Identification of early risk factors for anti-citrullinated-protein-antibody positive rheumatoid arthritis-a prospective cohort study.

OBJECTIVE: Individuals positive for anti-cyclic-peptide-antibodies (anti-CCP) and musculoskeletal complaints (MSK-C) are at risk for developing rheumatoid arthritis (RA). In this study we aimed to investigate factors involved in arthritis progression. METHODS: Anti-CCP2-positive individuals with MSK-C referred to a rheumatologist were recruited. Individuals lacked arthritis at clinical and ultrasound examination and were followed for ≥three years or until clinical arthritis diagnosis. Blood samples from inclusion were analyzed for; nine anti-citrullinated-protein-antibody (ACPA) reactivities (citrullinated α-1-enolase, fibrinogen, filaggrin, histone, vimentin and tenascin peptides); 92 inflammation-associated proteins; and HLA-shared epitope alleles. Cox regression was applied to the data to identify independent predictors in a model. RESULTS: 267 individuals were included with median follow up of 49 months (IQR: 22-60). 101 (38%) developed arthritis after median 14 months (IQR: 6-27). The analysis identified that presence of at least one ACPA reactivity (HR 8.0, 95% CI 2.9-22), ultrasound detected tenosynovitis (HR 3.4, 95% CI 2.0-6.0), IL6 levels (HR 1.5, 95% CI 1.2-1.8) and IL15-Rα levels (HR 0.6, 95% CI 0.4-0.9) are significant independent predictors for arthritis progression in a prediction model (Harrell's C 0.76 [SE 0.02], AUC 0.82 [95% CI 0.76-0.89], cross-validated AUC 0.70 [95% CI 0.56-0.85]). CONCLUSION: We propose a high-Risk-RA phase characterized by presence of ACPA reactivity, tenosynovitis, IL6, and IL15-Rα and suggest that these factors need to be further investigated for their biological effects and clinical values, to identify individuals at particular low risk and high risk for arthritis progression.

Enhancing petunia tissue culture efficiency with machine learning: A pathway to improved callogenesis.

The important feature of petunia in tissue culture is its unpredictable and genotype-dependent callogenesis, posing challenges for efficient regeneration and biotechnology applications. To address this issue, machine learning (ML) can be considered a powerful tool to analyze callogenesis data, extract key parameters, and predict optimal conditions for petunia callogenesis, facilitating more controlled and productive tissue culture processes. The study aimed to develop a predictive model for callogenesis in petunia using ML algorithms and to optimize the concentrations of phytohormones to enhance callus formation rate (CFR) and callus fresh weight (CFW). The inputs for the model were BAP, KIN, IBA, and NAA, while the outputs were CFR and CFW. Three ML algorithms, namely MLP, RBF, and GRNN, were compared, and the results revealed that GRNN (R2≥83) outperformed MLP and RBF in terms of accuracy. Furthermore, a sensitivity analysis was conducted to determine the relative importance of the four phytohormones. IBA exhibited the highest importance, followed by NAA, BAP, and KIN. Leveraging the superior performance of the GRNN model, a genetic algorithm (GA) was integrated to optimize the concentration of phytohormones for maximizing CFR and CFW. The genetic algorithm identified an optimized combination of phytohormones consisting of 1.31 mg/L BAP, 1.02 mg/L KIN, 1.44 mg/L NAA, and 1.70 mg/L IBA, resulting in 95.83% CFR. To validate the reliability of the predicted results, optimized combinations of phytohormones were tested in a laboratory experiment. The results of the validation experiment indicated no significant difference between the experimental and optimized results obtained through the GA. This study presents a novel approach combining ML, sensitivity analysis, and GA for modeling and predicting callogenesis in petunia. The findings offer valuable insights into the optimization of phytohormone concentrations, facilitating improved callus formation and potential applications in plant tissue culture and genetic engineering.

Distinct Fluorescence Optical Imaging Patient Clusters Emerge for Seropositive and Seronegative Rheumatoid Arthritis.

