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Background: Previous phase 3 studies showed that the AS01E-adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine for older adults (RSVPreF3 OA) is well tolerated and efficacious in preventing RSV-associated lower respiratory tract disease in adults ≥ 60 years of age. This study evaluated lot-to-lot immunogenicity consistency, reactogenicity, and safety of three RSVPreF3 OA lots. Methods: This phase 3, multicenter, double-blind study randomized (1:1:1) participants ≥ 60 years of age to receive one of three RSVPreF3 OA lots. Serum RSVPreF3-binding immunoglobulin G (IgG) concentration was assessed at baseline and 30 days post-vaccination. Lot-to-lot consistency was demonstrated if the two-sided 95 % confidence intervals (CIs) of the RSVPreF3-binding IgG geometric mean concentration (GMC) ratios between each lot pair at 30 days post-vaccination were within 0.67 and 1.50. Solicited adverse events (AEs) within four days, unsolicited AEs within 30 days, and serious AEs (SAEs) and potential immune-mediated diseases within six months post-vaccination were recorded. Results: A total of 757 participants received RSVPreF3 OA, of whom 708 were included in the per-protocol set (234, 237, and 237 participants for each lot). Lot-to-lot consistency was demonstrated: GMC ratios were 1.06 (95 % CI: 0.94–1.21), 0.92 (0.81–1.04), and 0.87 (0.77–0.99) between the lot pairs (lot 1/2; 1/3; 2/3). For the three lots, the RSVPreF3-binding IgG concentration increased 11.84-, 11.29-, and 12.46-fold post-vaccination compared to baseline. The reporting rates of solicited and unsolicited AEs, SAEs, and potential immune-mediated diseases were balanced between lots. Twenty-one participants reported SAEs; one of these–a case of atrial fibrillation–was considered by the investigator as vaccine-related. SAEs with a fatal outcome were reported for four participants, none of which were considered by the investigator as vaccine-related. Conclusion: This study demonstrated lot-to-l

Multidomain interventions have shown tremendous potential for improving cognition in older adults. It is unclear if multidomain interventions can be delivered remotely and whether remote intervention is beneficial for older adults who are vulnerable or at risk of cognitive decline. In a 26-week multi-site, home-based, double-blind, randomized controlled trial, 120 cognitively healthy older adults (75 robust, 45 pre-frail; age range = 60–94) recruited from Switzerland, Canada, and Belgium were randomized to receive either the StayFitLonger (SFL) computerized multidomain training program or an active control intervention. Delivered on tablets, the SFL intervention combined adapted physical exercises (strength, balance, and mobility), cognitive training (divided attention, problem solving, and memory), opportunities for social and contributive interactions, and psychoeducation. The active control intervention provided basic mobilization exercises and access to video games. Cognitive outcomes were global cognition (Z-scores of attention, verbal fluency, and episodic memory for nondemented older adults; ZAVEN), memory, executive function, and processing speed. Linear mixed model analyses indicated improved performance on the ZAVEN global cognition score in the SFL group but not in the active control group. Stratified analyses by frailty status revealed improved ZAVEN global cognition and processing speed scores following SFL in the pre-frail group but not in the robust group. Overall, the study indicates that a computerized program providing a multidomain intervention at home can improve cognition in older adults. Importantly, pre-frail individuals, who are at higher risk of cognitive decline, seem to benefit more from the intervention. Trial registration: ClinicalTrials.gov, NCT037519 Registered on January 22, 2020—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04237519.

