Progression of Bone Marrow Lesions and the Development of Knee Osteoarthritis: Osteoarthritis Initiative Data.

Background Bone marrow lesions (BMLs) are a known risk factor for incident knee osteoarthritis (OA), and deep learning (DL) methods can assist in automated segmentation and risk prediction. Purpose To develop and validate a DL model for quantifying tibiofemoral BML volume on MRI scans in knees without radiographic OA and to assess the association between longitudinal BML changes and incident knee OA. Materials and Methods This retrospective study included knee MRI scans from the Osteoarthritis Initiative prospective cohort (February 2004-October 2015). The DL model, developed between August and October 2023, segmented the tibiofemoral joint into 10 subregions and measured BML volume in each subregion. Baseline and 4-year follow-up MRI scans were analyzed. Knees without OA at baseline were categorized into three groups based on 4-year BML volume changes: BML-free, BML regression, and BML progression. The risk of developing radiographic and symptomatic OA over 9 years was compared among these groups. Results Included were 3869 non-OA knees in 2430 participants (mean age, 59.5 years ± 9.0 [SD]; female-to-male ratio, 1.3:1). At 4-year follow-up, 2216 knees remained BML-free, 1106 showed an increase in BML volume, and 547 showed a decrease in BML volume. BML progression was associated with a higher risk of developing radiographic knee OA compared with remaining BML-free (hazard ratio [HR] = 3.0; P < .001) or BML regression (HR = 2.0; P < .001). Knees with BML progression also had a higher risk of developing symptomatic OA compared with BML-free knees (HR = 1.3; P < .001). Larger volume changes in BML progression were associated with a higher risk of developing both radiographic OA (HR = 2.0; P < .001) and symptomatic OA (HR = 1.7; P < .001). In almost all subchondral plates, especially the medial femur and tibia, BML progression was associated with a higher risk of developing both radiographic and symptomatic OA compared with remaining BML-free. Conclusion Knees with BML progression, according to subregion and extent of volume changes, were associated with an increased risk of OA compared with BML-free knees and knees with BML regression, highlighting the potential utility of monitoring BML volume changes in evaluating interventions to prevent OA development. ClinicalTrials.gov Identifier: NCT00080171 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Said and Sakly in this issue.

Erosive hand osteoarthritis and sarcopenia: data from Osteoarthritis Initiative cohort.

OBJECTIVES: There is no evidence linking specific osteoarthritis (OA) types, such as erosive hand OA (EHOA), with distant generalised changes in muscle composition (sarcopenia), which can potentially be modified. This study pioneers the exploration of the association between EHOA and sarcopenia, both of which are predominantly observed in the older adults. METHODS: Using the Osteoarthritis Initiative cohort, we selected hand OA (modified Kellgren and Lawrence (grade ≥2 in ≥1 hand joint) participants with radiographic central erosions in ≥1 joints (EHOA group) and propensity score-matched hand OA participants with no erosion (non-EHOA group). MRI biomarkers of thigh muscles were measured at baseline, year 2 and year 4 using a validated deep-learning algorithm. To adjust for 'local' effects of coexisting knee OA (KOA), participants were further stratified according to presence of radiographic KOA. The outcomes were the differences between EHOA and non-EHOA groups in the 4-year rate of change for both intramuscular adipose tissue (intra-MAT) deposition and contractile (non-fat) area of thigh muscles. RESULTS: After adjusting for potential confounders, 844 thighs were included (211 EHOA:633 non-EHOA; 67.1±7.5 years, female/male:2.9). Multilevel mixed-effect regression models showed that EHOA is associated a different 4-year rate of change in intra-MAT deposition (estimate, 95% CI: 71.5 mm2/4 years, 27.9 to 115.1) and contractile area (estimate, 95% CI: -1.8%/4 years, -2.6 to -1.0) of the Quadriceps. Stratified analyses showed that EHOA presence is associated with adverse changes in thigh muscle quality only in participants without KOA. CONCLUSIONS: EHOA is associated with longitudinal worsening of thigh muscle composition only in participants without concomitant KOA. Further research is needed to understand the systemic factors linking EHOA and sarcopenia, which unlike EHOA is modifiable through specific interventions.

Thigh muscle composition changes in knee osteoarthritis patients during weight loss: Sex-specific analysis using data from osteoarthritis initiative.

