Activation of receptor-interacting protein kinase 1 (RIPK1), a broadly expressed serine/threonine protein kinase, by pro-inflammatory cytokines and pathogens can result in apoptosis, necroptosis, or inflammation. RIPK1 inhibition has been shown to reduce inflammation and cell damage in preclinical studies and may have therapeutic potential for degenerative and inflammatory diseases. SIR2446 is a potent and selective novel small molecule RIPK1 kinase inhibitor. This phase I, randomized, double-blind, placebo-controlled study in Australia (ACTRN12621001621808) evaluated the safety (primary objective), pharmacokinetics, and pharmacodynamics of single (3-600 mg) and multiple (5-400 mg for 10 days) ascending oral doses of SIR2446M (SIR2446 magnesium salt form) in healthy adults from Nov 24, 2021, until May 01, 2023. All treatment-emergent adverse events (TEAEs) were mild/moderate. The most reported TEAEs were vascular access site pain, headache, and rash morbilliform. SIR2446M plasma half-lives ranged from 11 to 19 h and there were no major deviations from dose proportionality for maximum concentration and area under the curve across doses. Renal excretion of unchanged SIR2446 was minimal. No marked accumulation was observed (mean accumulation ratio, 1.2-1.6) after multiple daily doses. A high-fat meal mildly reduced the exposure but was not considered clinically significant. SIR2446M had a rapid and sustained inhibitory effect on the activity of RIPK1, with an overall 90% target engagement at repeated doses ranging from 30 to 400 mg in peripheral blood mononuclear cells ex vivo stimulated to undergo necroptosis. The favorable safety, pharmacokinetic, and pharmacodynamic profile of SIR2446M in healthy participants supports its further clinical development in patients with degenerative and inflammatory diseases.

UNASSIGNED: Musician\'s focal task-specific dystonia is a complex disorder of fine motor control, with incomplete understanding of its etiology. There have been relatively few trials of botulinum toxin in upper limb task-specific dystonia, and prior studies have yielded variable results, leading to skepticism regarding the utility of this approach in elite performers.
UNASSIGNED: We conducted a double-blind, placebo-controlled, randomized, cross-over study of incobotulinum toxin-A in 21 professional musicians with focal upper extremity task-specific dystonia affecting performance on their instrument, using a novel paradigm of initial injections followed by booster injections at two- and four-week intervals. The primary outcome measure was the change in blinded dystonia rating of the active arm by two expert raters using a Clinical Global Impression numeric scale at week 8 compared to enrollment.
UNASSIGNED: 19 men and 2 women with musicians\' dystonia were enrolled over a six-year period. Nineteen patients completed the study. Analysis of the primary outcome measure in comparison to baseline revealed a change in dystonia severity of P = 0.04 and an improvement in overall musical performance of P = 0.027. No clinically significant weakness was observed, and neutralizing antibodies to toxin were not found.
UNASSIGNED: Despite its small sample size, our study demonstrated a statistically significant benefit of incobotulinum toxin-A injections as a treatment for musicians\' task-specific dystonia. Tailoring the use of toxin with booster injections allowed refinement of dosing strategy and outcomes, with benefits that were meaningful to patients clearly visible on videotaped evaluations. In addition to its application to musicians\' dystonia, this approach may have relevance to optimize application of botulinum toxin in other forms of focal dystonia such as blepharospasm, cervical dystonia, writer\'s cramp, and spasmodic dysphonia.

Excessive immune response and inflammation are associated with an increased risk of various diseases. In particular, excessive myeloperoxidase (MPO) activity in neutrophils causes inflammatory reactions and lifestyle-related diseases. Adlay has a long history of being used as a traditional Chinese medicine. Polyphenols present in adlay seeds are expected to have the effect of suppressing excessive immune and inflammatory responses. Here, we conducted a randomized, double-blind, parallel group, placebo-controlled study was conducted to evaluate the suppressing effects of adlay seeds extract on excessive immune responses. One hundred and twenty adults participated in the study and they were equally divided into an adlay tea intake group and a placebo group. MPO activity was significantly elevated in the placebo group after 8-wk ingestion, while no significant change was observed in the adlay group. Vascular endothelial functions improved in the adlay group, especially in subjects over 40 y old. These results indicate that adlay tea intake may suppress an excessive immune and inflammatory responses, and improve arterial stiffness. Since caffeic acid, p-coumaric acid, and ferulic acid detected in adlay tea are known to inhibit MPO activity, these polyphenols may be the major functional molecules. Collectively, adlay tea is considered to have a preventative effect against lifestyle-related diseases through improving vascular endothelial function by effects to maintain immune homeostasis of the contained polyphenols. This trial was registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN000032263).