Introduction: Periodontitis is a biofilm-mediated disease that is usually treated by non-surgical biofilm elimination with or without antibiotics. Antibiotic treatment in periodontal patients is typically selected empirically or using qPCR or DNA hybridization methods. These approaches are directed towards establishing the levels of different periodontal pathogens in periodontal pockets to infer the antibiotic treatment. However, current methods are costly and do not consider the antibiotic susceptibility of the whole subgingival biofilm. Methods: In the current manuscript, we have developed a method to culture subgingival samples ex vivo in a fast, label-free impedance-based system where biofilm growth is monitored in real-time under exposure to different antibiotics, producing results in 4 hours. To test its efficacy, we performed a double-blind, randomized clinical trial where patients were treated with an antibiotic either selected by the hybridization method (n=32) or by the one with the best effect in the ex vivo growth system (n=32). Results: Antibiotic selection was different in over 80% of the cases. Clinical parameters such as periodontal pocket depth, attachment level, and bleeding upon probing improved in both groups. However, dental plaque was significantly reduced only in the group where antibiotics were selected according to the ex vivo growth. In addition, 16S rRNA sequencing showed a larger reduction in periodontal pathogens and a larger increase in health-associated bacteria in the ex vivo growth group. Discussion: The results of clinical and microbiological parameters, together with the reduced cost and low analysis time, support the use of the impedance system for improved individualized antibiotic selection.

OBJECTIVE: Colonoscopy is one of the most frequently performed interventional endoscopic procedures for diagnosis and treatment. During the procedure, the increase in intraabdominal pressure can cause undesirable spikes in intraocular pressure. In the literature, there are no studies on agent combinations that cause the least effect on intraocular pressure and hemodynamic response in colonoscopic procedures, which are performed more frequently in the elderly, the patient group at the greatest risk for glaucoma. This study aimed to compare ketamine-propofol and ketamine-midazolam protocols in terms of their effects on hemodynamic parameters and intraocular pressure. MATERIALS AND METHODS: The research was a randomized clinical controlled double-blind study. The study was conducted on 60 healthy adults who underwent elective colonoscopy. Ketamin-midazolam and ketamine-propofol combinations were used. Hemodynamic parameters, intraocular pressures at five different times, and the satisfaction levels of the endoscopist and the patient were recorded. RESULTS: In both groups, there was a statistically significant difference between the pre-procedure intraocular pressure values and the values at the 1st minute of the procedure and at recovery (p0.05). No statistically significant difference was found between the intraocular pressure values of the study groups at any time point (p>0.05). CONCLUSIONS: Both combinations can be used safely. The combination of ketamine and propofol in subanesthetic doses provides better sedation without disturbing the hemodynamics and is preferable. © 2022 Verduci Editore s.r.l. All rights reserved.

OBJECTIVE: Colonoscopy is one of the most frequently performed interventional endoscopic procedures for diagnosis and treatment. During the procedure, the increase in intraabdominal pressure can cause undesirable spikes in intraocular pressure. In the literature, there are no studies on agent combinations that cause the least effect on intraocular pressure and hemodynamic response in colonoscopic procedures, which are performed more frequently in the elderly, the patient group at the greatest risk for glaucoma. This study aimed to compare ketamine-propofol and ketamine-midazolam protocols in terms of their effects on hemodynamic parameters and intraocular pressure. MATERIALS AND METHODS: The research was a randomized clinical controlled double-blind study. The study was conducted on 60 healthy adults who underwent elective colonoscopy. Ketamin-midazolam and ketamine-propofol combinations were used. Hemodynamic parameters, intraocular pressures at five different times, and the satisfaction levels of the endoscopist and the patient were recorded. RESULTS: In both groups, there was a statistically significant difference between the pre-procedure intraocular pressure values and the values at the 1st minute of the procedure and at recovery (p0.05). No statistically significant difference was found between the intraocular pressure values of the study groups at any time point (p>0.05). CONCLUSIONS: Both combinations can be used safely. The combination of ketamine and propofol in subanesthetic doses provides better sedation without disturbing the hemodynamics and is preferable. © 2022 Verduci Editore s.r.l. All rights reserved.