OBJECTIVES: Sex of patients with knee osteoarthritis (KOA) may impact changes in thigh muscle composition during weight loss, the most well-known disease-modifying intervention. We investigated longitudinal sex-based changes in thigh muscle quality during weight loss in participants with KOA. METHODS: Using Osteoarthritis Initiative (OAI) cohort data, we included females and males with baseline radiographic KOA who experienced > 5 % reduction in Body Mass Index (BMI) over four years. Using a previously validated deep-learning algorithm, we measured Magnetic Resonance Imaging (MRI)-derived biomarkers of thigh muscles at baseline and year-4. Outcomes were the intra- and inter-muscular adipose tissue (Intra-MAT and Inter-MAT) and contractile percentage of thigh muscles between females and males. The analysis adjusted for potential confounders, such as demographics, risk factors, BMI change, physical activity, diet, and KOA status. RESULTS: A retrospective selection of available thigh MRIs from KOA participants who also had a 4-year weight loss (>5 % of BMI) yielded a sample comprising 313 thighs (192 females and 121 males). Female and male participants exhibited a comparable degree of weight loss (females: -9.72 ± 4.38, males: -8.83 ± 3.64, P-value=0.060). However, the changes in thigh muscle quality were less beneficial for females compared to males, as shown by a less degree of longitudinal decrease in Intra-MAT (change difference,95 %CI: 783.44 mm2/4-year, 505.70 to 1061.19, P-value<0.001) and longitudinal increase in contractile percentage (change difference,95 %CI: -3.9 %/4-year, -6.5 to -1.4, P-value=0.019). CONCLUSIONS: In participants with KOA and 4-year weight loss, the longitudinal changes in thigh muscle quality were overall beneficial but to a less degree in females compared to males. Further research is warranted to investigate the underlying mechanisms and develop sex-specific interventions to optimize muscle quality during weight loss.

Statin use and longitudinal changes in quantitative MRI-based biomarkers of thigh muscle quality: data from Osteoarthritis Initiative.

OBJECTIVE: To assess whether changes in MRI-based measures of thigh muscle quality associated with statin use in participants with and without/at-risk of knee osteoarthritis. METHODS: This retrospective cohort study used data from the Osteoarthritis Initiative study. Statin users and non-users were matched for relevant covariates using 1:1 propensity-score matching. Participants were further stratified according to baseline radiographic knee osteoarthritis status. We used a validated deep-learning method for thigh muscle MRI segmentation and calculation of muscle quality biomarkers at baseline, 2nd, and 4th visits. Mean difference and 95% confidence intervals (CI) in longitudinal 4-year measurements of muscle quality biomarkers, including cross-sectional area, intramuscular adipose tissue, contractile percent, and knee extensors and flexors maximum and specific contractile force (force/muscle area) were the outcomes of interest. RESULTS: After matching, 3772 thighs of 1910 participants were included (1886 thighs of statin-users: 1886 of non-users; age: 62 ± 9 years (average ± standard deviation), range: 45-79; female/male: 1). During 4 years, statin use was associated with a slight decrease in muscle quality, indicated by decreased knee extension maximum (mean-difference, 95% CI: - 1.85 N/year, - 3.23 to - 0.47) and specific contractile force (- 0.04 N/cm2/year, - 0.07 to - 0.01), decreased thigh muscle contractile percent (- 0.03%/year, - 0.06 to - 0.01), and increased thigh intramuscular adipose tissue (3.06 mm2/year, 0.53 to 5.59). Stratified analyses showed decreased muscle quality only in participants without/at-risk of knee osteoarthritis but not those with established knee osteoarthritis. CONCLUSIONS: Statin use is associated with a slight decrease in MRI-based measures of thigh muscle quality over 4 years. However, considering statins' substantial cardiovascular benefits, these slight muscle changes may be relatively less important in overall patient care.

Musculoskeletal CT Imaging: State-of-the-Art Advancements and Future Directions.

CT is one of the most widely used modalities for musculoskeletal imaging. Recent advancements in the field include the introduction of four-dimensional CT, which captures a CT image during motion; cone-beam CT, which uses flat-panel detectors to capture the lower extremities in weight-bearing mode; and dual-energy CT, which operates at two different x-ray potentials to improve the contrast resolution to facilitate the assessment of tissue material compositions such as tophaceous gout deposits and bone marrow edema. Most recently, photon-counting CT (PCCT) has been introduced. PCCT is a technique that uses photon-counting detectors to produce an image with higher spatial and contrast resolution than conventional multidetector CT systems. In addition, postprocessing techniques such as three-dimensional printing and cinematic rendering have used CT data to improve the generation of both physical and digital anatomic models. Last, advancements in the application of artificial intelligence to CT imaging have enabled the automatic evaluation of musculoskeletal pathologies. In this review, the authors discuss the current state of the above CT technologies, their respective advantages and disadvantages, and their projected future directions for various musculoskeletal applications.

Diabetes-associated thigh muscle degeneration mediates knee osteoarthritis-related outcomes: results from a longitudinal cohort study.

