Future Disease Severity Research Articles

Amino acid catabolite markers for early prognostication of pneumonia in patients with COVID-19

Effective early-stage markers for predicting which patients are at risk of developing SARS-CoV-2 infection have not been fully investigated. Here, we performed comprehensive serum metabolome analysis of a total of 83 patients from two cohorts to determine that the acceleration of amino acid catabolism within 5 days from disease onset correlated with future disease severity. Increased levels of de-aminated amino acid catabolites involved in the de novo nucleotide synthesis pathway were identified as early prognostic markers that correlated with the initial viral load. We further employed mice models of SARS-CoV2-MA10 and influenza infection to demonstrate that such de-amination of amino acids and de novo synthesis of nucleotides were associated with the abnormal proliferation of airway and vascular tissue cells in the lungs during the early stages of infection. Consequently, it can be concluded that lung parenchymal tissue remodeling in the early stages of respiratory viral infections induces systemic metabolic remodeling and that the associated key amino acid catabolites are valid predictors for excessive inflammatory response in later disease stages.

Integrated multi-omic analyses provide insight into colon adenoma susceptibility modulation by the gut microbiota.

Colon cancer onset is strongly associated with the differences in microbial taxa in the gastrointestinal tract. Although recent studies highlight the role of individual taxa, the effect of a complex gut microbiome (GM) on the metabolome and host transcriptome is still unknown. We used a multi-omics approach to determine how differences in the GM affect the susceptibility to adenoma development in a rat model of human colon cancer. Ultra-high performance liquid chromatography mass spectrometry of feces collected prior to observable disease onset identified putative metabolite profiles that likely predict future disease severity. Transcriptome analyses performed after disease onset from normal colonic epithelium and tumor tissues show a correlation between GM and host gene expression. Integrated pathway analyses of the metabolome and transcriptome based on putatively identified metabolic features indicate that bile acid biosynthesis is enriched in rats with high tumors along with increased fatty acid metabolism and mucin biosynthesis. Targeted pyrosequencing of the Pirc allele indicates that the GM alters the mechanism of adenoma development and may drive an epigenetic pathway of tumor suppressor silencing. This study reveals how untargeted metabolomics identifies signatures of susceptibility and integrated analyses uncover pathways of differential mechanisms of loss of tumor suppressor gene function and for potential prevention and therapeutic intervention. IMPORTANCE The association between the gut microbiome and colon cancer is significant but difficult to test in model systems. This study highlights the association of differences in the pathogen-free gut microbiome to changes in the host transcriptome and metabolome that correlate with colon adenoma initiation and development in a rat genetic model of early colon cancer. The utilization of a multi-omics approach integrating metabolomics and transcriptomics reveals differences in pathways including bile acid biosynthesis and fatty acid metabolism. The study also shows that differences in gut microbiomes significantly alter the mechanism of adenoma formation, shifting from genetic changes to epigenetic changes that initiate the early loss of tumor suppressor function. These findings enhance our understanding of the gut microbiome's role in colon cancer susceptibility, offer insights into potential biomarkers and therapeutic targets, and may pave the way for future prevention and intervention strategies.

Increased Abundance of Achromobacter xylosoxidans and Bacillus cereus in Upper Airway Transcriptionally Active Microbiome of COVID-19 Mortality Patients Indicates Role of Co-Infections in Disease Severity and Outcome.

