Efficacy and Safety of Pemafibrate, a Novel Selective PPARα Modulator in Chinese Patients with Dyslipidemia: A Double-Masked, Randomized, Placebo- and Active-Controlled Comparison Trial.

AIMS: Pemafibrate substantially lowers serum triglyceride (TG) levels and increases high-density lipoprotein cholesterol (HDL-C) levels primarily in Japan, but it has not been evaluated in China. We aimed to confirm the efficacy and safety of pemafibrate in Chinese patients with hypertriglyceridemia and low HDL-C levels by comparing placebo and fenofibrate. METHODS: A multicenter, double-masked trial was conducted in China involving 344 patients with high TG and low HDL-C levels randomly assigned to one of four groups: pemafibrate 0.2 mg/d, pemafibrate 0.4 mg/d, fenofibrate 200 mg/d, or placebo for 12 weeks. The primary endpoint was the percentage change in fasting TG levels. RESULTS: The percentage change in TG levels from baseline was -34.1%, -44.0%, -30.5%, and 6.5% in the pemafibrate 0.2 mg/d, pemafibrate 0.4 mg/d, fenofibrate 200 mg/d, and placebo groups, respectively. Pemafibrate 0.4 mg/d significantly reduced TG levels compared with that in both placebo (p＜0.0001) and fenofibrate groups (p=0.0083). Significant improvements in HDL-C, remnant cholesterol, and apolipoprotein A1 levels were also observed with both doses of pemafibrate than with the placebo. Pemafibrate showed significantly smaller changes in alanine aminotransferase, aspartate aminotransferase, and serum creatinine levels than those with fenofibrate. CONCLUSIONS: In Chinese patients, pemafibrate exhibited superior efficacy in improving TG levels and enhanced hepatic and renal safety compared to fenofibrate. Thus, pemafibrate may represent a promising therapeutic option for dyslipidemia in Chinese patients.

Effectiveness of Low-Level Laser Therapy in Reducing Postoperative Pain After Dental Implant Surgery: A Randomized Clinical Trial.

BACKGROUND: A clinical trial was conducted to measure the effectiveness of a combined wavelength of 660 nm and 808 nm Low-Level Laser Therapy (LLLT) in reducing postoperative pain in partially and totally edentulous patients who underwent dental implant surgery. MATERIALS AND METHODS: The study included 20 blinded individuals divided in a randomized split-mouth fashion; the experimental group in one hemiarch and the control group in the other hemiarch. The experimental group received a total of 22.5 Joules (J) of LLLT divided into 5 points per implant immediately after surgery. The control group received a placebo treatment. At 24 hours, 72 hours, and 7 days, a blinded surveyor administered a pain questionnaire using a Numerical Rating Scale (NRS) combined with a Verbal Rating Scale (VRS) to assess pain onset after surgery, duration of the first pain episode, and pain evolution. Group data were analyzed with an ANOVA test for repeated measures and a paired t-test at defined time intervals. RESULTS: The experimental group showed a significant decrease in postoperative pain at 24 hours and at 72 hours for fully edentulous patients. There was a non-significant difference in the duration of the first pain episode. The mean pain levels decreased over time for both the experimental and control treatments, but only statistically significantly for the experimental group in the 24-72 hours and 24 hours to 7 days intervals. The same was true for the control group when comparing 24 and 72 hours and between 24 hours and 1 week. The time range between 72 hours and 1 week showed no statistically significant differences. CONCLUSION: Within the limitations of this study, a single dose of 22.5 J LLLT per implant helps to decrease postoperative pain in dental implant surgery at 24 hours for partially edentulous patients and at 24 and 72 hours for fully edentulous patients.

Placental cord drainage impact on third stage of labor: A randomized controlled trial.