OBJECTIVES: We examined the association between diabetes mellitus (DM) and longitudinal MRI biomarkers for thigh muscle degeneration in patients with knee osteoarthritis (KOA) and their mediatory role in worsening KOA-related symptoms. METHODS: The Osteoarthritis Initiative (OAI) participants with radiographic KOA (Kellgren-Lawrence grade ≥ 2) were included. Thighs and corresponding knees of KOA patients with versus without self-reported DM were matched for potential confounders using propensity score (PS) matching. We developed and used a validated deep learning method for longitudinal thigh segmentation. We assessed the association of DM with 4-year longitudinal muscle degeneration in biomarkers of muscle cross-sectional area (CSA) and contractile percentage (non-fat CSA/total CSA). We further investigated whether DM is associated with 9-year risk of KOA radiographic progression, knee replacement (KR), and symptoms worsening. Finally, we evaluated whether the DM-KOA worsening association is mediated through preceding muscle degeneration. RESULTS: After PS matching, 698 thighs/knees were included (185:513 with:without DM; average ± SD age:64 ± 8-years; female/male:1.4). Baseline DM was associated with a decreased contractile percent of total thigh muscles and quadriceps (mean difference, 95%CI -0.16%/year, -0.25 to -0.07, and -0.21%/year, -0.33 to -0.08). DM was also associated with an increased risk of worsening KOA-related symptoms (hazard ratio, 95%CI 1.70, 1.18-2.46) but not radiographic progression or KR. The decrease in quadriceps contractile percent partially mediated the increased risk of symptoms worsening in patients with DM. CONCLUSIONS: Baseline DM is associated with thigh muscle degeneration and KOA-related symptoms worsening. As a potentially modifiable risk factor, DM-associated longitudinal thigh muscle degeneration may partially mediate the symptoms worsening in patients with DM and coexisting KOA. KEY POINTS: • Diabetes mellitus (DM) is associated with worsening knee osteoarthritis (KOA)-related symptoms. • As a potentially modifiable factor, DM-associated thigh muscle (quadriceps) degeneration partially mediates the worsening of KOA-related symptoms.

Role of Thigh Muscle Changes in Knee Osteoarthritis Outcomes: Osteoarthritis Initiative Data.

Background Longitudinal data on the association of quantitative thigh muscle MRI markers with knee osteoarthritis (KOA) outcomes are scarce. These associations are of clinical importance, with potential use for thigh muscle-directed disease-modifying interventions. Purpose To measure KOA-associated longitudinal changes in MRI-derived muscle cross-sectional area (CSA) and adipose tissue and their association with downstream symptom worsening and knee replacement (KR). Materials and Methods In a secondary analysis of the Osteoarthritis Initiative multicenter prospective cohort (February 2004 through October 2015), knees of participants with available good-quality thigh MRI scans at baseline and at least one follow-up visit were included and classified as with and without KOA according to baseline radiographic Kellgren-Lawrence grade of 2 or higher and matched for confounders with use of propensity score matching. An automated deep learning model for thigh MRI two-dimensional segmentation was developed and tested. Markers of muscle CSA and intramuscular adipose tissue (intra-MAT) were measured at baseline and 2nd- and 4th-year follow-up (period 1) and compared between knees with and without KOA by using linear mixed-effect regression models. Furthermore, in knees with KOA, the association of period 1 changes in muscle markers with risk of KR (Cox proportional hazards) and symptom worsening (mixed-effect models) during the 4th to 9th year (period 2) was evaluated. Results This study included 4634 matched thighs (2317 with and 2317 without KOA) of 2344 participants (mean age, 62 years ± 9 [SD]; 1292 women). Compared with those without, knees with KOA had a decrease in quadriceps CSA (mean difference, -8.21 mm2/year; P = .004) and an increase in quadriceps intra-MAT (1.98 mm2/year; P = .007). Decreased CSA and increased intra-MAT of quadriceps during period 1 was predictive of downstream (period 2) KOA symptom worsening (Western Ontario and McMaster Universities Osteoarthritis Index total score: odds ratio, 0.24 [negative association] [P < .001] and 1.38 [P = .012], respectively). Quadriceps CSA changes were negatively associated with higher future KR risk (hazard ratio, 0.70; P < .001). Conclusion Knee osteoarthritis was associated with longitudinal MRI-derived decreased quadriceps cross-sectional area and increased intramuscular adipose tissue. These potentially modifiable risk factors were predictive of downstream symptom worsening and knee replacement. Clinical trial registration no. NCT00080171 © RSNA, 2022 Online supplemental material is available for this article.

Statin use and MRI subchondral bone marrow lesion worsening in generalized osteoarthritis: longitudinal analysis from Osteoarthritis Initiative data.