The purpose of this study was to examine whether 4 wk of daily ingestion of milk fat globule membrane (MFGM) combined with exercise training improves physical performance-muscle strength, agility and muscle power-in healthy young adults. The study was designed as a randomized, double-blind, and placebo-controlled trial. Twenty healthy young adults received either an MFGM powder containing 1.6 g of fat and 160 mg of sphingomyelin or an isocaloric placebo powder daily throughout 4 wk of power or agility training. Physical performance tests and body composition measurements were conducted before and after the 4-wk intervention. Ingestion of MFGM did not affect isometric or isokinetic muscle strength, but it was associated with a greater increase in vertical jump peak power compared with placebo. There were no significant changes in body weight or lean body mass during the intervention period in either group, and no significant differences between groups. We conclude that daily MFGM supplementation combined with exercise training has the potential to improve physical performance in young adults; however, further studies with larger sample sizes should be conducted to obtain more evidence supporting achievement of improved physical performance through MFGM supplementation.

Alaska pollack protein (APP), has been reported as a protein source that can enhance muscle hypertrophy more than other protein sources in animal studies. This study aimed to examine the effects of APP ingestion on muscle quantity and quality in young adults. Fifty-five young college students were assigned to two groups: APP and placebo (whey protein: WP) groups, and instructed to ingest 4.5 g of each protein in addition to daily meals, and to maintain their usual daily physical activities for 3 mo. Twenty-one and 23 students completed the intervention and were analyzed in APP and WP groups, respectively. The maximum knee extension torque significantly increased in both groups during the intervention. The motor unit discharge rate, which is an indicator of activation, for a given force level significantly decreased in both groups during the intervention, but its decrease in the APP group was significantly greater than in the WP group. Echo intensity of the vastus lateralis evaluated by ultrasound images significantly decreased in both groups. The muscle thickness and skeletal muscle mass did not change. Small amount of additional APP intake induces greater effects on neural activation than WP, suggesting the greater neural economy of generation of force.

D-Allulose has blood glucose suppression effects in both animal and clinical studies. The mechanism mediating glucose suppression in animals is controlled by several actions including the inhibition of sucrase. To investigate the dose-response effects of D-allulose with a sucrose beverage on glucose tolerance and insulin levels using Thai volunteers. This was a prospective, randomized, double-blinded, crossover study. Subjects had five oral sucrose tolerance tests (OSTT) with escalating doses of D-allulose (0, 2.5, 5, 7.5 or 10 g) with a 50 g sucrose beverage in a random order once a week for five consecutive weeks. The five drinks were consumed in a random order; the order being blinded for both subjects and investigators. Blood samples were drawn immediately before consumption and at 30, 60, 90 and 120 min after consumption of the study product for measurement of plasma glucose and insulin levels. Thirty healthy subjects (11 men and 19 women) completed the study. The peak postprandial glucose (PePPG) and insulin levels (PePPI) were lower when D-allulose was added in a dose-dependent manner. The lowest plasma glucose and insulin levels occurred at 120 min after OSTT in all five products and they were raised when D-allulose was added in a dose-dependent manner. D-Allulose has a suppression response on glucose and insulin shown by the decrease in postprandial plasma glucose and insulin levels following the addition of D-allulose to sucrose in a dose-dependent manner. The more D-allulose added, the less marked the glucose and insulin response occurred.

BACKGROUND: Music therapy has been used as a complementary intervention to provide synergistic analgesia for various procedures.
OBJECTIVE: To evaluate the effects of natural sound therapy on pain intensity and agitation scores in intubated adult Chinese patients who received endotracheal suctioning in a critical care unit.
METHODS: A prospective, real-world, randomized, double-blind, controlled study was conducted from July 2021 through February 2022 among intubated surgical intensive care unit patients in a Chinese hospital. Patients were randomly assigned to a control group receiving conventional treatment or an intervention group receiving natural sound therapy plus conventional treatment (50 patients in each group). Patients\' pain intensity and agitation levels were analyzed before, during, immediately after, 5 minutes after, and 15 minutes after completion of endotracheal suctioning. Pain intensity was assessed with the Critical-Care Pain Observation Tool (CPOT); agitation was assessed with the Richmond Agitation-Sedation Scale (RASS).
RESULTS: According to CPOT scores, patients in the intervention group had significant relief of pain intensity during, immediately after, and 5 minutes after endotracheal suctioning compared with patients in the control group (all P < .001). The RASS scores showed that agitation levels were significant lower in the intervention group than in the control group during (P = .002) and immediately after (P < .001) endotracheal suctioning.
CONCLUSIONS: In this real-world study, natural sound therapy was part of a holistic bundle of interventions used to reduce pain and agitation in surgical intensive care unit patients during endotracheal suctioning.

