First-in-human study evaluating safety, pharmacokinetics, and pharmacodynamics of lorundrostat, a novel and highly selective aldosterone synthase inhibitor.

Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11ß-hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone-dependent, uncontrolled hypertension, including treatment-resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374-fold selectivity for CYP11B2 vs. CYP11B1. A first-in-human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single- and multiple-dose administration, lorundrostat plasma levels peaked 1-3 h after administration with a t1/2 of 10-12 h. Plasma aldosterone decreased up to 40% with single 100-mg to 200-mg doses and up to 70% with single 400 to 800-mg doses. Plasma aldosterone returned to baseline within 16 h after single 100-mg doses and multiple once-daily 120-mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose- and exposure-dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin-stimulated cortisol production and only a modest increase in mean serum potassium.

Occupational Therapy Practice With Cognitive Behavioral Therapy for Early Postoperative Pain: A Case Report.

Structuring psychological interventions using cognitive behavioral therapy in the early postoperative period is crucial to mitigate the risk of chronic pain. In this study, specific practices were presented through the case of a woman in her 60s who experienced psychological factors, such as catastrophic thinking and anxiety, due to pain after high tibial osteotomy. The aim was to evaluate the structure of cognitive behavioral therapy and its application in the early postoperative period. Cognitive behavioral therapy was initiated postoperatively, incorporating three phases: cognitive restructuring, coping skills and active pacing, and occupational therapy. As a result of occupational therapy using cognitive behavioral therapy, the patient's pain and anxiety are reduced while achieving the goals. This case study suggests that cognitive behavioral therapy may promote goal attainment in cases where postoperative pain exacerbates psychological factors, such as catastrophic thinking and anxiety, ultimately leading to functional impairments. Implementation of cognitive behavioral therapy in Japan is lacking, necessitating urgent development. This case report serves as a foundational step in structuring cognitive behavioral therapy during the early postoperative period in Japan.

Psychological Factors Mediate the Relationship between Physical Activity and Goal Attainment for Occupational Therapy Practice: An Observational Study in Japan.

Occupational therapy can improve physical activity, anxiety, and goal achievement after high tibial osteotomy. However, the role of psychological factors in physical activity and goal attainment after high tibial osteotomy is unclear. We examined how psychological factors mediate the relationship between physical activity and goal achievement. Participants included 55 individuals post-high tibial osteotomy. Physical activity and performance and satisfaction in everyday tasks had a significant indirect effect on the anxiety and depression. Anxiety and depression mediated the physical activity-goal attainment relationship. Thus, occupational therapy practices focusing on anxiety and depression may be important in post- high tibial osteotomy rehabilitation.

Effects of Occupational Therapy Practice on Patient Outcomes after High Tibial Osteotomy: A Non-randomized Study in Japan.

We examined the effectiveness of occupational therapy intervention combined with standard rehabilitation in patients undergoing high tibial osteotomy (HTO). Overall, 115 patients with HTO for knee osteoarthritis were examined. An intervention group (n = 50), who received occupational therapy and standard rehabilitation, was compared to a control group (n = 65), who underwent standard rehabilitation only (n = 65). Compared with the control group, the intervention group had significantly lower Hospital Anxiety and Depression Scale depression and anxiety scores (both p < 0.05), with between-group differences showing large- and medium-effect sizes, respectively (d = 1.06 and 0.61). Results suggest occupational therapy with rehabilitation during hospitalization improves depression and anxiety rates in patients post-HTO.

Mediating Effect of Upper Limb Use on the Relationship Between Upper Limb Performance and Activities of Daily Living: A Longitudinal Mediation Analysis.

