriction, but not diet composition, impacted weight loss and adiposity, whereas lean tissue mass (except in the kidney) was not influenced by diet composition. Levels of neoglucogenic amino acids tended to fall under energy restriction (P<0.06) but this was reversed by a high level of protein. The postprandial protein synthesis rates in different organs were similar in all groups. By contrast, mRNA levels encoding proteolytic enzymes rose under energy restriction in the muscle and kidney, but this was counteracted by a HP level. CONCLUSIONS: In adult obese rats, energy restriction but not diet composition affected fat pads and had little impact on protein metabolism, despite marked effects on proteolysis in the kidney and muscle.

Possible pathogenic role of the transmembrane isoform of CD160 NK lymphocyte receptor in paroxysmal nocturnal hemoglobinuria.

PIGA mutations in paroxysmal nocturnal hemoglobinuria (PNH) patients lead to a glycosylphosphatidylinositol (GPI)-linked membrane proteins expression deficiency. Herein, we report the constitutive expression of the transmembrane CD160 (CD160-TM) activating receptor on non PIGA-mutated PNH patients circulating NK cells. In healthy individuals, only the GPI-anchored isoform of CD160 receptors is expressed on the circulating NK lymphocytes, while the transmembrane isoform appears after ex vivo activation. Similarly to CD160-GPI, we identified CD160-TM as a receptor for the MHC class I molecules. We demonstrate that PNH patients NK lymphocytes spontaneously produce significant amounts of IFN-γ that is inhibited by anti-CD160-TM or anti-MHC class I mAbs. These results indicate that circulating NK cells from PNH patients exhibit a self-MHC class I molecule reactive effector function, which could be mediated through the recruitment of CD160-TM receptor. Our data provide new insights regarding the possible role of CD160-TM on PNH patients NK lymphocytes and in the pathogenesis of the disease.

Molecular subtypes of systemic sclerosis in association with anti-centromere antibodies and digital ulcers.

The objective of this study was to identify molecular profiles that may distinguish clinical subtypes in systemic sclerosis (SSc). Large-scale gene expression profiling was performed on peripheral blood (PB) from 12 SSc patients and 6 healthy individuals. Significance analysis of microarrays, two-way hierarchical cluster analysis and PANTHER (Protein ANalysis THrough Evolutionary Relationships) ontology classification were used to analyze the data. Quantitative PCR was applied for validation in a cohort of 43 SSc patients. The results show that the expression of genes involved in immune defense, cell cycle and signal transduction was significantly elevated in PB of SSc patients (n=12) compared with healthy individuals (n=6). SSc patients could be stratified into subgroups based on differential expression of genes induced by type I interferon (IFN) and genes involved in antimicrobial (AM) activity. Differential expression of type I IFN or AM signature genes was validated and extended in an independent cohort of 31 patients by quantitative PCR. Low expression of IFN response genes was associated with the presence of anti-centromere antibodies, whereas increased expression was associated with the appearance of digital ulcers. In conclusion, patients with SSc can be classified on the basis of differential expression of immune defense genes. Differences in the activity of the type I IFN response program stratify patients into two clinically relevant subgroups.