Importance: More than half of patients with alcohol use disorder who receive inpatient withdrawal treatment relapse within weeks of discharge, hampering subsequent uptake and effectiveness of psychological and pharmacologic interventions. Cognitive bias modification (CBM) improves outcomes after alcohol rehabilitation, but the efficacy of delivering CBM during withdrawal treatment has not yet been established. Objective(s): To test the hypothesis that CBM would increase the likelihood of abstaining from alcohol during the 2 weeks following discharge from inpatient withdrawal treatment. Design, Setting, and Participant(s): In a randomized clinical trial, 950 patients in 4 inpatient withdrawal units in Melbourne, Australia, were screened for eligibility between June 4, 2017, and July 14, 2019, to receive CBM or sham treatment. Patients with moderate or severe alcohol use disorder aged 18 to 65 years who had no neurologic illness or traumatic brain injury were eligible. Two-week follow-up, conducted by researchers blinded to the participant's condition, was the primary end point. Both per-protocol and intention-to-treat analysis were conducted. Intervention(s): Randomized to 4 consecutive daily sessions of CBM designed to reduce alcohol approach bias or sham training not designed to modify approach bias. Main Outcomes and Measures: Primary outcome was abstinence assessed using a timeline followback interview. Participants were classified as abstinent (no alcohol use in the first 14 days following discharge) or relapsed (any alcohol use during the first 14 days following discharge or lost to follow-up). Result(s): Of the 950 patients screened for eligibility, 338 did not meet inclusion criteria, 108 were discharged before being approached, and 192 refused. Of the 312 patients who consented (referred sample), 12 withdrew before being randomized. In the final population of 300 randomized patients (CBM, n = 147; sham, n = 153), 248 completed the intervention and 272 comple

Background/Purpose: BICLA is a validated composite global measure of SLE disease activity that incorporates BILAG, an instrument that distinguishes between partial and complete improvement. BICLA was an endpoint in the phase 3 TULIP-1 and TULIP-2 trials of anifrolumab.1,2 This study investigated the relationships between BICLA response and SLE clinical and laboratory assessments in TULIP-1 and -2, irrespective of treatment assignment. Method(s): This was a post hoc analysis of pooled data from the 52-week (wk), double-blind TULIP-1 and -2 trials. Patients with moderately to severely active SLE, despite standard of care, were randomized to receive anifrolumab (150 or 300 mg IV Q4W) or placebo for 48 wks. BICLA responses were defined by the following: reduction of all baseline BILAG-2004 A and B domain scores to B/C/D and C/D, respectively, and no worsening in any organ system; no worsening of SLEDAI-2K score; and no worsening >=0.3 points in Physician's Global Assessment (range 0-3).3 Attempts to taper oral corticosteroids (OCS) to <=7.5 mg/day between Wks 8 and 40 were required for patients receiving OCS >=10 mg/day at baseline. Sustained OCS dosage reduction was defined as OCS dosage <=7.5 mg/day achieved by Wk 40 and sustained through Wk 52. Result(s): Baseline characteristics were generally similar between BICLA responders (n=318) and nonresponders (n=501). Overall, improved outcomes were observed in BICLA responders vs nonresponders, including numerically greater improvements in SLEDAI-2K (-7.4 [SD: 3.64] vs -4.2 [SD: 4.28]) from baseline to Wk 52 (Table 1). Greater mean daily OCS dosage reduction was observed in BICLA responders vs nonresponders (-5.41 [SD: 6.84] vs -1.67 [SD: 8.08] mg/day) from baseline to Wk 52, and sustained OCS dosage reduction was achieved by more BICLA responders vs nonresponders (79.2% vs 19.1%). A >=50% reduction in Cutaneous Lupus Erythematosus Disease Area and Severity Index activity (CLASI-A) score, for patients with baseline score >

Background: Melasma is an acquired cutaneous disorder characterised by prominent hyperpigmentation which presents with brown macules or patches on photo-exposed areas. Current first-line treatments for melasma include non-pharmacological measures as photoprotection, cosmetic camouflage and topical therapies such as hydroquinone. 1 Although hydroquinone remains as the gold standard treatment for melasma, its actions are limited by side effects and potential relapses.1 More recently cysteamine cream has been trialled as an alternative therapy for melasma and an early trial has shown benefits compared to placebo.2 There have been no direct comparisons between cysteamine cream and hydroquinone cream. Objective(s): Our study aims to determine the efficacy of cysteamine cream compared to hydroquinone cream in the treatment of melasma. Method(s): Female patients, 18 years and older, with at least three months history of moderate to severe melasma and satisfied the exclusion criteria were included in the study. Patients were randomised to the two study arms; the control was advised to apply hydroquinone daily for 16 weeks and the treatment group was advised to apply cysteamine cream daily for 16 weeks. Both groups were advised on regular sunscreen application. The primary endpoint measurement was the modified Melasma Area and Severity Index (mMASI) score. Result(s): 20 patients have satisfied the inclusion/exclusion criteria and are enrolled in the study. Results to be updated prior to the conference. Conclusion(s): This randomised control study will evaluate the efficacy of cysteamine cream for the treatment of melasma and whether it may be superior compared to the current gold standard treatment hydroquinone.