OBJECTIVES: To determine the association between statin therapy and knee MRI-detected subchondral bone marrow lesion (BML) longitudinal worsening in patients with Heberden's nodes (HNs) as the hallmark of generalized osteoarthritis (OA) phenotype. METHODS: All participants gave informed consent, and IRB approved HIPAA-compliant protocol. We assessed the worsening in BML volume and number of affected subregions in the Osteoarthritis Initiative (OAI) participants with HNs at baseline clinical examination (HN+), using the semi-quantitative MRI Osteoarthritis Knee Scores at baseline and 24 months. Participants were classified according to baseline BML involvement as "no/minimal" (≤ 2/14 knee subregions affected and maximum BML score ≤ 1) or "moderate/severe." Statin users and non-users were selected using 1:1 propensity-score (PS) matching for OA and cardiovascular disease (CVD)-related potential confounding variables. We assessed the association between statin use and increasing BML score and affected subregions using adjusted mixed-effect regression models. RESULTS: The PS-matched HN+ participants (63% female, aged 63.5 ± 8.5-year-old) with no/minimal and moderate/severe BML cohorts consisted of 332 (166:166, statin users: non-users) and 380 (190:190) knees, respectively. In the HN+ participants with no/minimal BML, statin use was associated with lower odds of both BML score worsening (odds ratio, 95% confidence interval: 0.62, 0.39-0.98) and increased number of affected subregions (0.54, 0.33-0.88). There was no such association in HN- participants or those HN+ participants with baseline moderate/severe BML. CONCLUSION: In patients with CVD indications for statin therapy and generalized OA phenotype (HN+), statin use may be protective against the OA-related subchondral bone damage only in the subgroup of participants with no/minimal baseline BML. KEY POINTS: • Statin use may reduce the risk of subchondral bone damage in specific osteoarthritis patients with a generalized phenotype, minimal subchondral bone damage, and cardiovascular statin indications.

A global study of the association of cesarean rate and the role of socioeconomic status in neonatal mortality rate in the current century.

INTRODUCTION: Caesarean section (C/S) rates have significantly increased across the world over the past decades. In the present population-based study, we sought to evaluate the association between C/S and neonatal mortality rates. MATERIAL AND METHODS: This retrospective ecological study included longitudinal data of 166 countries from 2000 to 2015. We evaluated the association between C/S rates and neonatal mortality rate (NMR), adjusting for total fertility rate, human development index (HDI), gross domestic product (GDP) percentage, and maternal age at first childbearing. The examinations were also performed considering different geographical regions as well as regions with different income levels. RESULTS: The C/S rate and NMR in the 166 included countries were 19.97% ± 10.56% and 10 ± 10.27 per 1000 live birth, respectively. After adjustment for confounding variables, C/S rate and NMR were found correlated (r = -1.1, p < 0.001). Examination of the relationship between C/S rate and NMR in each WHO region resulted in an inverse correlation in Africa (r = -0.75, p = 0.005), Europe (r = -0.12, p < 0.001), South-East Asia (r = -0.41, p = 0.01), and Western Pacific (r = -0.13, p = 0.02), a direct correlation in America (r = 0.06, p = 0.04), and no correlation in Eastern Mediterranean (r = 0.01, p = 0.88). Meanwhile, C/S rate and NMR were inversely associated in regions with upper-middle (r = -0.15, p < 0.001) and lower-middle (r = -0.24, p < 0.001) income levels, directly associated in high-income regions (r = 0.02, p = 0.001), and not associated in low-income regions (p = 0.13). In countries with HDI below the centralized value of 1 (the real value of 0.9), the correlation between C/S rate and NMR was negative while it was found positive in countries with HDI higher than the mentioned cut-off. CONCLUSIONS: This study indicated that NMR associated with C/S is dependent on various socioeconomic factors such as total fertility rate, HDI, GDP percentage, and maternal age at first childbearing. Further attentions to the socioeconomic status are warranted to minimize the NMR by modifying the C/S rate to the optimum cut-off.

Efficacy and safety of sulforaphane for treatment of mild to moderate depression in patients with history of cardiac interventions: A randomized, double-blind, placebo-controlled clinical trial.