BACKGROUND: The third stage of labor is a pivotal phase in obstetric care. Management may be physiological or active. Although the use of prophylactic placental cord drainage has been assessed in prior data, there is still no clear-cut evidence supporting its effectiveness in improving key obstetric outcomes. OBJECTIVE: The aim of the study was to investigate the impact of placental cord drainage during the third stage of labor on the amount of maternal bleeding, duration of the third stage, and incidence of postpartum hemorrhage. STUDY DESIGN: A randomized controlled trial was conducted at a high-volume tertiary obstetric center between May 2021 and December 2022. A total of 212 pregnant women with a singleton uncomplicated pregnancy were randomly assigned to undergo placental cord drainage or standard care without drainage. The randomization was manual, using pre-marked cards drawn by the participants. The power calculation determined a sample size of 92 participants per group to achieve 80% power at a 5% significance level, aiming to detect 20% difference in bleeding amount between the groups. In practice, we included more than 100 women in each group. The primary outcome was the amount of bleeding during the third stage of labor, while secondary outcomes included the duration of the third stage and incidence of postpartum hemorrhage. After delivery, all participants received 10 units of oxytocin via intravenous drip and delayed cord clamping was performed. In the study group, the maternal umbilical cord was then unclamped. Blood was allowed to drain into a plastic bag placed under the women's buttocks. If an episiotomy or perineal tear was observed, pressure packing was applied to reduce bleeding. The collected blood was measured in milliliters after placental expulsion. RESULTS: A total of 212 women were recruited of whom 104 underwent placental cord drainage and 108 received standard care without drainage. No significant differences were observed between the intervention and control groups in mean duration of the third stage of labor (10.56±6.12 vs. 10.95±6.33 minutes, P=0.65), incidence of postpartum hemorrhage (3.84% vs. 7.41%, P=0.38), or mean amount of bleeding during the third stage of labor (292±200 vs. 300±242 ml, P=0.79). Furthermore, there were no significant between-group differences in the mean amount of bleeding on separate analysis of nulliparous women (356±246 vs. 330±240 ml, P=0.68), multiparous women (265±171 vs. 289±244 ml, P=0.50), women who were not exposed to external oxytocin during labor (287±204 vs. 317±250 ml, P=0.59), and women who were exposed to external oxytocin (296±198 vs. 289±238 ml, P=0.39). CONCLUSIONS: Placental cord drainage during the third stage of labor showed no statistically significant impact on bleeding amount, third-stage length, or postpartum hemorrhage rate. The findings suggest that placental cord drainage may not offer additional benefits in preventing postpartum hemorrhage in women with uncomplicated pregnancies.

Obstetrics and Gynecologic Hospitalists and Their Focus: Impact on Safety and Quality Metrics.

Obstetrics and gynecologic hospitalists play a pivotal role in the evolution of perinatal care. Hospitalists improve patient safety by providing on-site, reliable, high-quality care. Hospitalists help to reduce the rates of unnecessary cesarean deliveries and increase the rates of vaginal deliveries.

[Network Meta-analysis of Chinese patent medicines in treatment of chronic pulmonary heart disease].

Network Meta-analysis was performed to compare the efficacy and safety of Chinese patent medicines in treating chronic pulmonary heart disease. CNKI, VIP, Wanfang, SinoMed, PubMed, Web of Science, EMbase, and Cochrane Library were searched for randomized controlled trial(RCT) of treating chronic pulmonary heart disease with Chinese patent medicines with the time interval from inception to December 2023. The Cochrane risk-of-bias tool was used for quality assessment of the included articles. RevMan 5.4 and Stata 17.0 were employed to establish the risk of bias map and perform the network Meta-analysis, respectively. Ultimately, a total of 95 RCTs involving 8 787 cases and 11 different Chinese patent medicines were included. Network Meta-analysis yielded the following results based on the surface under the cumulative ranking curve(SUCRA).(1)In terms of cardiac function improves clinical total effective rate, SUCRA the top three were Wenxin Granules + conventional western medicine, Tongxinluo Capsules + conventional western medicine, and Qishen Yiqi Dropping Pills + conventional western medicine.(2)For improving forced expiratory volume in the first se-cond(FEV1), SUCRA the top three were Danting Feixin Granules + conventional western medicine, Tongxinluo Capsules + conventional western medicine, and Bufei Huoxue Capsules + conventional western medicine.(3)Regarding increasing the FEV1/forced vital capacity(FVC%) value, SUCRA the top three were Qili Qiangxin Capsules + conventional western medicine, Shexiang Baoxin Pills + conventional western medicine, and Qishen Yiqi Dropping Pills + conventional western medicine.(4)In terms of increasing the partial pressure of oxygen(PaO_2), SUCRA the top three were Qili Qiangxin Capsules + conventional western medicine, Qishen Yiqi Dropping Pills + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(5)In terms of reducing the partial pressure of carbon dioxide(PaCO_2), SUCRA the top three were Tongxinluo Capsules + conventional western medicine, Qishen Yiqi Dropping Pills + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(6)In terms of increasing left ventricular ejection fraction(LVEF), SUCRA the top three were Bufei Huoxue Capsules + conventional western medicine, Qishen Yiqi Dropping Pills + conventional western medicine, and Shexiang Baoxin Pills + conventional western medicine.(7)In terms of decreasing brain natriu-retic peptide(BNP), SUCRA the top three were Compound Danshen Dropping Pills + conventional western medicine, Qili Qiangxin Capsules + conventional western medicine, and Tongxinluo Capsules + conventional western medicine.(8)In terms of improving the hematocrit level, SUCRA the top three were Qishen Yiqi Dropping Pills + conventional western medicine, Compound Danshen Dropping Pills + conventional western medicine, and Tongxinluo Capsules + conventional western medicine. In terms of safety, 26 RCTs reported adverse reactions, which primarily involved the circulatory and digestive systems. The combination of Chinese patent medicines with conventional western medicine has demonstrated enhanced therapeutic effects on chronic pulmonary heart disease. However, due to the varying quality and sample sizes of included studies and the absence of direct comparisons between Chinese patent medicines, the conclusions should be further validated by multicenter studies with larger sample sizes and higher methodological rigor.