Introduction Active surveillance (AS) for patients with prostate cancer (PC) with low risk of PC death is an alternative to radical treatment. A major drawback of AS is the uncertainty whether a patient truly has low risk PC based on biopsy alone. Multiparametric MRI scan together with biopsy, appears useful in separating patients who need curative therapy from those for whom AS may be safe. Two small clinical trials have shown short-term high-dose vitamin D supplementation may prevent PC progression. There is no substantial evidence for its long-term safety and efficacy, hence its use in the care of men with PC on AS needs assessment. This protocol describes the ProsD clinical trial which aims to determine if oral high-dose vitamin D supplementation taken monthly for 2 years can prevent PC progression in cases with low-to-intermediate risk of progression. Method and analysis This is an Australian national multicentre, 2:1 double-blinded placebo-controlled phase II randomised controlled trial of monthly oral high-dose vitamin D supplementation (50 000 IU cholecalciferol), in men diagnosed with localised PC who have low-to-intermediate risk of disease progression and are being managed by AS. This trial will assess the feasibility, efficacy and safety of supplementing men with an initial oral loading dose of 500 000 IU cholecalciferol, followed by a monthly oral dose of 50 000 IU during the 24 months of AS. The primary trial outcome is the commencement of active therapy for clinical or non-clinical reason, within 2 years of AS. Ethics and dissemination This trial is approved by Bellberry Ethics Committee (2016-06-459). All results will be reported in peer-reviewed journals. Trial registration number ACTRN12616001707459.Copyright © BMJ Publishing Group Limited 2021

Introduction The time-lapse imaging system (TLS) is a newly developed non-invasive embryo assessment system. Compared with conventional incubators, a TLS provides stable culture conditions and consistent observations of embryo development, thereby potentially improving embryo quality and selection of the best quality embryo. Although TLSs have been routinely used in many in vitro fertilisation (IVF) centres globally, there is insufficient evidence to indicate that TLSs result in higher cumulative live birth rates over conventional incubators. The purpose of this study is to compare the cumulative live birth rates and safety including miscarriage in infertile patients with diminished ovarian reserve (DOR) from both TLSs and conventional incubators. Methods and analysis This study is a double-blind randomised controlled clinical trial (1:1 treatment ratio of TLSs vs conventional incubator). A total of 730 patients with DOR undergoing the first or second cycle of IVF or intracytoplasmic sperm injection (ICSI) will be enrolled and randomised into two parallel groups. Participants will undergo embryo culture in the TLSs (group A) or the conventional incubators (group B), respectively. Embryos are selected for transfer in both groups by the morphological characteristics. The embryo selection algorithm software is not used in the TLSs. The primary outcome is the cumulative live birth rate of the trial IVF/ICSI cycle within 12 months after randomisation. This study is powered to detect an absolute difference of 10% (35% vs 25%) at the significance level of 0.05% and 80% statistical power based on a two-sided test. Ethics and dissemination This trial has been approved by the Institutional Ethical Committee of Shanghai First Maternity and Infant Hospital (KS1958). All participants in the trial will provide written informed consent. The study will be conducted according to the principles outlined in the Declaration of Helsinki and its amendments. Results of this study will be