ABSTRACTThe modulators of severe COVID-19 have emerged as the most intriguing features of SARS-CoV-2 pathogenesis. This is especially true as we are encountering variants of concern (VOC) with increased transmissibility and vaccination breakthroughs. Microbial co-infections are being investigated as one of the crucial factors for exacerbation of disease severity and complications of COVID-19. A key question remains whether early transcriptionally active microbial signature/s in COVID-19 patients can provide a window for future disease severity susceptibility and outcome? Using complementary metagenomics sequencing approaches, respiratory virus oligo panel (RVOP) and Holo-seq, our study highlights the possible functional role of nasopharyngeal early resident transcriptionally active microbes in modulating disease severity, within recovered patients with sub-phenotypes (mild, moderate, severe) and mortality. The integrative analysis combines patients’ clinical parameters, SARS-CoV-2 phylogenetic analysis, microbial differential composition, and their functional role. The clinical sub-phenotypes analysis led to the identification of transcriptionally active bacterial species associated with disease severity. We found significant transcript abundance of Achromobacter xylosoxidans and Bacillus cereus in the mortality, Leptotrichia buccalis in the severe, Veillonella parvula in the moderate, and Actinomyces meyeri and Halomonas sp. in the mild COVID-19 patients. Additionally, the metabolic pathways, distinguishing the microbial functional signatures between the clinical sub-phenotypes, were also identified. We report a plausible mechanism wherein the increased transcriptionally active bacterial isolates might contribute to enhanced inflammatory response and co-infections that could modulate the disease severity in these groups. Current study provides an opportunity for potentially using these bacterial species for screening and identifying COVID-19 patient sub-groups with severe disease outcome and priority medical care.IMPORTANCE COVID-19 is invariably a disease of diverse clinical manifestation, with multiple facets involved in modulating the progression and outcome. In this regard, we investigated the role of transcriptionally active microbial co-infections as possible modulators of disease pathology in hospital admitted SARS-CoV-2 infected patients. Specifically, can there be early nasopharyngeal microbial signatures indicative of prospective disease severity? Based on disease severity symptoms, the patients were segregated into clinical sub-phenotypes: mild, moderate, severe (recovered), and mortality. We identified significant presence of transcriptionally active isolates, Achromobacter xylosoxidans and Bacillus cereus in the mortality patients. Importantly, the bacterial species might contribute toward enhancing the inflammatory responses as well as reported to be resistant to common antibiotic therapy, which together hold potential to alter the disease severity and outcome.

Metabolomic profiling in small vessel disease identifies multiple associations with disease severity.

Cerebral small vessel disease is a major cause of vascular cognitive impairment and dementia. There are few treatments, largely reflecting limited understanding of the underlying pathophysiology. Metabolomics can be used to identify novel risk factors to better understand pathogenesis and to predict disease progression and severity.We analysed data from 624 patients with symptomatic cerebral small vessel disease from two prospective cohort studies. Serum samples were collected at baseline and patients underwent MRI scans and cognitive testing at regular intervals with up to 14 years of follow-up. Using ultra-performance liquid chromatography–mass spectrometry and nuclear magnetic resonance spectroscopy, we obtained metabolic and lipidomic profiles from 369 annotated metabolites and 54 764 unannotated features and examined their association with respect to disease severity, assessed using MRI small vessel disease markers, cognition and future risk of all-cause dementia.Our analysis identified 28 metabolites that were significantly associated with small vessel disease imaging markers and cognition. Decreased levels of multiple glycerophospholipids and sphingolipids were associated with increased small vessel disease load as evidenced by higher white matter hyperintensity volume, lower mean diffusivity normalized peak height, greater brain atrophy and impaired cognition. Higher levels of creatine, FA(18:2(OH)) and SM(d18:2/24:1) were associated with increased lacune count, higher white matter hyperintensity volume and impaired cognition. Lower baseline levels of carnitines and creatinine were associated with higher annualized change in peak width of skeletonized mean diffusivity, and 25 metabolites, including lipoprotein subclasses, amino acids and xenobiotics, were associated with future dementia incidence.Our results show multiple distinct metabolic signatures that are associated with imaging markers of small vessel disease, cognition and conversion to dementia. Further research should assess causality and the use of metabolomic screening to improve the ability to predict future disease severity and dementia risk in small vessel disease. The metabolomic profiles may also provide novel insights into disease pathogenesis and help identify novel treatment approaches.

Preventive Effect of Allergen Immunotherapy on Asthma and New Sensitizations

Allergen immunotherapy (AIT) is a disease-modifying treatment for some IgE-mediated allergic diseases with the potential to have important preventive effects. Children with allergic rhinitis have a high risk of developing asthma, and treating allergic rhinitis with AIT may interfere with disease progression and prevent onset of asthma. Although the evidence is limited due to relatively few and heterogeneous studies, data nevertheless suggest that AIT has a preventive effect on development of asthma especially in children with rhinitis due to grass pollen allergy. AIT may also affect the development of new sensitizations. Both the degree of sensitization and the specific sensitization pattern may influence future disease severity and development of comorbidities. Hitherto, the indication for AIT for prevention of development of asthma in grass/birch pollen allergic children has been the same as for treatment of allergic rhinitis. Probably, AIT should be applied in the early stage of the allergic disease to have the greatest preventive effect on disease progression. Consequently, in the future, the potential preventive effects should influence the timing of initiating AIT. The window of opportunity to prevent asthma may primarily exist in young children with mild symptoms and a low degree of sensitization.