Randomized controlled trial on the efficacy of a custom-made, fully guided implant system for flapless crestal sinus floor elevation: Accuracy and patient-reported outcomes.

OBJECTIVE: To compare fully guided flapless implant surgery using a light-cured surgical guide (FG group) with partially guided open flap surgery (PG group) in the posterior maxilla when performing simultaneous sinus floor elevation in terms of the accuracy, time requirements, and patient/clinician-reported outcomes (PROMs and CROMs). MATERIALS AND METHODS: In this study, 56 tissue-level implants were placed with crestal sinus floor elevation in 56 patients at single-tooth sites, with 28 implants allocated to the PG group and 28 to the FG group. The deviations of the placed implants from the virtually planned positions were measured at the implant platform and apex and for the angular deviation. The presurgical preparation time and the duration of surgery were measured. PROMs and CROMs were made by administering questionnaires at multiple time points. RESULTS: Horizontal deviations at the platform and apex and the angular deviation were significantly smaller in the FG group than the PG group (p < .05). Presurgical preparation and surgery times were significantly shorter in the FG group (p < .001). Patient satisfaction and willingness to receive repeat treatment were significantly better in the FG group than in the PG group (p < .005 and .025, respectively). Clinicians were more satisfied in the FG group than the PG group (p < .05). CONCLUSION: When placing an implant with sinus floor elevation, the flapless approach using a fully guided surgical system can be more accurate, faster, and increase the satisfaction of both the clinician and patient compared to the partially guided surgery.

Hip Arthroscopy Versus Physical Therapy for the Treatment of Symptomatic Acetabular Labral Tears in Patients Older Than 40 Years: 24-Month Results From a Randomized Controlled Trial.

BACKGROUND: The indications for hip arthroscopy in patients aged ≥40 years remain controversial, as observational studies have suggested that advanced age portends poor functional outcomes, poor durability of improvement, and high rates of conversion to total hip arthroplasty. PURPOSE: To compare hip arthroscopy versus nonoperative management for symptomatic labral tears in patients aged ≥40 years with limited radiographic osteoarthritis. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: This single-surgeon, parallel randomized controlled trial included patients aged ≥40 years with limited osteoarthritis (Tönnis grades 0-2) who were randomized 1:1 to arthroscopic surgery with postoperative physical therapy (SPT) or physical therapy alone (PTA). Patients who received PTA and achieved unsatisfactory improvement were permitted to cross over to SPT after completing ≥14 weeks of physical therapy (CO). The primary outcomes were the International Hip Outcome Tool-33 score and modified Harris Hip Score at 24 months after surgery, and secondary outcomes included other patient-reported outcome measures and the visual analog scale for pain. The primary analysis was performed on an intention-to-treat basis using linear mixed-effects models. Sensitivity analyses included modified as-treated and treatment-failure analyses. RESULTS: A total of 97 patients were included, with 52 (53.6%) patients in the SPT group and 45 (46.4%) patients in the PTA group. Of the patients who underwent PTA, 32 (71.1%) patients crossed over to arthroscopy at a mean of 5.10 months (SD, 3.3 months) after physical therapy initiation. In both intention-to-treat and modified as-treated analyses, the SPT group displayed superior mean patient-reported outcome measure and pain scores across the study period for nearly all metrics relative to the PTA group. In the treatment-failure analysis, the SPT and CO groups showed greater improvement across all metrics compared with PTA; however, post hoc analyses revealed no significant differences in improvement between the SPT and CO groups. No significant differences were observed between groups in rates of total hip arthroplasty conversion. CONCLUSION: In patients ≥40 years of age with limited osteoarthritis, hip arthroscopy with postoperative physical therapy led to better outcomes than PTA at a 24-month follow-up. However, additional preoperative physical therapy did not compromise surgical outcomes and allowed some patients to avoid surgery. When surgery is indicated, age ≥40 years should not be considered an independent contraindication to arthroscopic acetabular labral repair. REGISTRATION: NCT03909178 (ClinicalTrials.gov identifier).