Background ENZA, a potent androgen receptor inhibitor, provides benefit in men with castration-resistant prostate cancer (CRPC). Objectives In post hoc analyses, the role of ENZA + ADT in mHSPC patients (pts) randomized within the multinational, double-blind, PBOcontrolled, Phase 3 ARCHES study (NCT02677896) was determined by disease volume and risk group stratification. Materials and methods mHSPC pts were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints included prostate-specific antigen (PSA) progression and radiographic responses, overall survival (OS), and quality of life (QoL). Analyses were completed by CHAARTED-defined disease volume and LATITUDE-defined risk groups. Results and conclusion 1150 pts were randomized (ENZA + ADT, n = 574; PBO + ADT, n = 576). Median follow-up was 14.4 months. ENZA + ADT significantly improved rPFS (hazard ratio [95% CI] 0.39 [0.30, 0.50]; P < 0.0001). ENZA + ADT pts significantly benefited from prolonged rPFS in all subgroups (Table). Significant treatment benefits were observed with ENZA + ADT in several secondary clinical endpoints in the overall population and in both high and low disease volume and risk groups (Table). High QoL at baseline was maintained over time. OS data are immature. Adverse events (AEs) were reported in 85.1% of ENZA + ADT vs. 85.9% of PBO + ADT pts, with no unexpected AEs. ENZA + ADT treatment showed efficacy benefit across all mHSPC pts, irrespective of disease volume and risk group. Similar delays in rPFS, symptomatic skeletal events, PSA progression, castration resistance, and improvements in radiographic responses and PSA declines, with maintenance of high QoL over time, were observed. Preliminary safety analysis appears consistent with the safety profile of ENZA in previous CRPC clinical trials. Funding This study was funded by Astellas Pharma Inc. and Medivation LLC, a Pfizer Company, the co-develop

Background: Despite intracerebral haemorrhage causing 5% of deaths worldwide, few evidence-based therapeutic strategies other than stroke unit care exist. Tranexamic acid decreases haemorrhage in conditions such as acute trauma and menorrhoea. We aimed to assess whether tranexamic acid reduces intracerebral haemorrhage growth in patients with acute intracerebral haemorrhage. Method(s): We did a prospective, double-blind, randomised, placebo-controlled, investigator-led, phase 2 trial at 13 stroke centres in Australia, Finland, and Taiwan. Patients were eligible if they were aged 18 years or older, had an acute intracerebral haemorrhage fulfilling clinical criteria (eg, Glasgow Coma Scale score of >7, intracerebral haemorrhage volume <70 mL, no identified or suspected secondary cause of intracerebral haemorrhage, no thrombotic events within the previous 12 months, no planned surgery in the next 24 h, and no use of anticoagulation), had contrast extravasation on CT angiography (the so-called spot sign), and were treatable within 4.5 h of symptom onset and within 1 h of CT angiography. Patients were randomly assigned (1:1) to receive either 1 g of intravenous tranexamic acid over 10 min followed by 1 g over 8 h or matching placebo, started within 4.5 h of symptom onset. Randomisation was done using a centralised web-based procedure with randomly permuted blocks of varying size. All patients, investigators, and staff involved in patient management were masked to treatment. The primary outcome was intracerebral haemorrhage growth (>33% relative or >6 mL absolute) at 24 h. The primary and safety analyses were done in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT01702636). Finding(s): Between March 1, 2013, and Aug 13, 2019, we enrolled and randomly assigned 100 participants to the tranexamic acid group (n=50) or the placebo group (n=50). Median age was 71 years (IQR 57-79) and median intracerebral haemorrhage volume was 14.6 mL (7.9

Background: Melasma is an acquired cutaneous disorder characterised by hyperpigmentation which presents with brown macules or patches on photo-exposed areas. Current first-line treatments for melasma include non-pharmacological measures such as photoprotection, cosmetic camouflage and topical therapies including hydroquinone. Although hydroquinone remains the gold standard treatment for melasma, its actions are sometimes limited by side effects and potential relapses. Recently 5% cysteamine cream has been trialled as an alternative therapy for melasma and an early trial has shown benefits compared to placebo. There have been no direct comparisons between cysteamine cream and hydroquinone cream to date. Objective(s): Our study aims to determine the efficacy of cysteamine cream compared to hydroquinone cream in the treatment of melasma. Method(s): Female patients, 18 years and older, with at least three months history of moderate to severe melasma and satisfied the exclusion criteria were included in the study. Patients were randomised to the two study arms; the control was applied 4% hydroquinone cream daily for 16 weeks and the treatment group applied 5% cysteamine cream daily for 16 weeks. Both groups were advised to apply sunscreen daily with re-application during the day. The primary endpoint measurement was the modified Melasma Area and Severity Index (mMASI) score. Result(s): 20 patients satisfied the inclusion/exclusion criteria and are enrolled in the study. Results to be updated prior to the conference. Conclusion(s): This randomised control study will evaluate the efficacy of cysteamine cream for the treatment of melasma and whether it may be superior compared to the current gold standard treatment hydroquinone.