OBJECTIVE: To investigate whether digital activity fluorescence optical imaging (FOI) patterns of inflammation can identify distinct rheumatoid arthritis (RA) phenotypes. METHODS: The hands of newly diagnosed patients with RA were evaluated by clinical examination, musculoskeletal ultrasound, and FOI. Inflammation on FOI was defined when capillary leakage and/or fluorophore perfusion was present. The FOI composite image was quantified into a digital disease activity (DACT) score, using novel computerized algorithms. Unsupervised clustering on FOI inflammatory patterns was used to identify subgroups of patients relative to anticyclic citrullinated peptides (ACPA) and/or rheumatoid factor (RF). RESULTS: Of 1326 examined hand joints in 39 patients with RA (72% female; 56% ever-smokers; 54% RF positive and 69% ACPA positive), 400 (30%) showed inflammation by FOI, and 95% (37 of 39) of patients had DACT-FOI scores greater than 1. Unsupervised analysis on FOI patterns revealed two patient clusters, cluster 1 (n = 29) and cluster 2 (n = 10). The proportion of seropositive patients was significantly higher in cluster 1 versus cluster 2 (90%, 26 of 29 vs. 30%, 3 of 10; P < 0.01), whereas C-reactive-protein levels (minimum-maximum) were significantly higher in cluster 2 (20 mg/l [1-102]) versus cluster 1 (2 mg/l [0-119]; P = 0.01). A wider variety and proportion of inflamed joints emerged for patients with RA in cluster 2 versus cluster 1, in which inflammation was more concentrated around the wrists and the right metacarpophalangeal 2 (MCP2), bilateral MCP3, and, to a lesser degree, left MCP2 and proximal interphalangeal joint and tendon regions. Cluster 1 displayed lower mean (±SD) DACT scores compared with cluster 2 (3.6 ± 2.1 vs. 5.4 ± 2.1; P = 0.03). CONCLUSION: FOI-based digital quantification of hand joint inflammation revealed two distinct RA subpopulations with and without ACPA and RF related autoantibodies.

Comparison of Caregivers' Burden among Family Members of Patients with Severe Mental Disorders and Patients with Substance Use Disorder.

Objective: The burden on caregivers of patients with severe mental disorders is significantly higher than the care burden of patients with other medical conditions. Substance use disorder is also one of the most common psychiatric disorders that has negative effects on people's quality of life. This study was designed to investigate caregiver burden in severe mental disorders versus substance use disorder. Method : First-degree relatives of patients admitted to the Razi Psychiatric Hospital of Tehran with a diagnosis of schizophrenia, bipolar disorder type1, schizoaffective disorder, or substance use disorder entered this study. They completed the sociodemographic questionnaire for patients and caregivers and the Zarit burden interview for caregivers. Results: Our study shows that caregiver burden in substance use disorder has no significant difference with that in severe mental disorders (P > 0.05). In both groups, the highest spectrum of burden was moderate to severe. To find caregiver burden related factors, a general linear regression model with multiple predictor variables was fitted. In this model, caregivers' burden was significantly higher in patients with comorbidity (P = 0.007), poor compliance (P < 0.001), and in female caregivers (P = 0.013). Conclusion: Statistically speaking, the caregiver burden in substance use disorders is as severe as other mental disorders. The considerable burden on both groups necessitates serious efforts to minimize its negative effects.

Comparative analysis of different artificial neural networks for predicting and optimizing in vitro seed germination and sterilization of petunia.

The process of optimizing in vitro seed sterilization and germination is a complicated task since this process is influenced by interactions of many factors (e.g., genotype, disinfectants, pH of the media, temperature, light, immersion time). This study investigated the role of various types and concentrations of disinfectants (i.e., NaOCl, Ca(ClO)2, HgCl2, H2O2, NWCN-Fe, MWCNT) as well as immersion time in successful in vitro seed sterilization and germination of petunia. Also, the utility of three artificial neural networks (ANNs) (e.g., multilayer perceptron (MLP), radial basis function (RBF), and generalized regression neural network (GRNN)) as modeling tools were evaluated to analyze the effect of disinfectants and immersion time on in vitro seed sterilization and germination. Moreover, non­dominated sorting genetic algorithm­II (NSGA­II) was employed for optimizing the selected prediction model. The GRNN algorithm displayed superior predictive accuracy in comparison to MLP and RBF models. Also, the results showed that NSGA­II can be considered as a reliable multi-objective optimization algorithm for finding the optimal level of disinfectants and immersion time to simultaneously minimize contamination rate and maximize germination percentage. Generally, GRNN-NSGA-II as an up-to-date and reliable computational tool can be applied in future plant in vitro culture studies.