INTRODUCTION: Upper limb performance, frequency of upper limb use, and psychological factors are associated with activities of daily living (ADLs) after stroke. We performed a mediation analysis to investigate how the frequency of upper limb use and some psychological factors mediate the relationship between upper limb performance and ADLs. METHODS: Twenty-two patients with stroke were included in this longitudinal study. We utilized the frequency of upper limb use outcome measures (amount of use and quality of motion of the motor activity log), psychological factors outcome measures (General Self-Efficacy Scale), upper limb performance outcome measures (Fugl-Meyer Assessment (FMA)), and ADLs outcome measure (Functional Independence Measure (FIM) motor subscale (M)). Mediation analysis with a bootstrap sampling procedure was used to assess the indirect effects. RESULTS: Mediation analysis showed that the FMA, as measured by the FIM (M), had significant indirect effects on the amount of use (95% bootstrapped confidence interval (CI): 0.36-2.42) and quality of motion (95% bootstrapped CI: 0.06-1.88). The relationship between upper limb performance and ADLs was mediated by the frequency of upper limb use. CONCLUSION: Our findings suggest that improving the frequency of upper limb use may accelerate post-stroke recovery.

Occupational Therapy Using Coping Lists After Total Knee Arthroplasty: A Case Series.

Total knee arthroplasty (TKA) can improve the postoperative quality of life in patients with severe knee osteoarthritis. Although occupational therapy (OT) using a coping list may be useful for post-TKA patients, its use has not been documented. This study aimed to explore the effectiveness of OT using coping skills. Five post-TKA patients underwent OT using coping skills. The Canadian Occupational Performance Measure (COPM), numerical rating scale (NRS), Hospital Anxiety and Depression Scale (HADS), EQ-5D (EuroQol-5-dimension)-5-level (5L), EQ-5D Visual Analogue Scale (VAS), modified fall efficacy scale (MFES), Pain Disability Assessment Scale (PDAS), and coping skills were measured at the start and end of the study. Significant improvements were observed in COPM, NRS, HADS, EQ-5D-5L, and PDAS scores (p <0.05). No significant improvements were found in the EQ-5D VAS and MFES scores. All evaluations showed a large effect size (r ≤ 0.5). The total number of coping skills also increased. This report suggests that OT with coping strategies is effective for pain, psychological factors, quality of life, and activities of daily living. Incorporating coping skills in OT may be useful in postoperative TKA pain management. However, larger studies are needed to validate this.

Combining goal setting and achievement with occupational therapy to improve pain, psychological factors and physical activity in patients after high tibial osteotomy: A non-randomized controlled study.

BACKGROUND: Psychological factors contribute to chronic pain and may lead to physical inactivity and poor functional outcomes. PURPOSE: We conducted a non-randomized controlled study to evaluate the effectiveness of goal setting and achievement following occupational therapy (OT) intervention to improve pain, psychological factors, and physical activity among patients after high tibial osteotomy (HTO). METHOD: We analyzed the data of 31 patients who underwent HTO, allocated into OT intervention and control groups. Goal achievement was encouraged through OT in the intervention groups; the control groups did not receive OT intervention. Outcome measures included the Canadian Occupational Performance Measure (COPM) score (before and after the OT intervention), walking pain, pain catastrophizing, anxiety, depression, pain self-efficacy, and physical activity level. RESULTS: OT significantly improved the COPM score, depression, and physical activity. At the final assessment, the depression score was lower while the step count and physical activity time were significantly higher in the intervention group than in the control group (p < 0.05). CONCLUSION: Embedding goal setting and achievement as part of an OT intervention improved the outcomes after HTO.

AST-120 Treatment Alters the Gut Microbiota Composition and Suppresses Hepatic Triglyceride Levels in Obese Mice.

Background: The prevalence of nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide. The existence of a relationship between the microbiota and the pathology of hepatic steatosis is also becoming increasingly clear. AST-120, an oral spherical carbon adsorbent, has been shown to be useful for delaying dialysis initiation and improving uremic symptoms in patients with chronic kidney disease. However, little is known about the effect of AST-120 on fatty liver.Methods: AST-120 (5% w/w) was administrated to 6-week-old male db/db mice for 8 weeks. The body weight, blood glucose and food consumption were examined. Hepatic triglyceride (TG) levels, lipid droplets and epididymal fat cell size were measured. The gut microbiota compositions were investigated in feces and cecum.Results: Significant decreases of the hepatic weight and hepatic TG levels were observed in the AST-120-treated db/db mice. Furthermore, AST-120 treatment was also associated with a decrease of Bacteroidetes, increase of Firmicutes, and a reduced ratio of Bacteroidetes to Firmicutes (B/F ratio) in the feces in the db/db mice. The B/F ratio in the feces was correlated with the liver weight and area of the liver occupied by lipid droplets in the db/db mice.Conclusions: These data suggest that AST-120 treatment alters the composition of the fecal microbiota and suppresses hepatic TG levels in the db/db mice.