COVID-19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD+) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID-19 patients. CMAs include l-serine, N-acetyl-l-cysteine, nicotinamide riboside, and l-carnitine tartrate, salt form of l-carnitine. Placebo-controlled, open-label phase 2 study and double-blinded phase 3 clinical trials are conducted to investigate the time of symptom-free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems., QC 20220323

Turmeric extracts (TEs) have been shown to be suitable as a pain treatment for human joint arthritis. In a pilot, randomized clinical trial, 68 individuals with mild/moderate knee joint pain (KJP) consumed a new formulation of water-soluble TEs and insoluble curcuminoids (B-Turmactive(R)) or brewer's yeast as a placebo for 1 week. Our hypothesis was that B-Turmactive would have a short-term analgesic effect on KJP measured by the self-reported Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). After 3 days and 1 week, both treatments reduced pain when walking on a flat surface (P < .01), going up or down stairs (P < .001), and sitting or lying (P < .05), but only B-Turmactive reduced pain at night while in bed and in an upright standing position (P < .01). Concerning global KJP, it was reduced by both treatments after 3 days and 1 week of the intervention (P < .001), being less with B-Turmactive after 1 week (P = .012 vs. 3 weeks). Although no intertreatment differences were observed, only B-Turmactive decreased high-sensitivity C-reactive protein levels (P = .045) at 1 week, which indicates a prompt analgesic effect mediated by a decrease in inflammatory status.

Introduction Reduction of milk protein content in infant formula provided during the first year of life has been shown to reduce early weight gain and obesity later in life. While rapid weight gain during the first 2 years of life is one of the strongest early predictors of obesity, the role of animal protein intake beyond the first year of life is unclear. The aim of this study is to examine the role of milk protein during the second year of life in healthy children on weight gain and obesity risk in preschool age.Methods and analysis This randomised, double-blinded study enrolled 1618 children aged 11.5-13.5 months in Spain and Germany into two groups receiving isocaloric toddler milk with differing protein content during the second year of life. The experimental formula contains 1.5g/100 kcal and the control formula 6.15 g/100 kcal protein and otherwise equal formula composition, except for modified fat content to achieve equal energy density. The primary endpoint is body mass index (BMI)-for-age z-score at the age of 24 months adjusted for BMI at 12 months of age. The children are followed until 6 years of age.Ethics and dissemination Ethics approval was obtained from the ethical committees of the LMU University Hospital Munich, Germany (Nr. 555-15) and at Institut d'Investigacio Sanitaria Pere Virgili, Reus, Spain (Ref. CEIm IISPV 013/2016). We aim at publishing results in peer-reviewed journals and sharing of results with study participants.

Scope: To identify a metabolomic profile related to postprandial satiety sensations involved in appetite control would help for a better understanding of the regulation of food intake. Methods and Results: A cross-sectional analysis of plasma metabolites was conducted over 151 overweight/obese adults from the Satiety Innovation-SATIN study, a randomized clinical trial of a 12-week weight-loss maintenance period. Postprandial satiety sensations (3 h-iAUC) were assessed by visual analogue scale (VAS) at the beginning and at the end of the study. Fasting plasma metabolites were profiled using a targeted multiplatform metabolomics approach before each appetite test meal. Associations between 124 metabolites and iAUC-satiety were assessed using elastic net linear regression analyses. The accuracy of the multimetabolite weighted models for iAUC-VAS was evaluated using a 10-fold cross-validation (CV) approach and the Pearson's correlation coefficients were estimated. Five and three metabolites were selected in the first and the second assessments, respectively. Circulating glycine and linoleic acid concentrations were consistently and positively associated with higher iAUC-satiety in both visits. Sucrose and sphingomyelins (C32:2, C38:1) were negatively associated with iAUC-satiety in the first visit. The Pearson correlations coefficients between the metabolomic profiles and iAUC-satiety in the first and the second appetite assessments were 0.37 and 0.27, respectively. Conclusion: Higher glycine and linoleic acid were moderately but consistently associated with higher postprandial satiety in two different appetite assessments in overweight and obese subjects.