AIM: Depression has been recognized as one of the disorders associated with cardiac interventions such as percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). In the present study, we evaluated the efficacy and safety of sulforaphane in treatment of depression induced by cardiac interventions. METHODS: After initial screening, 66 patients with previous history of at least one cardiac intervention and current mild to moderate depression were randomly assigned to two parallel groups receiving either sulforaphane (n = 33) or placebo (n = 33) for six successive weeks. Efficacy was assessed using the Hamilton Rating Scale for Depression (HAM-D) at baseline and week 2, 4, and 6. Safety of the treatments was checked during the trial period. RESULTS: Sixty participants completed the clinical trial (n = 30 in each group). Baseline demographic and clinical parameters were all similar among groups. Repeated measures analysis indicated that the sulforaphane group exhibited greater improvement in HAM-D scores throughout the trial (P < 0.001). Response to treatment (≥50% reduction in the HAM-D score) rate was higher in the sulforaphane group at trial endpoint (30% vs 6.67%, P = 0.042). Remission (HAM-D score ≤ 7) rate was also higher in the sulforaphane group; however, the difference was not significant (23.33% vs 3.33%, P = 0.052). Finally, no significant difference was observed between the two groups in terms of frequency of side effects. CONCLUSIONS: Sulforaphane could safely improve depressive symptoms induced by cardiac interventions. Further clinical trials with larger sample sizes and longer follow-up periods are warranted to confirm our results.

Resveratrol adjunct to methylphenidate improves symptoms of attention-deficit/hyperactivity disorder: a randomized, double-blinded, placebo-controlled clinical trial.

Current pharmacological approaches have failed to provide complete remission for patients with Attention-Deficit/Hyperactivity Disorder (ADHD). This study aimed to evaluate the efficacy and tolerability of resveratrol (that have been shown to have antioxidative, anti-inflammatory, and anti-apoptotic effects) as an adjunct to methylphenidate in pharmacologic treatment of ADHD. This 8-week, double-blinded, placebo-controlled trial randomized 66 participants to receive either 500 mg/day resveratrol or matched placebo in addition to methylphenidate. ADHD symptoms were evaluated in the patients using the Parent and Teacher versions of ADHD-Rating Scale (ADHD-RS) at three measurement points with time intervals of 4 weeks. Furthermore, the tolerability of the treatment strategies was systematically compared. Repeated measures analysis demonstrated a significant effect for time-treatment interaction on all three subscales of the Parent ADHD-RS during the trial period (total: p = 0.015; inattention: p = 0.032; hyperactivity/impulsivity: p = 0.036). Nevertheless, the effect for time-treatment interaction was not significant for the Teacher version of ADHD-RS (total: F = 0.81, df = 1.33, p = 0.401; inattention: F = 0.57, df = 1.37, p = 0.507; hyperactivity/impulsivity: F = 0.65, df = 1.34, p = 0.466). The frequencies of complications in the treatment groups were similar. Resveratrol administration for a duration of 8 weeks improved characteristic symptoms in patients with ADHD according to their parents. Further investigations containing larger sample sizes, longer supplementation periods, and dose-response evaluations are required to replicate these findings in ADHD children more confidently.

Resveratrol Adjunct Therapy for Negative Symptoms in Patients With Stable Schizophrenia: A Double-Blind, Randomized Placebo-Controlled Trial.

BACKGROUND: Patients with schizophrenia can generally manifest a broad variety of primary negative symptoms. The current study aimed to assess the efficacy and tolerability of resveratrol add-on therapy in the treatment of negative symptoms in patients with stable schizophrenia. METHODS: In a randomized, double-blind, and placebo-controlled setting, schizophrenia patients were assigned to receive either 200 mg/d resveratrol or matched placebo in addition to a stable dose of risperidone for 8 weeks. Patients were assessed using the positive and negative syndrome scale, the extrapyramidal symptom rating scale, and Hamilton Depression Rating Scale over the trial period. The primary outcome was considered as the change in positive and negative subscale score from baseline to week 8 between the treatment arms. RESULTS: A total 52 patients completed the trial (26 in each arm). Baseline characteristics of both groups were statistically similar (P > .05). Despite the statistically similar behavior of positive symptoms between the groups across time (Greenhouse-Geisser corrected: F = 1.76, df = 1.88, P = .180), the resveratrol group demonstrated greater improvement in negative, general psychopathology, and total scores (Greenhouse-Geisser corrected: F = 12.25, df = 2.04, P < .001; F = 5.42, df = 1.56, P = .011; F = 7.64, df = 1.48, P = .003). HDRS scores and its changes, ESRS score, and frequency of other complications were not significantly different between resveratrol and placebo groups. CONCLUSION: Adding resveratrol to risperidone can exhibit remarkable efficacy and safety in terms of management of schizophrenia-related negative symptoms.

Application of muscle ultrasound for the evaluation of patients with amyotrophic lateral sclerosis: An observational cross-sectional study.