Vaginal dinoprostone versus Foley catheter for induction of labor at term with an unfavorable cervix: an open-label randomized controlled trial.

BACKGROUND: Induction of labor with mechanical methods or pharmacological agents is used in about 20-30% of all pregnant women. We specialized in comparing the effectiveness and safety of dinoprostone versus transcervical Foley catheter for induction of labor in term pregnant women with an unfavorable cervix with adequate samples. OBJECTIVE: To compare the effectiveness and safety of dinoprostone versus transcervical Foley catheter for induction of labor in term pregnant women with an unfavorable cervix. STUDY DESIGN: This is a parallel, open-label randomized controlled trial in two maternal centers in Shanghai, China between October 2019 and July 2022. Women with a singleton pregnancy in cephalic presentation at term and an unfavorable cervix (Bishop score < 6) scheduled for induction of labor were eligible. 1,860 women were randomly allocated to cervical ripening with either a dinoprostone vaginal insert (10mg) or a 60cc Foley catheter for up to 24 hours. The primary outcomes were vaginal delivery rate and time to vaginal delivery. Secondary outcomes included time to delivery and maternal and neonatal morbidity. Analysis was done from an intention-to-treat perspective. The trial was registered with the China trial registry (CTR2000038435). RESULTS: The vaginal birth rates were 72.8% (677/930) vs. 69.9% (650/930) in vaginal dinoprostone and Foley catheter, respectively (aRR 1.04, 95% CI 0.98 to 1.10, risk difference: 0.03). Time to vaginal delivery was not significantly different between the two groups (sub-distribution hazard ratio 1.11, 95% CI 0.99-1.24). Vaginal dinoprostone was more likely complicated with hyperstimulation with fetal heart rate changes (5.8% vs. 2.8%, aRR 2.09, 95% CI 1.32-3.31) and placenta abruption (0.9% vs. 0.1%, aRR: 8.04, 95% CI 1.01-64.15), while Foley catheter was more likely complicated with suspected intrapartum infection (5.1% vs. 8.2 %, aRR: 0.62, 95% CI 0.44-0.88) and postpartum infection (1.4% vs. 3.7%, aRR: 0.38, 95% CI 0.20-0.72). The composite of poor neonatal outcomes was not significantly different between the two groups (4.5% vs. 3.8%, aRR 1.21, 95% CI 0.78 to 1.88), while more neonatal asphyxia occurred in the dinoprostone group (1.2% vs. 0.2%, aRR 5.39, 95% CI 1.22 to 23.92). In a subgroup analysis, vaginal dinoprostone decreased vaginal birth rate slightly in multiparous women (90.6% vs. 97.0%, aRR 0.93, 95% CI 0.88 to 0.99). CONCLUSIONS: In term pregnant women with an unfavorable cervix, induction of labor with vaginal dinoprostone or Foley catheter has similar effectiveness. Foley catheter leads to better safety for neonates, while it may result in a higher risk of maternal infection. Furthermore, Foley catheter should be preferred in multiparous women.

First-Line Treatment with Atezolizumab plus Bevacizumab and Chemotherapy for US Patients with Metastatic, Persistent, or Recurrent Cervical Cancer: A Cost-Effectiveness Analysis.