Effect of Irrigation Solution Temperature on Complication of Percutaneous Nephrolithotomy: A Randomized Clinical Trial.

PURPOSE: Many factors affecthypothermia and shivering during percutaneous nephrolithotomy and in recovery.Hence this study was carried out to determine the effect of irrigation solution temperature on complications ofpercutaneous nephrolithotomy. MATERIALS AND METHODS: In this randomized clinical trial, 60 patients undergoing PCNL in Sina University Hospitalwere enrolled. The patients were randomly assigned in three groups according to simple random manner. Thegroups included three groups of room temperature fluid (24 degree), warm solution (37 degree), and cold fluid (20degree) during nephroscopy. RESULTS: Although the initial core temperature was alike across the groups (P > .05); the hypothermia rate occuredin all 20 patients in the cold fluid group (P = .012). There was significant difference between the groups interms of final temperature and alteration amount (P = .001). The mean VAS scores were significantly lower in thewarm fluid group compared with the others groups at recovery, and 8hrs post-operatively (P = .03). Assessmentof shivering rates revealed that 3(15%) patients in warm solution group shivered compared to8 (40%) patients incold fluid group (P = .018). CONCLUSION: Warm irrigation solution during PCNL results in significantly decreased hypothermia, mean postoperativepain score and shivering. Hence use of warm irrigation fluid for this matter is recommended.

Association of Limb-Girdle muscular dystrophy with multiple sclerosis: A case report.

BACKGROUND: The association of limb-girdle muscular dystrophy (LGMD) with other neurological disorders is uncommon. CASE PRESENTATION: We report a 25-year-old female with LGMD who suffered from slowly progressive proximal muscular weakness and atrophy since she was 12 years of age. The patient recently presented with acute loss of left side visual acuity. After evaluation, findings were suggestive of multiple sclerosis. CONCLUSIONS: This is the first report of LGMD in association with MS. The simultaneous occurrence of MS with myopathies may be incidental but there may be a genetic susceptibility for both diseases. This comorbidity may influence the treatment of MS.

Recurrent isolated optic neuritis: A study on 22 patients.

Background: Isolated relapsing optic neuropathy is a recurrent painful optic nerve inflammation without any sign of other demyelinating diseases such as multiple sclerosis (MS) or neuromyelitis optica (NMO) spectrum disorders, and the attacks are purely responsive to steroid therapy. Methods: Recurrent isolated optic neuritis (RION) was diagnosed in patients who presented with at least two disseminating episodes of optic neuritis, and negative clinical, para-clinical, and radiological features of the demyelinating, infiltrative and vasculitis disorders involving optic nerve. The patients were assigned into two groups, chronic recurrent isolated optic neuritis (CRION) entailing patients with steroid dependent attack of optic neuritis and RION patients without steroid dependent attack of optic neuritis. They were monitored over a median of 4.0 ± 2.5 years. Results: There were 16 women and six men with CRION and RION; with the median age of 31.7 ± 9.8 (29.3 ± 9.7 for women and 37.7 ± 7.7 for men). The women to men ratio was 2.6:1. The mean optic neuritis attack was 2.95 ± 1.32 in total. Eight patients were RION while 14 patients fulfilled CRION criteria and took long term immuno-suppressive drugs. In their follow-up, 4 out of 14 CRION cases (28.5%) showed clinical and concordant para-clinical features of NMO spectrum disorder. The analysis of demographic data showed that the average number of ON attacks in CRION patients (3.79 ± 2.32) was significantly more than the average in patients with RION (2.25 ± 0.46, P = 0.02). Conclusion: CRION is a disease which requires aggressive glucocorticoid and long-term immunosuppressive therapy to restore visual acuity.

Totally tubeless percutaneous nephrolithotomy is feasible in morbidly obese patients.

