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.

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.

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.

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.

l-carnitine adjunct to risperidone for treatment of autism spectrum disorder-associated behaviors: a randomized, double-blind clinical trial.

Present study was designed to evaluate the efficacy and safety of l-carnitine as an adjuvant agent to risperidone in the treatment of autism spectrum disorder (ASD)-associated behaviors. In this study, 68 children with confirmed ASD were randomly allocated to receive either l-carnitine (150 mg/day) or matched placebo in addition to risperidone. We utilized the Aberrant Behavior Checklist-Community Edition scale (ABC-C) and a checklist of potential adverse effects to assess changes in behavioral status and safety profile at weeks 0, 5 and 10 of the trial. The primary outcome was defined as a change in the irritability subscale score. Sixty patients with similar baseline characteristics completed the trial period. Although scores of ABC-C subscales significantly decreased in both groups over the trial period, the combination of l-carnitine and risperidone resulted in more reduction on the irritability and hyperactivity subscales compared to the combination of risperidone and placebo (P = 0.033 and P < 0.001, respectively). However, changes in lethargy, stereotypic behavior and inappropriate speech subscales were similar between groups. In conclusion, l-carnitine adjuvant to risperidone could improve irritability and hyperactivity features in children with ASD. Results of this study should be considered preliminary and further clinical trials with larger sample sizes and longer follow-up periods are warranted.

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.

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.

Levothyroxine use and longitudinal changes in thigh muscles in at-risk participants for knee osteoarthritis: preliminary analysis from Osteoarthritis Initiative cohort.

BACKGROUND: We examined the association between levothyroxine use and longitudinal MRI biomarkers for thigh muscle mass and composition in at-risk participants for knee osteoarthritis (KOA) and their mediatory role in subsequent KOA incidence. METHODS: Using the Osteoarthritis Initiative (OAI) data, we included the thighs and corresponding knees of participants at risk but without established radiographic KOA (baseline Kellgren-Lawrence grade (KL) < 2). Levothyroxine users were defined as self-reported use at all annual follow-up visits until the 4th year and were matched with levothyroxine non-users for potential confounders (KOA risk factors, comorbidities, and relevant medications covariates) using 1:2/3 propensity score (PS) matching. Using a previously developed and validated deep learning method for thigh segmentation, we assessed the association between levothyroxine use and 4-year longitudinal changes in muscle mass, including cross-sectional area (CSA) and muscle composition biomarkers including intra-MAT (within-muscle fat), contractile percentage (non-fat muscle CSA/total muscle CSA), and specific force (force per CSA). We further assessed whether levothyroxine use is associated with an 8-year risk of standard KOA radiographic (KL ≥ 2) and symptomatic incidence (incidence of radiographic KOA and pain on most of the days in the past 12 months). Finally, using a mediation analysis, we assessed whether the association between levothyroxine use and KOA incidence is mediated via muscle changes. RESULTS: We included 1043 matched thighs/knees (266:777 levothyroxine users:non-users; average ± SD age: 61 ± 9 years, female/male: 4). Levothyroxine use was associated with decreased quadriceps CSAs (mean difference, 95%CI: - 16.06 mm2/year, - 26.70 to - 5.41) but not thigh muscles' composition (e.g., intra-MAT). Levothyroxine use was also associated with an increased 8-year risk of radiographic (hazard ratio (HR), 95%CI: 1.78, 1.15-2.75) and symptomatic KOA incidence (HR, 95%CI: 1.93, 1.19-3.13). Mediation analysis showed that a decrease in quadriceps mass (i.e., CSA) partially mediated the increased risk of KOA incidence associated with levothyroxine use. CONCLUSIONS: Our exploratory analyses suggest that levothyroxine use may be associated with loss of quadriceps muscle mass, which may also partially mediate the increased risk of subsequent KOA incidence. Study interpretation should consider underlying thyroid function as a potential confounder or effect modifier. Therefore, future studies are warranted to investigate the underlying thyroid function biomarkers for longitudinal changes in the thigh muscles.

Efficacy and safety of adjunctive therapy with fingolimod in patients with schizophrenia: A randomized, double-blind, placebo-controlled clinical trial.