OBJECTIVE: The BETAcc clinical trial demonstrated that chemotherapy combined with bevacizumab plus atezolizumab (CBA) significantly prolonged progression-free survival (PFS) and overall survival (OS) in patients with metastatic, persistent, or recurrent cervical cancer. However, to our knowledge, the economic value of using this new therapy for this indication is currently unknown. Therefore, our study aims to evaluate the cost-effectiveness of CBA for the first-line treatment of metastatic, persistent, or recurrent cervical cancer from the United States healthcare payers perspective. METHODS: A state-transition Markov model over a 10-year lifetime horizon was developed to compare the cost and effectiveness of CBA versus chemotherapy plus bevacizumab (CB). The primary outcomes of our study included costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the results. RESULTS: CBA was associated with an additional 0.58 QALY at an extra cost of $172,495.90 compared to CB. The ICER was $295,972.43/QALY, significantly higher than the willingness-to-pay (WTP) threshold value of $150,000/QALY. One-way sensitivity analyses revealed that results were most sensitive to the PFD utility, the unit cost of atezolizumab, and PD utility. Probabilistic sensitivity analysis indicated that CBA achieved a 4.3% probability of cost-effectiveness at a $150,000/QALY threshold. To achieve cost-effectiveness, the unit price of atezolizumab must be reduced by approximately 56.6%. CONCLUSIONS: CBA treatment is unlikely to be a cost-effective option compared with CB for patients with persistent, recurrent, or metastatic cervical cancer in the United States.

Effects of a prenatal anxiety randomized controlled trial intervention on infant development in Pakistan.

OBJECTIVES: Given that infant development is influenced by caregiver mental health, we tested whether an intervention to reduce antenatal anxiety could affect infant development. A secondary aim was to test depressive symptoms, maternal responsiveness, and maternal infant bonding as mediators of this relationship. METHODS: Between 2020 and 2022, pregnant women participated in a randomized controlled trial of the Happy Mother-Healthy Baby (HMHB) program based on cognitive behavioral therapy. We collected data on child development from 202 intervention and 198 control participants in a public hospital in Pakistan. Child development was measured using the Ages and Stages Questionnaires-Version 3 at six weeks postpartum. Using intent-to-treat analyses, we examined whether the intervention was associated with performance on the five ASQ-3 domains. Causal mediation analysis was used to assess depressive symptoms, bonding, and maternal-infant responsiveness as mediators. RESULTS: Socio-demographic characteristics were evenly distributed between study arms. Intervention arm infants showed a 2.1-point increase (95% CI: 0.12, 4.17) in communication scores compared to controls. Though not achieving statistical significance, intervention infants also showed a 2.0-point increase (95% CI:-0.06, 4.09) in gross motor development performance. Bonding, depression, and responsiveness were mediators between the intervention and infant communication (Bindirect=1.94 (95%CI: 0.86, 3.25) depression; Bindirect=0.57 (95% CI: 0.09, 1.16) bonding; Bindirect=0.53 (95% CI: 0.01, 1.21) responsiveness; and Bindirect=1.94 (95%CI: 0.86, 3.25). Bonding, responsiveness, and depression mediated 25%, 23%, and 87% of the total association, respectively. CONCLUSIONS: HMHB positively affected infant communication at six-week follow-up. Larger studies with longer follow-up are needed to confirm and extend these findings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03880032; https://clinicaltrials.gov/ct2/show/NCT03880032.

Airway proteomics reveals broad residual anti-inflammatory effects of prednisolone in mepolizumab-treated asthma.

BACKGROUND: Mepolizumab is an anti-interleukin-5 monoclonal antibody treatment for severe eosinophilic asthma (SEA) that reduces asthma exacerbations. Residual airway inflammation on mepolizumab may lead to persistent exacerbations. Oral corticosteroids remain the main treatment for these residual exacerbations. OBJECTIVE: Our study aimed to explore the corticosteroid-responsiveness of airway inflammation after mepolizumab treatment to find potentially treatable inflammatory mechanisms beyond the IL-5 pathway. METHOD: The MAPLE trial was a multi-centre, randomized, double-blind, placebo-controlled, crossover study of 2 weeks of high-dose oral prednisolone treatment at stable state in 27 patients treated with mepolizumab for SEA. We analysed paired sputum (n=16) and plasma (n=25) samples from the MAPLE trial using high-throughput Olink® proteomics. We also analysed additional sputum proteins using ELISA. RESULTS: In patients receiving mepolizumab, prednisolone significantly downregulated sputum proteins related to type-2 inflammation and chemotaxis including IL-4, IL-5, IL-13, CCL24, CCL26, EDN, CCL17, CCL22, OX40 receptor, FCER2, and the ST2 receptor. Prednisolone also downregulated cell adhesion molecules, prostaglandin synthases, mast cell tryptases, MMP1, MMP12, and neuroimmune mediators. Neutrophilic pathways were upregulated. Type-2 proteins were also downregulated in plasma, combined with IL-12, IFN-γ, and IP-10. IL-10 and amphiregulin were upregulated. CONCLUSION: At stable state, prednisolone has broad anti-inflammatory effects on top of mepolizumab. These effects are heterogeneous and may be clinically relevant in residual exacerbations.