The mediating effect of psychological factors on the relationship between pain intensity and wrist joint function: a longitudinal study with mediation analysis.

PURPOSE: Psychological factors and pain intensity are associated with wrist function. However, the mediating role of psychological factors in the relationship between pain intensity and wrist function in distal radius fractures remains unclear. We performed mediation analysis to investigate how psychological factors mediate the relationship between pain intensity and wrist function. METHODS: Twenty-one patients with distal radius fractures were included in this longitudinal study. Patient-rated wrist evaluation, one pain intensity-related outcome measure (numerical rating scale), and three psychological outcome measures (pain catastrophizing scale, hospital anxiety and depression scale, and pain self-efficacy questionnaire) were assessed. The mediation analysis with a bootstrap sampling procedure was used to assess indirect effects. The level of significance was set at 5%. RESULTS: Mediation analysis showed that the pain intensity, as measured by patient-rated wrist evaluation, had significant indirect effects on the hospital anxiety and depression scale-anxiety (95% bootstrapped confidence interval: 0.96-9.62) and pain self-efficacy questionnaire (95% bootstrapped confidence interval: 0.43-8.11) scores. CONCLUSIONS: The relationship between pain intensity and wrist function was mediated by anxiety and self-efficacy. Our findings suggest that interventions focused on psychological factors, particularly anxiety and self-efficacy, may be important in distal radius fractures rehabilitation.IMPLICATIONS FOR REHABILITATIONIn patients with distal radius fractures, early post-operative pain mediates psychological factors and affects wrist function.Anxiety and self-efficacy are psychological factors that should be noted, and rehabilitation, including self-management, should be considered.Rehabilitative interventions for distal radius fractures should focus on psychological factors and management of post-operative pain.

Clinical Intervention Using Body Shadows for a Patient with Complex Regional Pain Syndrome Who Reported Severe Pain and Self-Disgust Toward the Affected Site: A Case Report.

A woman in her thirties developed complex regional pain syndrome in her left shoulder due to a traffic accident. She demonstrated autonomic nervous symptoms (swelling, sweating, and skin color asymmetry) in her left hand, severe allodynia, neglect-like symptoms (NLS), impaired body image associated with impaired body awareness, and functional impairment of the left shoulder and elbow. She also reported physical self-disgust toward her affected limb, describing it as "reptilian," as well as aversion to touching others; this body awareness exacerbated her pain and NLS. We therefore conducted stepwise interventions using body shadows. The intervention did not trigger physical self-disgust, enabling formation of body ownership and a body image unaccompanied by pain. Consequently, the patient showed improvements in pain, NLS, and autonomic nervous symptoms.

Effects of using activity diary for goal setting in occupational therapy on reducing pain and improving psychological and physical performance in patients after total knee arthroplasty: A non-randomised controlled study.

BACKGROUND: Psychological factors have been reported to affect chronic pain and may lead to inactivity after total knee arthroplasty. This study aimed to determine whether the use of an activity diary for goal setting during occupational therapy would reduce pain, and improve psychological and physical performance in patients after total knee arthroplasty. METHODS: A total of 41 total knee arthroplasty participants from two cohorts were recruited in the study and allocated by convenience to either the experimental group using an activity diary (n = 20) or the control group (n = 21). Occupational therapy intervention (1-2 weeks postoperatively) to promote goal achievement was performed in both groups, and self-monitoring was performed in the diary group by using the activity diary. The outcome indices were Canadian Occupational Performance Measure, pain (resting pain, walking pain), pain catastrophizing (rumination, helplessness, and magnification), anxiety, depression, pain self-efficacy, and physical activity level. Data were evaluated by using analysis of variance analyses with post hoc tests. RESULTS: A time-by-group interaction emerged for Canadian Occupational Performance Measure, walking pain, pain catastrophizing, anxiety, depression, and physical activity level (p < 0.05), both favouring the diary group. The diary group also showed greater improvement in Canadian Occupational Performance Measure, walking pain, anxiety, and physical activity levels at four weeks postoperatively, compared to the control group (p < 0.05). CONCLUSION: The use of the activity diary in this study increased occupational therapy effectiveness, reduced patients' pain, and prevented a decline in physical performance. We believe that the use of an activity diary is an effective and feasible addition for total knee arthroplasty patients.

Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2.

It is necessary for aldosterone synthase (CYP11B2) inhibitors to have both high potency and high selectivity over 11ß-hydroxylase (CYP11B1), a critical enzyme for cortisol synthesis. Previous studies have reported a number of CYP11B2 inhibitors, most of which have an imidazole or pyridine ring to coordinate the heme-iron motif of CYP11B2; however, highly selective inhibitors of human CYP11B2 are still needed. To expand the selectivity in humans, we explored alternative templates and found that pyrazoles were suitable templates for CYP11B2 inhibitors. Investigation of pyrazoles, especially N-alkyl pyrazoles, as a new template to coordinate the heme-iron motif led to a potent and highly selective CYP11B2 inhibitor 28 with an aldosterone-lowering effect at 1 mg/kg dosing in cynomolgus monkeys.

Palmitoylation of the sphingosine 1-phosphate receptor S1P is involved in its signaling functions and internalization.

The lipid mediator sphingosine 1-phosphate (S1P) regulates several cellular processes through binding to its receptors (S1P(1)-S1P(5)), which are heterotrimeric G protein-coupled receptors. Here, we report that all S1P receptors are palmitoylated. In S1P(1), three Cys residues in the cytoplasmic tail are palmitoylated. We examined the roles of palmitoylation of S1P(1) using model cells in which wild-type S1P(1) or a non-palmitoylated mutant S1P(1) was overproduced. Compared with wild-type S1P(1), the non-palmitoylated S1P(1) exhibited binding affinity similar to the natural ligand S1P but lower to the synthetic ligand FTY720 phosphate (FTY720-P), the active form of the immunomodulator FTY720. However, downstream signaling of non-palmitoylated S1P(1) was similarly affected by S1P and FTY720-P stimulation. Moreover, upon stimulation with S1P, internalization of the mutant non-palmitoylated S1P(1) was retarded, compared with that of the wild-type protein. This effect was much more pronounced with FTY720-P stimulation. Similar differences were observed for the phosphorylation of S1P(1) and its mutant. These findings may provide insights into the molecular mechanisms of the pharmacological effects of FTY720. Finally, palmitoylation of wild-type S1P(1) increased upon treatment with S1P, suggesting that S1P(1) undergoes a palmitoylation/depalmitoylation cycle after stimulation by its ligands.

Changes in S1P1 and S1P2 expression during embryonal development and primitive endoderm differentiation of F9 cells.

Sphingosine 1-phosphate (S1P) is a ligand for S1P family receptors (S1P(1)-S1P(5)). Of these receptors, S1P(1), S1P(2), and S1P(3) are ubiquitously expressed in adult mice, while S1P(4) and S1P(5) are tissue specific. However, little is known of their expression during embryonal development. We performed Northern blot analyses in mouse embryonal tissue and found that such expression is developmentally regulated. We also examined the expression of these receptors during primitive endoderm (PrE) differentiation of mouse F9 embryonal carcinoma (EC) cells, a well-known in vitro endoderm differentiation system. S1P(2) mRNA was abundantly expressed in F9 EC cells, but little S1P(1) and no S1P(3), S1P(4), or S1P(5) mRNA was detectable. However, S1P(1) mRNA expression was induced during EC-to-PrE differentiation. Studies using small interference RNA of S1P(1) indicated that increased S1P(1) expression is required for PrE differentiation. Thus, S1P(1) may play an important function in PrE differentiation that is not substituted for by S1P(2).