OBJECTIVES: Studies have suggested that fingolimod, a sphingosine-1-phosphate receptor modulator, exerts neuroprotective and anti-inflammatory effects. Although fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis, limited studies have investigated its effects in patients with schizophrenia. This study investigated the efficacy and safety of fingolimod adjuvant to risperidone in schizophrenia treatment. METHODS: This eight-week, randomized, double-blinded, placebo-controlled trial included 80 (clinical trials registry code: IRCT20090117001556N137) patients with chronic schizophrenia. Participants were assigned to two equal arms and received risperidone plus either fingolimod (0.5 mg/day) or a matched placebo. The positive and negative symptom scale (PANSS) was used to measure and compare the effectiveness of treatment strategies at baseline and weeks 2, 4, 6, and 8. Treatment side effects were also compared. RESULTS: Seventy participants completed the trial (35 in each arm). The baseline characteristics of the groups were comparable (P-value > 0.05). There were significant time-treatment interaction effects on negative symptoms (P-value = 0.003), general symptoms (P-value = 0.037), and the PANSS total score (P-value = 0.035), suggesting greater improvement in symptoms following the fingolimod adjuvant therapy. In contrast, the longitudinal changes in positive and depressive symptoms were similar between the groups (P-values > 0.05). Regarding the safety of treatments, there were no differences in extrapyramidal symptoms [assessed by the extrapyramidal symptom rating scale (ESRS)] or frequency of other complications between the fingolimod and the placebo groups (P-values > 0.05). CONCLUSIONS: This study indicated that fingolimod is a safe and effective adjuvant agent for schizophrenia treatment. However, further clinical trials are required to suggest extensive clinical application.

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.

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.

Investigating the Association Between Muscular Ultrasonographic Alterations and Clinical Symptoms in Patients With Inflammatory Myopathy.

Introduction: Muscle biopsy is commonly used to diagnose inflammatory myopathies. We evaluated the ability of muscle ultrasound, a non-invasive and simple tool, to distinguish between healthy subjects and patients with inflammatory myopathy. Methods: This study was conducted on 17 patients recently diagnosed with biopsy inflammatory myopathies (12 dermatomyositis, 5 polymyositis) compared with 17 age- and gender-matched healthy control adults. All patients underwent clinical assessments, including manual muscle testing, hand-held dynamometry, and muscle ultrasound evaluations, including thickness and echo intensity in predefined muscle groups. Results: The disease duration was seven months (interquartile range: 3 to 11 months). Except for the biceps and gastrocnemius, patients' muscles had significantly higher echo intensity and lower thickness than the control group. The echo intensity sum-score manifested the highest area under the curve compared to the sum-scores of other variables (echo intensity vs manual muscle testing: Area under curves-difference=0.18, P<0.01; echo intensity vs dynamometry: Area under curves-difference=0.14, P=0.02; echo intensity vs thickness: Area under curves-differences-difference=0.25, P<0.01). Conclusion: The echo intensity of muscles differed significantly between healthy individuals and patients with inflammatory myopathies and may serve as a useful diagnostic biomarker.

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.

Evidence for Anti-inflammatory Effects of Adalimumab in Treatment of Patients With Major Depressive Disorder: A Pilot, Randomized, Controlled Trial.

BACKGROUND: Literature has suggested that major depressive disorder (MDD) is accompanied by higher concentrations of inflammatory biomarkers, which could sabotage response to conventional treatments. AIMS: This study aimed to evaluate the efficacy and safety of adalimumab adjunct to sertraline in adults with MDD and increased levels of systemic inflammation. METHODS: In a 6-week, randomized, double-blind, placebo-controlled trial, 36 patients with MDD and high-sensitivity C-reactive protein ≥3 mg/L were equally assigned to receive sertraline plus either adalimumab or placebo. Participants were assessed using the Hamilton Depression Rating Scale (HAM-D) at baseline, week 3, and week 6. Moreover, serum concentrations of inflammatory biomarkers were measured at baseline and trial end point. Finally, patients were assessed for any adverse event during the trial. RESULTS: Fifteen patients in each group completed the trial course. All baseline characteristics of participants were similar between the groups. Adalimumab adjunct to sertraline resulted in a greater improvement in HAM-D score compared with placebo over the trial period ( P < 0.001). Participants receiving adalimumab significantly experienced greater response to treatment (≥50% reduction in the HAM-D score) than those receiving placebo ( P = 0.042). Furthermore, after 6 weeks of adalimumab combination therapy with sertraline, inflammatory biomarkers significantly decreased ( P ≤ 0.001), whereas no significant alteration was found in the placebo group. No serious adverse event was documented in the treatment arms. CONCLUSIONS: Adalimumab adjunctive therapy remarkably improves depressive symptoms of patients with MDD. Further investigations with larger sample sizes and longer follow-up periods are required to confirm the findings.

Adjuvant palmitoylethanolamide therapy with risperidone improves negative symptoms in patients with schizophrenia: A randomized, double-blinded, placebo-controlled trial.