OBJECTIVE: Regarding technical difficulties that obese body habitus might impose to percutaneous nephrolithotomy (PNL) success and higher risk of peri-operative complications in this group of patients, we decided to retrospectively gather data from our patients during past 8 years to determine the stone free and complication rates. MATERIAL AND METHODS: Between January 2007-December 2015, seventy-eight obese patients with body mass index over 35 who had indication for PNL including stones larger than 2 cm in pelvi-calyceal system or smaller extracorporeal shock wave lithotripsy (ESWL) resistant stones or who were not a fit candidate for ESWL due to increased skin to target distance, with no contraindication of PNL (including bleeding diathesis, inability to be positioned in prone) were enrolled. They were randomly assigned to group 1 (standard PNL with nephrostomy and ureteral stent) or group 2 (totally tubeless PNL with no ureteral stent and no nephrostomy). The outcomes were compared. RESULTS: The transfusion rate, operation time, and the hemoglobin drop were same across the groups (p>0.05). Total analgesic use was equivalent of 33.8 vs. 14.7 mgs of morphine sulfate (18-77 mg) and was significantly lower in total tubeless group (p=0.001). Return to normal activity was described as total number of in-patient and outpatient days from time of admission to the point which the patients returns to normal life activity such as going to job or school and was 19.4 vs. 9.3 days (6-30 days, p=0.001). CONCLUSION: Totally tubeless PNL in obese subjects would have lower analgesic use and return to normal activity versus standard PNL. Totally tubeless PNL is recommended for obese patients.

Screw as a Bladder Foreign Body.

Foreign bodies in the bladder are among the strangest differential diagnoses in the lower urinary tract symptoms (LUTS) and may be missed in initial medical evaluations. We present a 63-year-old man who was visited in the emergency department because of obstructive and irritative lower urinary tract symptoms. Two months earlier, he had a pelvic fracture due to motor vehicle accident and underwent an open reduction and internal fixation of the pubic rami and right acetabulum by an anterior ilioinguinal approach. After initial evaluation, an abdominopelvic X-ray revealed a 3 cm screw in the suprapubic area. He underwent urethrocystoscopy and a 3 cm screw was extracted by forceps.

Analysis of correlation and causes for discrepancy between quantitative and semi-quantitative Doppler scores in synovitis in rheumatoid arthritis.

OBJECTIVES: The aim of this study was to evaluate the association between two semi-quantitative Doppler US scoring systems (SQS), and the quantitative scoring (QS) of Doppler pixel count. METHODS: Adult patients with RA and inadequate clinical response to anti-rheumatic therapy were examined with musculoskeletal US (MSUS). Dorsal MSUS of the wrists, MCP and MTP 2-5 were performed. MSUS images with sign of synovitis were collected and the QS was measured. Five assessors blinded to the QS evaluated the images independently, according to either SQS method. Association between QS and SQS was studied using correlations and multilevel models taking into account the clustering of ratings at the rater, patient and joint levels. RESULTS: Analysis of the 1190 ratings revealed a strong correlation (ρ = 0.89, P < 0.0001) and significant associations (P < 0.0001) between QS and SQS. Correlations between QS and SQS according to Szkudlarek et al. (ρ = 0.87, P < 0.0001) or Hammer et al. (ρ = 0.91, P < 0.0001) were similar. A total of 239 (20.1%) images were given a SQS grade that did not match that expected based on initial QS, using pre-defined cut-offs. Main explanations for discrepancies were different perceived region of interest (40.7%) and Doppler pixel count near cut-offs between SQS grades (32.3%). CONCLUSION: We showed that both SQS methods correlated well with QS to assess synovitis, but SQS methods are intrinsically limited when the Doppler pixel count is close to the cut-offs between the SQS grades. Analysis discrepancies between these methods may help further revision of criteria used to assess disease activity with MSUS in RA.

Detection of clinically manifest and silent synovitis in the hands and wrists by fluorescence optical imaging.