Staphylococcus aureus and its IgE-inducing enterotoxins in asthma: current knowledge.

While immunoglobulin (Ig) E is a prominent biomarker for early-onset, its levels are often elevated in non-allergic late-onset asthma. However, the pattern of IgE expression in the latter is mostly polyclonal, with specific IgEs low or below detection level albeit with an increased total IgE. In late-onset severe asthma patients, specific IgE to Staphylococcal enterotoxins (se-IgE) can frequently be detected in serum, and has been associated with asthma, with severe asthma defined by hospitalisations, oral steroid use and decrease in lung function. Recently, se-IgE was demonstrated to even predict the development into severe asthma with exacerbations over the next decade. Staphylococcus aureus manipulates the airway mucosal immunology at various levels via its proteins, including superantigens, serine-protease-like proteins (Spls), or protein A (SpA) and possibly others. Release of IL-33 from respiratory epithelium and activation of innate lymphoid cells (ILCs) via its receptor ST2, type 2 cytokine release from those ILCs and T helper (Th) 2 cells, mast cell degranulation, massive local B-cell activation and IgE formation, and finally eosinophil attraction with consequent release of extracellular traps, adding to the epithelial damage and contributing to disease persistence via formation of Charcot-Leyden crystals are the most prominent hallmarks of the manipulation of the mucosal immunity by S. aureus In summary, S. aureus claims a prominent role in the orchestration of severe airway inflammation and in current and future disease severity. In this review, we discuss current knowledge in this field and outline the needs for future research to fully understand the impact of S. aureus and its proteins on asthma.

Inferring disease severity in rheumatoid arthritis using predictive modeling in administrative claims databases.

BackgroundConfounding by disease severity is an issue in pharmacoepidemiology studies of rheumatoid arthritis (RA), due to channeling of sicker patients to certain therapies. To address the issue of limited clinical data for confounder adjustment, a patient-level prediction model to differentiate between patients prescribed and not prescribed advanced therapies was developed as a surrogate for disease severity, using all available data from a US claims database.MethodsData from adult RA patients were used to build regularized logistic regression models to predict current and future disease severity using a biologic or tofacitinib prescription claim as a surrogate for moderate-to-severe disease. Model discrimination was assessed using the area under the receiver (AUC) operating characteristic curve, tested and trained in Optum Clinformatics® Extended DataMart (Optum) and additionally validated in three external IBM MarketScan® databases. The model was further validated in the Optum database across a range of patient cohorts.ResultsIn the Optum database (n = 68,608), the AUC for discriminating RA patients with a prescription claim for a biologic or tofacitinib versus those without in the 90 days following index diagnosis was 0.80. Model AUCs were 0.77 in IBM CCAE (n = 75,579) and IBM MDCD (n = 7,537) and 0.75 in IBM MDCR (n = 36,090). There was little change in the prediction model assessing discrimination 730 days following index diagnosis (prediction model AUC in Optum was 0.79).ConclusionsA prediction model demonstrated good discrimination across multiple claims databases to identify RA patients with a prescription claim for advanced therapies during different time-at-risk periods as proxy for current and future moderate-to-severe disease. This work provides a robust model-derived risk score that can be used as a potential covariate and proxy measure to adjust for confounding by severity in multivariable models in the RA population. An R package to develop the prediction model and risk score are available in an open source platform for researchers.

Effect of Climatic Variables on Abundance and Dispersal of Lecanosticta acicola Spores and Their Impact on Defoliation on Eastern White Pine.

The disease complex white pine needle damage (WPND), first reported in 2006, has now escalated to an epidemic state across the northeastern United States. Although this complex is composed of several fungal species, Lecanosticta acicola is considered to be the primary causal agent. Knowledge regarding the epidemiology, specific climatic factors that affect the spread of L. acicola on eastern white pine (Pinus strobus) in natural forest settings, and potential risks repeated defoliation may have on tree health is limited. Therefore, this study examined how climatic variables affect the abundance and distance of spore dispersal of L. acicola and compared litterfall caused by defoliation versus natural needle abscission. Conidia were observed on spore traps from May through August, with a peak in abundance occurring in June, corresponding to the defoliation of second- and third-year foliage measured in litter traps. During peak spore production, relative humidity and the occurrence of rainfall was found to have the greatest influence on spore abundance. Our results will aid managers in determining how far from infected trees natural regeneration will likely be affected and predicting future disease severity based on climatic conditions.