WATSU (Water-Shiatsu) increases body awareness and improves pain and mood: A randomised controlled study.

BACKGROUND AND PURPOSE: WATSU (Water-Shiatsu) is a body-oriented therapy in warm-water pool with passive movements, massage and breathing techniques. The present study investigated the short-term effect of a single session of WATSU on body awareness. MATERIALS AND METHODS: In a randomized-controlled study 60 volunteers (18-65 years) were assigned to a 20-min intervention of WATSU or to a 20-min lecture on WATSU. Immediately before and after the intervention they had to answer questionnaires. Primary endpoint of the investigation was the change of the total score of the non-verbal Awareness Body Chart (ABC). Secondary endpoints were the changes of the scores of the 14 single body parts of the ABC, of the Visual Analogue Pain Scale, of a German self-perception questionnaire (KEKS) and changes in mood scored with a German questionnaire on mood (Bf-SR). To compare groups, Mann-Whitney U tests were used. RESULTS: The WATSU group had a significantly higher increase in the ABC total score in comparison to the lecture group (WATSU: 0.3 (IQR 0 - 0.8), lecture: 0.1 (IQR -0.2 - 0.2), p = 0.014). In the KEKS no group differences were seen. In WATSU a significantly stronger improvement of pain (Visual Analogue Pain Scale: WATSU: -15 (IQR -29 to -8), lecture: -4 (IQR -9 - 2), p < 0.001) and of mood (Bf-SR: WATSU: -6 (IQR -14 to -2), lecture: -1 (IQR -5 - 1), p = 0.003) could be observed. CONCLUSION: This study showed that WATSU immediately increases body awareness and improves pain and mood.

A case management strategy to reduce falls in older people with a history of falls: A randomized controlled trial.

The present study aimed to determine whether a remotely delivered intervention, based on an individual case management, can reduce falls and their consequences in community-dwelling older people with a history of multiple falls. In this randomized controlled trial, 32 participants were randomized to the intervention group, which comprised a 16-week case management program involving a multidimensional assessment, targeted interventions according to the identified fall risk factors, and development of individualized care plans. The intervention was performed by trained gerontologists, under weekly supervision of professionals with experience in falls. The control group (n = 30) received usual care. Falls were monitored over 12 months with monthly falls calendars and telephone calls. Remotely delivered case management presented an 82 % uptake of recommendations. There was a trend toward a reduced fall incidence in the intervention vs control group, with lower fall, fall injury and fracture rates in the intervention group compared with the control group at both the 16-week and 12-month time-points, with the difference statistically significant for injurious fall rates at 12 months - IRR=0.18 (95 % CI = 0.04 to 0.74).

The effects of N-acetyl cysteine on intrinsic functional connectivity and neural alcohol cue reactivity in treatment-seeking individuals with alcohol use disorder: a preliminary study.

N-acetyl cysteine (NAC) is a potential pharmacotherapy for alcohol use disorder (AUD), but it is not known whether it modulates neural activation to alcohol cues or intrinsic functional connectivity. We investigated whether NAC attenuates (i) alcohol cue-elicited activation, and (ii) intrinsic functional connectivity compared to placebo in patients with AUD. In this preliminary study, twenty-three individuals (7 females) with moderate-severe AUD received daily NAC (2400 mg/day, n = 9), or a placebo (n = 14) for at least 2 weeks. Participants completed a pre-treatment functional magnetic resonance imaging session (T0) and a post-treatment session (T1) comprising resting-state and visual alcohol cue reactivity task acquisitions. Activation differences between sessions, treatment, and session-by-treatment interaction were assessed. Resting-state functional connectivity examined using 377 node ROI-to-ROIs evaluated whether NAC reduced intrinsic functional connectivity after treatment. There were no differences in alcohol cue reactivity for brain activation or subjective craving between NAC and placebo during treatment or across sessions, or significant interaction. A significant treatment-by-time interaction, with reduced intrinsic connectivity was observed after treatment (T1) for NAC-treated compared to placebo-treated patients in the posterior cingulate node (9, left hemisphere) of the dorsal attentional network and connections to salience, ventral-attentional, somatosensory, and visual-peripheral networks implicated in AUD. NAC reduced intrinsic functional connectivity in patients with moderate-severe AUD after treatment compared to placebo, but did not attenuate alcohol cue-elicited activation. However, the absence of cue reactivity findings may result from low power, rather than the absence of cue reactivity findings associated with NAC. These results provide preliminary evidence that NAC treatment may modulate intrinsic functional connectivity brain activation in patients with alcohol use disorder, but replication in larger studies are required to determine the strength of this effect and any associations with clinical outcomes. Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT03879759.