INTRODUCTION: We evaluated the association between muscle ultrasound, number of motor units, and clinical parameters, and assessed their utility for distinguishing amyotrophic lateral scleorisis (ALS) patients from healthy individuals. METHODS: Three muscle pairs (abductor pollicis brevis, abductor digiti minimi, and tibialis anterior) of 18 ALS patients and 18 controls underwent muscle ultrasound (echointensity and thickness) and assessment of motor unit number index (MUNIX). The clinical and functional status of participants were also assessed. RESULTS: Mean age of the patients was 53.8 ± 12.1 years, and score on the ALS Functional Rating Scale-Revised was 38.9 ± 4.1. Echointensity of all tested muscles of ALS participants was significantly higher than that of controls, but there was no significant difference in muscle thickness. Muscle echointensity correlated significantly with clinical and electrophysiological parameters. CONCLUSION: Echointensity of muscles was highly associated with clinical scales and MUNIX, confirming its relevance as an ancillary diagnostic test in ALS patients.

Efficacy and safety of tipepidine as adjunctive therapy in children with attention-deficit/hyperactivity disorder: Randomized, double-blind, placebo-controlled clinical trial.

AIM: This study evaluated the efficacy and safety of tipepidine as an add-on to methylphenidate in the drug treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS: This study was an 8-week, randomized, parallel group, double-blind, placebo-controlled trial recruiting 53 ADHD-diagnosed children. Patients were randomly divided to receive methylphenidate + tipepidine or methylphenidate + placebo for 8 weeks. Participants were assessed using the parent version of ADHD Rating Scale-IV and the Clinical Global Impression scale at baseline, at week 4, and at the end of the trial. Moreover, the safety and tolerability of the treatment strategies were compared. RESULTS: On general linear model repeated measures analysis a significant effect was seen for time × treatment interaction on the total and hyperactivity-impulsivity subscales of the Parent ADHD Rating Scale-IV during the trial period (Greenhouse-Geisser corrected: F = 3.45, d.f. = 1.52, P = 0.049, and F = 5.17, d.f. = 1.52, P = 0.014, respectively). The effect for time × treatment interaction, however, was not significant on Clinical Global Impression-Severity scale (Greenhouse-Geisser corrected: F = 1.79, d.f. = 1.43, P = 0.182). The frequencies of adverse events were similar between the two groups. CONCLUSION: Eight weeks of treatment with tipepidine, as a supplementary medication, resulted in satisfactory efficacy and safety of the adjuvant therapy in management of patients with ADHD. Rigorous investigations, however, involving larger sample sizes, more extended treatment periods, and dose responses should be considered.

Cachexia in preclinical rheumatoid arthritis: Longitudinal observational study of thigh magnetic resonance imaging from osteoarthritis initiative cohort.

BACKGROUND: Preclinical rheumatoid arthritis (Pre-RA) is defined as the early stage before the development of clinical RA. While cachexia is a well-known and potentially modifiable complication of RA, it is not known if such an association exists also in the Pre-RA stage. To investigate such issue, we aimed to compare the longitudinal alterations in the muscle composition and adiposity of participants with Pre-RA with the matched controls. METHODS: In this observational cohort study, the Osteoarthritis Initiative (OAI) participants were categorized into Pre-RA and propensity score (PS)-matched control groups. Pre-RA was retrospectively defined as the absence of RA from baseline to year-2, with progression to physician-diagnosed clinical RA between years 3-8 of the follow-up period. Using a validated deep learning algorithm, we measured MRI biomarkers of thigh muscles and adiposity at baseline and year-2 follow-ups of the cohort. The outcomes were the differences between Pre-RA and control groups in the 2-year rate of change for thigh muscle composition [cross-sectional area (CSA) and intramuscular adipose tissue (Intra-MAT)] and adiposity [intermuscular adipose tissue (Inter-MAT) and subcutaneous adipose tissue (SAT)]. Linear mixed-effect regression models were used for comparison. RESULTS: After 1:3 PS-matching of the groups for confounding variables (demographics, risk factors, co-morbidities, and knee osteoarthritis status), 408 thighs (102 Pre-RA and 306 control) of 322 participants were included (age mean ± SD: 61.7 ± 8.9 years; female/male: 1.8). Over a 2-year period, Pre-RA was associated with a larger decrease in total thigh muscle CSA [estimate, 95% confidence interval (CI): -180.13 mm2/2-year, -252.80 to -107.47, P-value < 0.001]. Further examination of thigh muscle composition showed that the association of the presence of Pre-RA with a larger decrease in muscle CSA over 2 years was noticeable in the quadriceps, flexors, and sartorius muscle groups (P-values < 0.05). Comparison of changes in total adipose tissue showed no difference between Pre-RA and control participants (estimate, 95% CI: 48.48 mm2/2-year, -213.51 to 310.47, P-value = 0.691). However, in the detailed analysis of thigh adiposity, Pre-RA presence was associated with a larger increase in Inter-MAT (estimate, 95% CI: 150.55 mm2/2-year, 95.58 to 205.51, P-value < 0.001). CONCLUSIONS: Preclinical rheumatoid arthritis is associated with a decrease in muscle cross-sectional area and an increase in intermuscular adipose tissue, similar to rheumatoid cachexia in clinical rheumatoid arthritis. These findings suggest the presence of cachexia in the preclinical phase of rheumatoid arthritis. Given that cachexia, which can exacerbate health outcomes, is potentially modifiable, this study emphasizes the importance of early identification of patients in their preclinical phase.