Evaluation of [18F]PFH PET renography to predict future disease progression in a rat model of autosomal dominant polycystic kidney disease

IntroductionPrognostic markers for progression of polycystic kidney disease (PKD) are limited. We evaluated the potential of early para-[18F]fluorohippurate ([18F]PFH) positron emission tomography (PET) renography to predict future progression of PKD in Han:SPRD rats with slowly progressive autosomal dominant PKD. Materials and methodsMale and female heterozygous (Cy/+) and normal littermate (+/+) Han:SPRD rats underwent [18F]PFH PET renography and blood sampling to measure serum creatinine (S-Cr) and serum urea nitrogen (SUN) concentrations at 6 and 26wk of age. T2 and T20 values, which represent the percent of the injected dose of [18F]PFH in kidneys at 2 and 20min after injection, were determined from imaging data. T20/T2 ratio was assessed as a prognostic marker. Rats were euthanized after renography at 26wk of age, and kidney weight/body weight ratios (KW/BW%) were determined as a measure of PKD progression. ResultsMale and female Cy/+ rats are known to manifest PKD of different severity, male Cy/+ rats display much more severe PKD than female rats. S-Cr and SUN concentrations did not differ between +/+ and Cy/+ rats and between female and male Cy/+ rats at 6wk of age, but they were higher at 26wk of age and male rats displayed higher values than female rats, which indicates inability of S-Cr and SUN to measure disease severity at an early stage. T20/T2 ratios were higher for Cy/+ than +/+ rats at 6wk of age. Importantly, male Cy/+ rats displayed higher T20/T2 ratios than female Cy/+ rats. T20/T2 ratios obtained at 6wk of age correlated well with S-Cr, SUN, and KW/BW% values obtained at 26wk of age. ConclusionsThis study indicates that T20/T2 ratio derived from [18F]PFH PET renography at an early age could be useful as a novel prognostic marker to predict future disease severity in a rat model of ADPKD.

Serum soluble bone turnover biomarkers in psoriatic arthritis and psoriatic spondyloarthropathy.

Because psoriatic arthritis (PsA) is an inflammatory disease of joints, serum soluble biomarkers specific for chronic joint and bone inflammation may predict future disease severity and response to therapy, thereby informing stratified medicine approaches. The objectives of our systematic review were to determine whether serum soluble bone and cartilage turnover biomarkers are (1) associated with PsA or psoriatic spondyloarthropathy; and (2) associated with disease activity, disease severity, or clinical phenotype. Ten studies met eligibility criteria. Matrix metalloproteinase (MMP)-3, Dickkopf (DKK)-1, macrophage colony-stimulating factor (M-CSF), crosslinked telopeptide of collagen-1, and tumor necrosis factor-related apoptosis-inducing ligand were associated with PsA, with equivocal results for osteoprotegerin (OPG) and bone alkaline phosphatase (ALP). MMP-3, DKK-1, M-CSF, CPII:C2C (ratio of cartilage degradation vs byproduct formation), and possibly OPG were associated with PsA independently of psoriasis. C1-2C (a neoepitope released when type 2 cartilage is degraded by collagenases) was associated with both tender and swollen joint counts, and bone morphogenetic protein-4 with patient global assessment of disease, pain score, and the Bath Ankylosing Spondylitis Disease Activity Index. Bone ALP was associated with disease activity. M-CSF and receptor activator of nuclear factor-κB ligand were associated with several plain radiographic features. No studies have investigated biomarker associations specifically with axial PsA.

Biomarkers of Joint Damage in Rheumatoid Arthritis: Where Are We in 2013?