Efficacy and Safety of Lurasidone vs. Quetiapine XR in Acutely Psychotic Patients With Schizophrenia in Korea: A Randomized, Double-Blind, Active-Controlled Trial.

OBJECTIVE: This study was performed to evaluate the efficacy and safety of lurasidone (160 mg/day) compared to quetiapine XR (QXR; 600 mg/day) in the treatment of acutely psychotic patients with schizophrenia. METHODS: Patients were randomly assigned to 6 weeks of double-blind treatment with lurasidone 160 mg/day (n=105) or QXR 600 mg/day (n=105). Primary efficacy measure was the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions severity (CGI-S) score. Adverse events, body measurements, and laboratory parameters were assessed. RESULTS: Lurasidone demonstrated non-inferiority to QXR on the PANSS total score. Adjusted mean±standard error change at week 6 on the PANSS total score was -26.42±2.02 and -27.33±2.01 in the lurasidone and QXR group, respectively. The mean difference score was -0.91 (95% confidence interval -6.35-4.53). The lurasidone group showed a greater reduction in PANSS total and negative subscale on week 1 and a greater reduction in end-point CGI-S score compared to the QXR group. Body weight, body mass index, and waist circumference in the lurasidone group were reduced, with significantly lower mean change compared to QXR. Endpoint changes in glucose, cholesterol, triglycerides, and low-density lipoprotein levels were also significantly lower. The most common adverse drug reactions with lurasidone were akathisia and nausea. CONCLUSION: Lurasidone 160 mg/day was found to be non-inferior to QXR 600 mg/day in the treatment of schizophrenia with comparable efficacy and tolerability. Adverse effects of lurasidone were generally tolerable, and beneficial effects on metabolic parameters can be expected.

Efficacy and Side Effects of Mixed-Strategy Electroconvulsive Therapy: A Proof-of-Concept Randomized Clinical Trial on Late Life Depression.

OBJECTIVE: Patients with late life depression sometimes refuse to receive electroconvulsive therapy (ECT) owing to its adverse reactions. To alleviate patient's resistance, a novel ECT stimulation strategy named mixed-strategy ECT (msECT) was designed in which patients are administered conventional ECT during the first three sessions, followed by low energy stimulation during the subsequent sessions. However, whether low energy electrical stimulation in the subsequent stage of therapy affect its efficacy and reduce adverse reactions in patients with late life depression remains unknown. To explore differences between msECT and regular ECT(RECT) with respect to clinical efficacy and side effects. METHODS: This randomized, controlled trial was conducted from 2019 to 2021 on 60 patients with late life depression who were randomly assigned to two groups: RECT or msECT. A generalized estimating equation (GEE) was used to compare the two stimulation strategies regarding their efficacy and side effects on cognition. Chi-squared test was used to compare side effects in the two strategies. RESULTS: In the intent-to-treat group, the GEE model suggested no differences between-group difference in Hamilton Depression Rating Scale-17 score over time (Wald χ2=7.275, p=0.064), whereas the comparison of side effects in the two strategies favored msECT (Wald χ2=8.463, p=0.015) as fewer patients had adverse events during the second phase of treatment with msECT (χ2 =13.467, p=0.004). CONCLUSION: msECT presents its similar efficacy to RECT. msECT may have milder side effects on cognition.

Sample size calculation for mixture cure model with restricted mean survival time as a primary endpoint.

It is not uncommon for a substantial proportion of patients to be cured (or survive long-term) in clinical trials with time-to-event endpoints, such as the endometrial cancer trial. When designing a clinical trial, a mixture cure model should be used to fully consider the cure fraction. Previously, mixture cure model sample size calculations were based on the proportional hazards assumption of latency distribution between groups, and the log-rank test was used for deriving sample size formulas. In real studies, the latency distributions of the two groups often do not satisfy the proportional hazards assumptions. This article has derived a sample size calculation formula for a mixture cure model with restricted mean survival time as the primary endpoint, and did simulation and example studies. The restricted mean survival time test is not subject to proportional hazards assumptions, and the difference in treatment effect obtained can be quantified as the number of years (or months) increased or decreased in survival time, making it very convenient for clinical patient-physician communication. The simulation results showed that the sample sizes estimated by the restricted mean survival time test for the mixture cure model were accurate regardless of whether the proportional hazards assumptions were satisfied and were smaller than the sample sizes estimated by the log-rank test in most cases for the scenarios in which the proportional hazards assumptions were violated.