OBJECTIVES: The correct identification of synovitis is critical for achieving optimal therapy results. Fluorescence optical imaging (FOI) is a novel modality based on the use of an intravenous fluorophore, which enables fluorescent imaging of the hands and wrists with increased focal optical signal intensities in areas of high perfusion and/or capillary leakage. The study objective was to determine the diagnostic utility of FOI in detecting apparent and clinically non-apparent active synovitis. METHODS: Bilateral hand and wrist joints (n=872) of 26 patients with inflammatory arthritis assessed by standard clinical examination, musculoskeletal ultrasound (MSUS) and FOI were studied. Synovitis was defined as tender and swollen joints on clinical examination, presence of synovial thickening and intra-articular Doppler signals on MSUS, and abnormal focal optical signal intensities on FOI, respectively. Subclinical synovitis was defined as being clinically non-apparent, but positively inflamed on MSUS. RESULTS: Depending on the standard used to define inflammation, FOI ranged from 73-83% sensitive and 83-95% specific for detecting manifest synovitis. For detecting clinically silent synovitis, the sensitivity, specificity and positive and negative predictive values of FOI were 80%, 96%, 77% and 97%, respectively. CONCLUSIONS: The high degree of agreement between MSUS and FOI suggest its use in clinical practice, especially when MSUS is not available, in order to identify synovitis earlier and with greater confidence. FOI may be particularly useful in identifying patients with clinically non-apparent joint inflammation of the hands and/or wrists.

Current smoking status is a strong predictor of radiographic progression in early rheumatoid arthritis: results from the SWEFOT trial.

OBJECTIVES: To study clinical predictors for radiographic progression after 1 year in an early rheumatoid arthritis (RA) trial. METHODS: In the SWEFOT trial population, disease modifying antirheumatic drug (DMARD) naïve RA patients started methotrexate; 3-month responders (DAS28 <3.2) continued (n=147), while non-responders were randomised to addition of sulfasalazine+hydroxychloroquine (n=130) or infliximab (n=128). X-rays were scored by the Sharp-van der Hejde score (SHS) method and radiographic progression was defined as a ≥5 increase after 1 year. Potential baseline predictors of radiographic progression were tested using multivariable logistic regression, adjusted for potential confounders. RESULTS: 79 of 311 patients with available radiographs at baseline and follow-up had radiographic progression. The following baseline parameters were independent predictors of radiographic progression at 1 year: baseline erosions (adjusted OR=2.29, 95% CI 1.24 to 4.24), erythrocyte sedimentation rate (adjusted OR per tertile increase=1.72, 95% CI 1.12 to 2.65) and C-reactive protein (adjusted OR per tertile increase=1.52, 95% CI 1.03 to 2.26). Current smoking was an independent predictor of radiographic progression (adjusted OR=2.17, 95% CI 1.06 to 4.45). These results remained after further adjustment for treatment strategy. Three-dimensional matrix including current smoking status, erosions and C-reactive protein tertiles showed a 12-63% risk gradient from patients carrying none compared with all predictors. Rheumatoid factor (RF)/anti-cyclic citrullinated peptide (anti-CCP) positivity did not significantly predict radiographic progression using SHS increase ≥5 as cut-off. In a secondary exploratory analysis using cut-off >1, both RF and anti-CCP positivity were significant predictors in the unadjusted, but not the adjusted analyses. The other parameters also remained significant using this lower cut-off. CONCLUSIONS: In addition to previously described predictors, we identified smoking as a strong independent risk factor for radiographic progression in early RA. TRIAL REGISTRATION NUMBER: NCT00764725.

Diagnostic utility of musculoskeletal ultrasound in patients with suspected arthritis--a probabilistic approach.

INTRODUCTION: This study aimed to assess the utility of musculoskeletal ultrasound (MSUS) in patients with joint symptoms using a probabilistic approach. METHODS: One hundred and three patients without prior rheumatologic diagnosis and referred to our clinic for evaluation of inflammatory arthritis were included. Patients were assessed clinically including joint examination, laboratory testing including acute-phase reactants, rheumatoid factor (RF) and anti citrulinated protein antibody (ACPA), and radiographs of hands and feet if clinically indicated. A diagnostic assessment was then performed by the responsible rheumatologist where the probability of a) any inflammatory arthritis and b) rheumatoid arthritis was given on a 5-point scale ranging from 0 to 20% up to 80 to 100% probability. Subsequently, an ultrasound examination of the wrist, metacarpophalangeal (MCP), proximal interphalangeal (PIP) joints 2 to 5 in both hands, metatarsophalangeal (MTP) joints 2 to 5 in both feet and any symptomatic joints was performed and the results presented to the same rheumatologist. The latter then assessed the diagnostic probabilities again, using the same scale. RESULTS: The rheumatologists' certainty for presence/absence of inflammatory arthritis and rheumatoid arthritis was increased significantly following ultrasound performance. The proportion of patient for whom diagnostic certainty for inflammatory arthritis was maximal was 33.0% before and 71.8% after musculoskeletal ultrasound (P <0.001). With regard to a diagnosis of RA, the proportions were 31.1% pre-test and 61.2% post-test (P <0.001). MSUS findings agreed with the final diagnosis in 95% of patients. CONCLUSION: Musculoskeletal ultrasound, when added to routine rheumatologic investigation, greatly increases the diagnostic certainty in patients referred for the evaluation of inflammatory arthritis. The changes from pre-test to post-test probability quantify the diagnostic utility of musculoskeletal ultrasound in probabilistic terms.