The search for biomarkers identifying key targets for the assessment of major outcomes in chronic diseases has become one of the most interesting topics of research in different areas of clinical medicine, in particular in oncology, hematology, and rheumatology. In rheumatoid arthritis (RA), one of the leading causes of disability among chronic diseases, possible biomarkers should help the rheumatologist to identify (in very early or early RA) the patients who are going to respond quickly and favorably to disease-modifying antirheumatic drugs (DMARD), those not responding to DMARD and receiving biologic therapies (among which there is great need of biomarkers to choose a “personalized” biologic agent), those not responding to any of the several biologics, and finally, in all the previous settings, those who will develop structural damage more rapidly. Currently, researchers have great interest in the field of “personalized medicine,” which should allow physicians to optimally match patient with treatment1. The ideal biomarker should be similar to glycated hemoglobin (i.e., target for HbA1c less than 7)2, which gives significant information on the metabolic status of the patient with diabetes before and after therapy, particularly the metabolic status that allows or prevents progression of vascular damage in terms of diabetes-related comorbidities such as acute myocardial infarction, stroke, or diabetic nephropathy3. RA is characterized by synovitis and joint tissue destruction, including cartilage loss and bone erosion, with variability in outcome in different patients, that is, a self-limiting disease in some, and one characterized by progressive joint destruction in others. Biomarkers could be devised to define the aggressiveness of synovitis and to monitor the structural damage, or there could be 1 ideal biomarker summarizing both aspects. The possibility of identifying the individual RA patient’s future disease severity could guide the choice of the best treatment … Address correspondence to Prof. G. Ferraccioli, Division of Rheumatology, Institute of Rheumatology and Affiliated Sciences, University of the Sacred Heart, Complesso Integrato Columbus, Via Giuseppe Moscati 31, 00168 Rome, Italy. E-mail: gf.ferraccioli{at}rm.unicatt.it

A rat model of Charcot–Marie–Tooth disease 1A recapitulates disease variability and supplies biomarkers of axonal loss in patients

Charcot-Marie-Tooth disease is the most common inherited neuropathy and a duplication of the peripheral myelin protein 22 gene causes the most frequent subform Charcot-Marie-Tooth 1A. Patients develop a slowly progressive dysmyelinating and demyelinating peripheral neuropathy and distally pronounced muscle atrophy. The amount of axonal loss determines disease severity. Although patients share an identical monogenetic defect, the disease progression is strikingly variable and the impending disease course can not be predicted in individual patients. Despite promising experimental data, recent therapy trials have failed. Established clinical outcome measures are thought to be too insensitive to detect amelioration within trials. Surrogate biomarkers of disease severity in Charcot-Marie-Tooth 1A are thus urgently needed. Peripheral myelin protein 22 transgenic rats harbouring additional copies of the peripheral myelin protein 22 gene ('Charcot-Marie-Tooth rats'), which were kept on an outbred background mimic disease hallmarks and phenocopy the variable disease severity of patients with Charcot-Marie-Tooth 1A. Hence, we used the Charcot-Marie-Tooth rat to dissect prospective and surrogate markers of disease severity derived from sciatic nerve and skin tissue messenger RNA extracts. Gene set enrichment analysis of sciatic nerve transcriptomes revealed that dysregulation of lipid metabolism associated genes such as peroxisome proliferator-activated receptor gamma constitutes a modifier of present and future disease severity. Importantly, we directly validated disease severity markers from the Charcot-Marie-Tooth rats in 46 patients with Charcot-Marie-Tooth 1A. Our data suggest that the combination of age and cutaneous messenger RNA levels of glutathione S-transferase theta 2 and cathepsin A composes a strong indicator of disease severity in patients with Charcot-Marie-Tooth 1A, as quantified by the Charcot-Marie-Tooth Neuropathy Score. This translational approach, utilizing a transgenic animal model, demonstrates that transcriptional analysis of skin biopsy is suitable to identify biomarkers of Charcot-Marie-Tooth 1A.