Sumatriptan attenuates fear-learning despair induced by social isolation stress in mice: Mediating role of hypothalamic-pituitary-adrenal axis.

OBJECTIVES: Research has demonstrated that chronic stress experienced early in life can lead to impairments in memory and learning. These deficits are attributed to an imbalance in the interaction between glucocorticoids, the end product of the hypothalamic-pituitary-adrenal (HPA) axis, and glucocorticoid receptors in brain regions responsible for mediating memory, such as the hippocampus. This imbalance can result in detrimental conditions like neuroinflammation. The aim of this study was to assess the impact of sumatriptan, a selective agonist for 5-HT 1B/1D receptors, on fear learning capabilities in a chronic social isolation stress model in mice, with a particular focus on the role of the HPA axis. METHODS: Mice were assigned to two opposing conditions, including social condition (SC) and isolated condition (IC) for a duration of five weeks. All mice underwent passive avoidance test, with their subsequent freezing behavior serving as an indicator of fear retrieval. Mice in the IC group were administered either a vehicle, sumatriptan, GR-127935 (a selective antagonist for 5-HT 1B/1D receptors), or a combination of sumatriptan and GR-127935 during the testing sessions. At the end, all mice were sacrificed and samples of their serum and hippocampus were collected for further analysis. RESULTS: Isolation was found to significantly reduce freezing behavior (p<0.001). An increase in the freezing response among IC mice was observed following the administration of varying doses of sumatriptan, as indicated by a one-way ANOVA analysis (p<0.001). However, the mitigating effects of sumatriptan were reversed upon the administration of GR-127935. An ELISA assay conducted before and after the passive avoidance test revealed no significant change in serum corticosterone levels among SC mice. In contrast, a significant increase was observed among IC mice, suggesting hyper-responsiveness of the HPA axis in isolated animals. This hyper-responsiveness was ameliorated following the administration of sumatriptan. Furthermore, both the sumatriptan and SC groups exhibited a similar trend, showing a significant increase in the expression of hippocampal glucocorticoid receptors following the stress of the passive avoidance test. Lastly, the elevated production of inflammatory cytokines (TNF-α, IL-1ß) observed following social isolation was attenuated in the sumatriptan group. CONCLUSION: Sumatriptan improved fear learning probably through modulation of HPA axis and hippocampus neuroinflammation.

Comparison of Clinical, Ultrasound, and Electrophysiologic Changes in Chronic Inflammatory Demyelinating Polyneuropathy: A Prospective Study.

PURPOSE: The follow-up and monitoring of response to immunomodulatory therapy in patients with chronic inflammatory demyelinating polyneuropathy are still challenging. Various outcome measures have been proposed in recent years, and some are now frequently used in daily clinical practice; however, reliable biomarkers for the disease activity and treatment response are lacking. METHODS: Cross-sectional nerve area of the bilateral vagus, fifth and the sixth cervical spinal, median, ulnar, tibial, peroneal, and sural nerves were measured at 2 time points with an interval of 6 months using nerve ultrasound. The results were used to calculate the ultrasound pattern sumscore (UPSS). The correlation between UPSS change (ΔUPSS) and changes in functional and nerve conduction studies measures over the study period were assessed. RESULTS: Sixteen patients completed this prospective, observational study. General linear model showed that ΔUPSS is significantly associated with ΔMedical Research Council sumscore (ß = -0.72, P = 0.003), Δhandgrip strength (ß = -0.57, P = 0.014), ΔRasch-built overall disability scale (ß = -0.57, P = 0.010), and Δoverall neuropathy limitations scale (ß = 0.75, P < 0.001), after adjustment of confounding variables. Nevertheless, ΔUPSS was not correlated with other clinical measures, including Δpinch power, Δ9-hole peg test, Δ10-m walking test, and Δnerve conduction study sumscore ( P values > 0.05). CONCLUSIONS: Nerve ultrasound might be an efficient method for monitoring the functional status of patients with chronic inflammatory demyelinating polyneuropathy over time because the alterations in its scores could significantly reflect clinical changes.