Effect of home-based and remotely supervised combined exercise and cognitive intervention on older adults with mild cognitive impairment (COGITO): study protocol for a randomised controlled trial.

INTRODUCTION: Mild cognitive impairment (MCI) is an intermediate phase between normal cognitive ageing and dementia and poses a serious threat to public health worldwide; however, it might be reversible, representing the best opportunity for secondary prevention against serious cognitive impairment. As a non-pharmacological intervention for those patients, interventions that combine physical exercise and cognitive training, whether delivered simultaneously or sequentially, may have superior effects on various cognitive domains, including global cognition, memory, executive function and attention. The supportive evidence remains incomplete. This study aims to assess the effectiveness of a combined exercise and cognitive intervention in Chinese older adults with mild cognitive impairment (COGITO), empowered by digital therapy and guided by the Health Action Process Model and the Theory of Planned Behaviour (HAPA-TPB theory) in a home-based setting. METHODS AND ANALYSIS: This study is a randomised controlled, assessor-blinded multi-centre study. Four parallel groups will include a total of 160 patients, receiving either a combined exercise and cognitive intervention, an isolated exercise intervention, an isolated cognitive intervention or only health education. These interventions will be conducted at least twice a week for 50 min each session, over 3 months. All interventions will be delivered at home and remotely monitored through RehabApp and Mini-programme, along with an arm-worn heart rate telemetry device. Specifically, supervisors will receive participants' real-time training diaries, heart rates or other online monitoring data and then provide weekly telephone calls and monthly home visits to encourage participants to complete their tasks and address any difficulties based on their training information. Eligible participants are community-dwelling patients with no regular exercise habit and diagnosed with MCI. The primary outcome is cognitive function assessed by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) and Community Screening Instrument for Dementia (CSI-D), with baseline and three follow-up assessments. Secondary outcomes include quality of life, physical fitness, sleep quality, intrinsic capacity, frailty, social support, adherence, cost-effectiveness and cost-benefit. ETHICS AND DISSEMINATION: The study was approved by the Institutional Review Board of Peking University. Research findings will be presented to stakeholders and published in peer-reviewed journals and at provincial, national and international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300073900.

Using polygenic risk modification to improve breast cancer prevention: study protocol for the PRiMo multicentre randomised controlled trial.

INTRODUCTION: Established personal and familial risk factors contribute collectively to a woman's risk of breast or ovarian cancer. Existing clinical services offer genetic testing for pathogenic variants in high-risk genes to investigate these risks but recent information on the role of common genomic variants, in the form of a Polygenic Risk Score (PRS), has provided the potential to further personalise breast and ovarian cancer risk assessment. Data from cohort studies support the potential of an integrated risk assessment to improve targeted risk management but experience of this approach in clinical practice is limited. METHODS AND ANALYSIS: The polygenic risk modification trial is an Australian multicentre prospective randomised controlled trial of integrated risk assessment including personal and family risk factors with inclusion of breast and ovarian PRS vs standard care. The study will enrol women, unaffected by cancer, undergoing predictive testing at a familial cancer clinic for a pathogenic variant in a known breast cancer (BC) or ovarian cancer (OC) predisposition gene (BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51C, RAD51D). Array-based genotyping will be used to generate breast cancer (313 SNP) and ovarian cancer (36 SNP) PRS. A suite of materials has been developed for the trial including an online portal for patient consent and questionnaires, and a clinician education programme to train healthcare providers in the use of integrated risk assessment. Long-term follow-up will evaluate differences in the assessed risk and management advice, patient risk management intentions and adherence, patient-reported experience and outcomes, and the health service implications of personalised risk assessment. ETHICS AND DISSEMINATION: This study has been approved by the Human Research Ethics Committee of Peter MacCallum Cancer Centre and at all participating centres. Study findings will be disseminated via peer-reviewed publications and conference presentations, and directly to participants. TRIAL REGISTRATION NUMBER: ACTRN12621000009819.