Increased Reticulocytosis in Infants with Sickle Cell Disease May Be a Marker for Future Disease Severity

Abstract▪2128▪This icon denotes a clinically relevant abstractThe first erythropoietic stress in term neonates occurs at the time of the erythrocyte nadir (around three months of age) and is associated with increased reticulocytosis. In infants with sickle cell disease (HbSS, SCD), this nadir generally precedes the onset of clinical signs and symptoms. The objective of this study was to determine if reticulocyte levels and properties during early infancy in SCD patients are useful in disease severity prediction. Peripheral blood from 111 children with SCD who were enrolled in this observational study was analyzed within 48 hours of collection and storage at 4°C. Reticulocytes were quantified by absolute reticulocyte count (ARC) as well as reticulocyte flow cytometry phenotyping and sorting using CD71 (CD71 Hi, CD71 Lo and CD71 Neg) and CD36 markers. Among the entire group, ARC is negatively correlated with HbF (r=−0.72, p<0.0001) and F-cells (r=−0.68, p<0.0001). Analysis of lysates from sorted reticulocytes and red blood cells revealed that the least mature reticulocytes (CD71 Hi) had the lowest HbF levels. CD71 Hi sickle reticulocytes also expressed the adhesion molecule CD36 on the cell surface. CD36 was barely detectable in reticulocytes from healthy infants and older children. The proportion of sickle red cells that expressed CD71 at Hi and Lo levels was compared to age-matched healthy controls. Although red blood cells with similar levels of CD71 Lo (mean healthy infant controls 0.71±0.36% vs. 0.92±0.30% in SCD infants, p=0.43) were present in both healthy infants and infants with SCD less than five months of age, CD71 Hi expression was significantly higher in infants with SCD (mean healthy infant controls 0.19±0.08% vs. 0.58±0.25% in SCD infants, p=0.02). Examination of the reticulocyte profiles of SCD patients older than 5 months of age revealed markedly increased CD71 Lo and Hi levels when compared to similarly aged healthy controls (mean CD71 Lo healthy controls 0.31±0.30% vs SCD patients 4.06±3.45%, p=0.0001; mean CD71 Hi healthy controls 0.01±0.01% vs. SCD patients 1.55±1.42%, p=0.0001). Clinically, increased reticulocytosis during this nadir period (2–5 months of age) was associated with a worse clinical course during infancy and childhood. The ARC at physiologic nadir was identified by retrospective chart review for 37 of the 111 enrolled subjects. Significantly higher ARCs were associated with hospitalization during the first three years of life. Of the twelve children who had not been hospitalized by 3 years of age, only one had an ARC greater than 200 K/uL during the nadir period (mean ARC for the no hospitalization group 151±54 K/uL). Among subjects who were first hospitalized before age 3 years for acute chest syndrome (ACS, n=6), there was no significant increase in ARC (mean ARC 174±95, p=0.53 vs. no hospitalization group). However, patients who were first hospitalized for splenic sequestration (n=8) and vaso-occlusive crisis (VOC, n=11) had significantly higher ARCs [splenic sequestration 223±66 K/uL (p=0.017), VOC 262±102 K/uL, (p=0.004) vs. the no hospitalization group]. Twelve of 37 (32%) patients received chronic therapy with either monthly transfusions or hydroxyurea before the age of 12 years (ARC range 123–384 K/uL, mean 250±82 K/uL). Nine of the twelve (75%) had a steady state ARC of greater than 200 K/uL between ages 2 and 5 months. These data support the hypothesis that completion of the fetal-to-adult hemoglobin switching phenomenon during infancy triggers the beginning of a pathologic cascade of increased sickle hemoglobin polymerization and hemolysis followed by increased release of immature reticulocytes that express adhesion molecules including CD36. Among SCD infants with lower expression of fetal hemoglobin, the magnitude of the reticulocyte response is predicted to be further driven by uncompensated tissue hypoxia. Overall, the data suggest that increased reticulocytosis is one of the earliest clinical features of SCD, and the level of reticulocytosis during the first five months of postnatal life may help predict disease severity later in life. Disclosures:No relevant conflicts of interest to declare.

Prediction of Disease Severity in Patients with Early Rheumatoid Arthritis by Gene Expression Profiling

In order to test the ability of peripheral blood gene expression profiles to predict future disease severity in patients with early rheumatoid arthritis (RA), a group of 17 patients (1 ± 0.2 years disease duration) was evaluated at baseline for gene expression profiles. Disease status was evaluated after a mean of 5 years using an index combining pain, global and recoded MHAQ scores. Unsupervised and supervised algorithms identified “predictor genes” whose combined expression levels correlated with follow-up disease severity scores. Unsupervised clustering algorithms separated patients into two branches. The only significant difference between these two groups was the disease severity score; demographic variables and medication usage were not different. Supervised T-Test analysis identified 19 “predictor genes” of future disease severity. Results were validated in an independent cohort of subjects of established RA with using Support Vector Machines and K-Nearest-Neighbor Classification. Our study demonstrates that peripheral blood gene expression profiles may be a useful tool to predict future disease severity in patients with early and established RA.