Cilostazol as adjunctive therapy in treatment of children with autism spectrum disorders: a double-blind and placebo-controlled randomized trial.

We aimed to evaluate cilostazol therapeutic effects on aberrant behaviors of autism spectrum disorder (ASD) children and its safety profile in a double-blind, randomized clinical trial. Sixty-six children with confirmed ASD were allocated to receive either daily 50-mg cilostazol (increased to 100 mg/day after 2 weeks) or matched placebo in addition to risperidone. The Aberrant Behavior Checklist-Community Edition (ABC-C) scale and a checklist of probable adverse effects were used to assess the behavioral outcomes and safety profile at weeks 0, 5, and 10 of the study. Sixty-one participants, with comparable baseline characteristics, completed the trial. Unlike other ABC-C subscales, repeated-measures analysis showed significant effect for time × treatment interaction in the hyperactivity subscale ( P = 0.047; partial eta squared = 0.06). We used the median value for the baseline score hyperactivity subscale [median (interquartile range) = 31 (24-37)] to stratify participants to higher hyperactivity and lower hyperactivity subgroups and found that only participants with higher hyperactivity benefit from cilostazol adjunctive therapy ( P = 0.028; partial eta squared = 0.14). Cilostazol could be considered as a safe agent with beneficial effects on hyperactivity in children with ASD and higher levels of hyperactivity.

Larger left hippocampal presubiculum is associated with lower risk of antisocial behavior in healthy adults with childhood conduct history.

Conduct Disorder (CD) is defined as aggressive, antisocial, and rule-breaking behavior during childhood. It is a major risk factor for developing antisocial personality disorder (ASPD) in adulthood. However, nearly half the CDs do not develop ASPD. Identification of reversion factors seems crucial for proper interventions. We identified 40 subjects with childhood history of CD (CC) and 1166 control subjects (HC) from Human Connectome Project. Their psychiatric, emotional, impulsivity, and personality traits were extracted. An emotion recognition task-fMRI analysis was done. We also did subregion analysis of hippocampus and amygdala in 35 CC and 69 demographically matched HCs. CC subjects scored significantly higher in antisocial-related evaluations. No differences in task-fMRI activation of amygdala and hippocampus were observed. CCs had larger subfields of the left hippocampus: presubiculum, CA3, CA4, and dentate gyrus. Further, an interaction model revealed a significant presubiculum volume × group association with antisocial, aggression, and agreeableness scores. Our study shows that healthy young adults with a prior history of CD still exhibit some forms of antisocial-like behavior with larger left hippocampal subfields, including presubiculum that also explains the variability in antisocial behavior. These larger left hippocampal subfield volumes may play a protective role against CD to ASPD conversion.

Eight Weeks of Vitamin C Supplementation Restores the Lost Correlation between Serum Leptin and C-reactive Protein (CRP) in Patients with Type 2 Diabetes; A Randomized, Double-blind, Parallel-group, Placebo-controlled Clinical Trial.

OBJECTIVE: Inflammation is a well-described factor in the pathophysiology of type 2 diabetes mellitus (DM), which has been a suspect in the alteration of correlations between CRP and leptin in patients with type 2 DM. AIM: This study aimed to show the effect of vitamin C as an antioxidant on the correlation of the serum levels of C-reactive protein (CRP) and leptin in patients with type 2 DM. METHODS: We recruited 70 patients with longstanding T2DM and randomly assigned them into two groups; one received 500 mg/day of vitamin C, and the other received a placebo for eight weeks. Both groups were matched regarding baseline characteristics such as age, gender, weight, and diabetic medications. RESULTS: Out of 70 individuals, 57 participants were left in the study. After eight weeks of follow-up, leptin level was significantly increased in the Vitamin C group (MD = 3.48 change = 24%, p-value = 0.001) but did not change in the placebo group. Other markers such as Fasting plasma glucose, HbA1c, Creatinine, uric acid, Urea, cholesterol, HDL, LDL, TG, AST, ALT, insulin, and CRP did not significantly change in both groups (p value > 0.05). The significant changes in the leptin level among the vitamin C group also remained after controlling for age, BMI, Blood pressure (BP), Triglyceride (TG), and cholesterol. Also, the correlation between serum CRP and leptin became significant in the vitamin C group after eight weeks of follow-up but not in the placebo group. (rs = 0.730, p < 0.001 vs. rs = 0.286, p-value = 0.266 in placebo group). CONCLUSION: This study shows vitamin C can restore CRP-leptin correlation in patients with type 2 diabetes and increase serum leptin levels. More studies are needed to clarify the mechanism of this restoration. CLINICAL TRIAL REGISTRATION NUMBER: IRCT20160811029306N1.