BACKGROUND: Primary negative symptoms of schizophrenia are usually resistant to monotherapy with antipsychotics. The present study sought to assess the efficacy and tolerability of Palmitoylethanolamide (PEA) adjunctive therapy in treatment of negative symptoms in patients with stable schizophrenia. METHODS: This 8-week (trial timepoints: baseline, week 4, week 8), double-blind, placebo-controlled clinical trial randomized patients with schizophrenia in a 1:1 ratio to compare the efficacy and safety of 600 mg twice a day of PEA and matched placebo alongside a stable dose of risperidone. Outcome measures were the positive and the negative syndrome scale (PANSS), the extrapyramidal symptom rating scale (ESRS), and the Hamilton depression rating scale (HDRS). The primary outcome was change in the negative subscale score during the trial period between the groups. Safety of interventions were controlled and addressed during the trial. RESULTS: A total of 50 participants completed the trial (25 in each group). Baseline characteristics of the groups were comparable (p>0.05). There was significant effect from time-treatment interaction on negative symptoms (p = 0.012) suggesting greater symptom improvement in the PEA group. In contrast, the longitudinal changes in positive symptoms and depressive symptoms were similar between groups (p values>0.05). Safety assessments showed no significant difference regarding extrapyramidal symptoms, measured by ESRS, and also frequency of other complications between PEA and placebo groups (p values>0.05). CONCLUSIONS: Adjunctive therapy with PEA and risperidone alleviates schizophrenia-related primary negative symptoms in a safe manner.

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.

The Transition of Mild Cognitive Impairment Over Time: An AV45- and FDG-PET Study of Reversion and Conversion Phenomena.

BACKGROUND: Mild cognitive impairment (MCI) is a state between normal cognition and dementia. However, MCI diagnosis does not necessarily guarantee the progression to dementia. Since no previous study investigated brain positron emission tomography (PET) imaging of MCI-- to-normal reversion, we provided PET imaging of MCI- to-normal reversion using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. METHODS: We applied comprehensive neuropsychological criteria (NP criteria), consisting of memory, language, and attention/executive function domains, to include patients with a baseline diagnosis of MCI (n=613). According to the criteria, the year 1 status of the patients was categorized into three groups (reversion: n=105, stable MCI: n=422, conversion: n=86). Demographic, neuropsychological, genetic, CSF, and cognition biomarker variables were compared between the groups. Additionally, after adjustment for confounding variables, the deposition pattern of amyloid-ß and cerebral glucose metabolism were compared between three groups via AV45- and FDG-PET modalities, respectively. RESULTS: MCI reversion rate was 17.1% during one year of follow-up. The reversion group had the lowest frequency of APOE ε4+ subjects, the highest CSF level of amyloid-ß, and the lowest CSF levels of t-tau and p-tau. Neuropsychological assessments were also suggestive of better cognitive performance in the reversion group. Patients with reversion to normal state had higher glucose metabolism in bilateral angular and left middle/inferior temporal gyri, when compared to those with stable MCI state. Meanwhile, lower amyloid-ß deposition at baseline was observed in the frontal and parietal regions of the reverted subjects. On the other hand, the conversion group showed lower cerebral glucose metabolism in bilateral angular and bilateral middle/inferior temporal gyri compared to the stable MCI group, whereas the amyloid-ß accumulation was similar between the groups. CONCLUSION: This longitudinal study provides novel insight regarding the application of PET imaging in predicting MCI transition over time.

Zytux in Refractory Myasthenia Gravis: A Multicenter, Open-Labeled, Clinical Trial Study of Effectiveness and Safety of a Rituximab Biosimilar.

Objectives: Myasthenia gravis (MG) is an immune-mediated neuromuscular disorder responsive to immunomodulatory treatments. 10-20% of MGs are not responsive to conventional first-line therapies. Here, we sought to investigate the efficacy and safety of rituximab therapy in the treatment of patients with refractory MG. Methods: In a 48-week, multicenter, open-labeled, prospective cohort setting, 34 participants with refractory MG were assigned to receive infusions of Zytux, which is a rituximab biosimilar, according to a validated protocol. Clinical, functional, and quality of life (QoL) measurements were recorded at baseline, and seven further visits using the Myasthenia Gravis Foundation of America (MGFA), Myasthenia Gravis Composite (MGC), Myasthenia Gravis Activities of Daily Living profile (MG-ADL), and Myasthenia Gravis Quality of Life (MGQoL-15) scales. Besides, the post-infusion side effects were systematically assessed throughout the study. Results: The correlation analysis performed by generalized estimating equations analysis represented a significant reduction of MGC, MG-ADL, and MGQoL-15 scores across the trial period. The subgroup analysis based on the patients' clinical status indicated a significant effect for the interaction between time and MGFA subtypes on MG-ADL score, MGC score, and pyridostigmine prednisolone dose, reflecting that the worse clinical condition was associated with a better response to rituximab. Finally, no serious adverse event was documented. Conclusions: Rituximab therapy could improve clinical, functional, and QoL in patients with refractory MG in a safe setting. Further investigations with larger sample size and a more extended follow-up period are warranted to confirm this finding. Clinical Trial Registration: The study was registered by the Iranian Registry of Clinical Trials (IRCT) (Code No: IRCT20150303021315N18).