Histologic Predictors of Future Ulcerative Colitis Disease Severity

Purpose: Accurate prediction of future disease severity course may optimize management of ulcerative colitis (UC) including tailoring “top-down” versus “step-up” approaches to therapy. We sought to determine if specific histologic variable could predict future clinical UC disease severity. Methods: The initial histopathology parameters from 19 patients with UC that later (≥ 6 months) underwent colectomy for severe disease (colectomy/severe course group) were compared to those from 25 patients who did not require colectomy (no colectomy/mild course group) from 1998–2007. The pathology variables assessed were cryptitis, cryptopenia, crypt branching, crypt abscesses, ulcerations and mucin depletion. The predictive value of disease extent, endoscopic severity, and initial serum albumin were also assessed. Groups were compared using Chi-square, Mann-Whitney or t-test with a significance level of 0.05. Patients with dysplasia were excluded. Results: Patients were followed for a median of 3 years. Median age was 39 years in no colectomy group versus 34 years in colectomy group (NS). Severe cryptitis occurred in 16/19 (84%) in colectomy group versus 13/25 (52%) in no colectomy group (P= 0.026). Cryptopenia was present in 11 (58%) colectomy group versus 10 (40%) no colectomy group (P= 0.239). In colectomy group, crypt abscesses were present in 16 (84%), crypt branching 16 (84%), mucin depletion 18 (96%), ulceration 6 (24%) at the initial histopathology. The prevalence of crypt abscess, crypt branching, cryptopenia, mucin depletion, ulceration were all not significantly different in the colectomy (severe course) versus no colectomy (mild course) group. A Mayo Score ≥2 on initial endoscopy was not significantly more common in colectomy group 13 (69%) versus no colectomy group 18 (75%) (P= 0.228). The initial albumin was significantly lower in the colectomy group 2.9 g/dL (SD ± 0.88) versus noncolectomy group 3.5 g/dL (SD ± 0.57) (P= 0.040). Pancolitis at initial endoscopy was not more prevalent in the colectomy group (32%) versus noncolectomy (32%). Immunosuppressant usage was not statistically different between groups: colectomy group (24%) versus no colectomy (32%). Conclusion: Cryptopenia, mucin depletion, crypt branching and crypt abscesses are common findings in UC but do not predict future clinical disease severity. The initial serum albumin and cryptitis were the only variables predictive of future progression to colectomy. Histopathology with extensive cryptitis was more predictive of future severe disease that eventually required colectomy than was the initial endoscopic severity or disease extent. Future prospective studies are required to confirm the prognostic value of diffuse cryptitis to predict a future colectomy in UC.

Health perceptions and treatment adherence in adults with cystic fibrosis.

Clinical and demographic variables are poor predictors of treatment adherence. This study therefore examined the relationships between the patients' perception of their cystic fibrosis and their reported adherence to physiotherapy, exercise, pancreatic enzyme and vitamin therapies. Sixty adults with cystic fibrosis completed the Health Perception Scale, Health Locus of Control Scale, and the Manchester Adult Cystic Fibrosis Compliance Questionnaire. Reported adherence to physiotherapy, exercise, pancreatic enzyme and vitamin therapies was not influenced by patients' perceptions of their past, current and future disease severity, or their perceived susceptibility to recurrent infections. The greater their level of worry regarding their disease, the more likely they were to adhere to their physiotherapy (p < 0.002), pancreatic enzyme (p < 0.001) and vitamin (p < 0.001) regimens. No difference between the exercise adherent and non-adherent groups emerged regarding their level of worry. Compared with patients who believed that they were in control of their health, those who believed that their cystic fibrosis was controlled by others (family and health professionals) reported greater levels of adherence to their physiotherapy (p < 0.001), pancreatic enzyme (p < 0.001) and vitamin (p < 0.001) therapies. In contrast, patients who adhered to their exercise regimen believed that they were in control of their disease to a greater extent than those who did not (p < 0.003). Worrying about cystic fibrosis and the perception of having little personal control over the disease facilitated treatment adherence. It is clear that patients perceive exercise therapy differently from other forms of treatment.