Evaluation of hand bone loss by digital X-ray radiogrammetry as a complement to clinical and radiographic assessment in early rheumatoid arthritis: results from the SWEFOT trial.

BACKGROUND: To investigate hand bone loss (HBL) measured by digital X-ray radiogrammetry (DXR) in patients with early rheumatoid arthritis (RA) receiving different treatment regimens, and to evaluate if DXR change rates during the first 12 months correlate with radiological damage after 24 months. METHODS: From the total SWEFOT trial population, 159 patients had hand radiographs correctly timed and taken with same modality to be analyzed with DXR. All patients started treatment with methotrexate. After 3-4 months, patients with DAS28 > 3.2 were randomized to add sulfasalazine and hydroxychloroquine (triple therapy) or infliximab (MTX + INF). Those with DAS28 ≤3.2 were followed in regular care. Radiographic progression over 24 months was scored according to the Sharp van der Heijde score (SHS) and defined as >5 increase in T-SHS over 24 months. Hand bone mineral density (BMD) was measured by DXR at inclusion and 12 months and a change ≥2.5 mg/cm2/month was used as a cut-off for HBL. RESULTS: In the MTX responders, triple therapy, and MTX + INF groups, the proportions with HBL were 4.1%, 22.2% and 16.4%, respectively (p = 0.01), and the mean (SD) radiological progression in these groups was 3.91 (6.72), 7.40 (14.63) and 2.72 (4.55) respectively (p = 0.06). Patients with HBL had significantly greater risk for radiographic progression, compared with patients without HBL (odds ratio 3.09, 95% CI =1.20-7.79, p = 0.02). CONCLUSIONS: Non-responders to MTX had a significantly greater risk of HBL than MTX-responders, despite the add-on therapies. Patients with HBL during the 12 months had greater risk of radiographic progression after 24 months. Evaluation of HBL may help to identify patients who are at risk of radiographic progression.

In early rheumatoid arthritis, patients with a good initial response to methotrexate have excellent 2-year clinical outcomes, but radiological progression is not fully prevented: data from the methotrexate responders population in the SWEFOT trial.

OBJECTIVE: To investigate the 2-year clinical and radiological outcomes of patients with early rheumatoid arthritis (RA; symptom duration <1 year) who had initially responded well to methotrexate monotherapy. METHODS: In the SWEFOT trial, all 487 patients started methotrexate (target dose 20 mg/week). After 3-4 months, 147 had low disease activity, 28-joint based disease activity score (DAS28) ≤3.2. These patients were not randomly selected but were followed in regular care for 2 years. Clinical outcomes and radiographic progression according to the van der Heijde modified Sharp (SvdH) score were analysed. RESULTS: The majority of the 147 patients continued on methotrexate monotherapy. After 1 and 2 years, DAS28 remission was achieved in 59.6% and 71.8% and mean observed DAS28 values were 2.53 and 2.25, respectively. Despite the favourable clinical course, a proportion of the patients progressed radiographically with a mean (SD) increase in the SvdH score after 2 years of 3.90 (6.84). There was no significant difference in progression between patients in DAS28 remission versus not in remission (p=0.73). At baseline, approximately half the patients had no radiographic damage, while after 2 years the proportion was approximately 20%. CONCLUSION: Most early RA patients who achieve low disease activity after 3-4 months of methotrexate monotherapy continue to have low disease activity during 2 years follow-up, and additional treatment is needed infrequently. Some radiological progression occurs in most patients, and may be marked or severe in some, even despite sustained DAS28 remission. Close monitoring for radiological progression is thus warranted.