OBJECTIVE: In the global phase 3 POETYK PSO-1 and PSO-2 trials, significantly greater proportions of deucravacitinib-treated patients met the coprimary endpoints (PASI 75, sPGA 0/1) at Week 16 versus placebo or apremilast-treated patients. This analysis evaluated onset of action and maintenance of response in patients randomized to deucravacitinib and placebo only.
METHODS: Adults with moderate to severe plaque psoriasis at baseline were randomized 1:2:1 to oral placebo, deucravacitinib, or apremilast. Onset of action was determined through changes from baseline in mean PASI, BSA, BSA × sPGA, and DLQI. Maintenance of response was assessed using PASI 75, PASI 90, PASI 100, sPGA 0/1, and sPGA 0 response rates through Week 52 in patients who were treated continuously with deucravacitinib, crossed over from placebo to deucravacitinib at Week 16, or received deucravacitinib and achieved PASI 75 by Week 24.
RESULTS: Deucravacitinib showed significantly higher increases in mean percent change from baseline in PASI versus placebo by Week 1. Significant improvement versus placebo was observed in all other efficacy measures by Week 8. Efficacy with deucravacitinib was maintained through Week 52.
CONCLUSIONS: Deucravacitinib displayed efficacy as early as 1 week and clinical responses were maintained over 52 weeks in patients with moderate to severe plaque psoriasis.

BACKGROUND: The creation of pneumoperitoneum using higher pressure is believed to be associated with increased postoperative abdominal pain.
OBJECTIVE: This study aimed to compare postoperative abdominal pain following low pressure laparoscopic appendectomy and standard pressure laparoscopic appendectomy.
METHODS: This was a prospective, double-blind, randomized controlled trial of 54 patients aged between 18 and 56 years with clinical and/or radiologic diagnosis of acute appendicitis. The patients were randomly allocated to two groups: low pressure laparoscopic appendectomy (n = 26) and standard pressure laparoscopic appendectomy (n = 28). The intra-abdominal pressure was kept in either low pressure (9 mm Hg) or standard pressure (13 mm Hg). Abdominal and shoulder pain scores were assessed using the visual analog scale at 6 hours and 3 days post procedure. Postoperative analgesia requirement, duration of surgery, complications, and hospital stay were recorded.
RESULTS: Both groups match for the demographic parameters. Three patients required conversion from low to standard pressure. There was no difference between the two groups in terms of abdominal pain (P = 0.86) and shoulder pain (P = 0.33), duration of surgery (P = 0.51), complications (P = 0.17), and length of hospital stay (P = 0.83).
CONCLUSIONS: The use of low pressure pneumoperitoneum did not reduce the incidence of abdominal pain in patients who had laparoscopic appendectomy. Patients with acute appendicitis can be treated with either low or normal pressure pneumoperitoneum depending on the experience of the surgeon.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death with type 2 diabetes; however, their effect on arrhythmias is unclear. The purpose of this study was to investigate the effects of empagliflozin on ventricular arrhythmias in patients with type 2 diabetes.
METHODS: A total of 150 patients with type 2 diabetes who were treated with an implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator (ICD/CRT-D) were randomized to once-daily empagliflozin or placebo for 24 weeks. The primary endpoint was the change in the number of ventricular arrhythmias from the 24 weeks before to the 24 weeks during treatment. Secondary endpoints included the change in the number of appropriate device discharges and other values.
RESULTS: In the empagliflozin group, the number of ventricular arrhythmias recorded by ICD/CRT-D decreased by 1.69 during treatment compared to before treatment, while in the placebo group, the number increased by 1.79. The coefficient for the between-group difference was - 1.07 (95% confidence interval [CI] - 1.29 to - 0.86; P < 0.001). The change in the number of appropriate device discharges during and before treatment was 0.06 in the empagliflozin group and 0.27 in the placebo group, with no significant difference between the groups (P = 0.204). Empagliflozin was associated with an increase in blood ketones and hematocrit and a decrease in blood brain natriuretic peptide and body weight.
CONCLUSIONS: In patients with type 2 diabetes treated with ICD/CRT-D, empagliflozin reduces the number of ventricular arrhythmias compared with placebo. Trial registration jRCTs031180120.