Introduction Induction of labour (IOL) is a common practice. In Australia, up to 40% of women undergoing labour induction will ultimately have a caesarean section. As a biological role for melatonin in the onset and progress of labour has been demonstrated, we aim to test the hypothesis that addition of melatonin will reduce the need for caesarean section. Methods and analysis This is a double-blind, randomised, placebo-controlled trial in women undergoing IOL at term. We plan to randomise 722 women (1:1 ratio) to receive either melatonin (four doses of 10 mg melatonin: first dose-in the evening at the time of cervical balloon or Dinoprostone PGE 2 vaginal pessary insertion, second dose-at time of oxytocin infusion commencement, third dose-6 hours after the second dose, fourth dose-6 hours after the third dose) or placebo (same dosing regime). Participants who are having artificial rupture of the membranes only as the primary means of labour induction will receive up to three doses of the trial intervention. The primary outcome measure will be the requirement for a caesarean section. Secondary outcomes will include duration of each stage of labour and time from induction to birth, total dose of oxytocin administration, epidural rate, indication for caesarean section, rate of instrumental deliveries, birth within 24 hours of induction commencement, estimated blood loss, Apgar score at 5 min, neonatal intensive care unit admissions and participant satisfaction. Maternal melatonin levels will be measured immediately before commencement of the oxytocin intravenous infusion and 3 hours after and at the time of birth in order to determine any differences between the two trial arms. Ethics and dissemination The study is conducted in accordance with the conditions of Monash Health HREC (RES-17-0000-168A). Findings from the trial will be disseminated through peer-reviewed publications and conference presentations. Protocol version V.7.0, 30 July 2019. Trial registration numb

Introduction Severe behavioural problems (SBPs) are a common contributor to morbidity and reduced quality of life in children with intellectual disability (ID). Current medication treatment for SBP is associated with a high risk of side effects. Innovative and safe interventions are urgently needed. Anecdotal reports and preliminary research suggest that medicinal cannabis may be effective in managing SBP in children with developmental disabilities. In particular, cannabidiol (CBD) may be a plausible and safe alternative to current medications. Families who are in urgent need of solutions are seeking cannabis for their ID children with SBP. However there is no evidence from randomised controlled trials to support the use of CBD for SBP. This pilot study aims to investigate the feasibility of conducting a randomised placebo-controlled trial of CBD to improve SBP in children with ID. Methods and analysis This is a single-site, double-blind, parallel-group, randomised, placebo-controlled pilot study of 10 participants comparing 98% CBD oil with placebo in reducing SBP in children aged 8-16 years with ID. Eligible participants will be randomised 1:1 to receive either CBD 20 mg/kg/day or placebo for 8 weeks. Data will be collected regarding the feasibility and acceptability of all study components, including recruitment, drop-out rate, study visit attendance, protocol adherence and the time burden of parent questionnaires. Safety outcomes and adverse events will be recorded. All data will be reported using descriptive statistics. These data will inform the design of a full scale randomised controlled trial to evaluate the efficacy of CBD in this patient group. Ethics and dissemination This protocol has received ethics approval from the Royal Children's Hospital ethics committee (Human Research Ethics Committee no. 38236). Results will be disseminated through peer-reviewed journals, professional networks, conferences and social media.Copyright © Author(s) (or their employ

Background: Sympathetic activity and insulin resistance have recently been linked with chronic tendon and musculoskeletal pain. Polycystic ovarian syndrome is linked with insulin resistance and increased sympathetic drive and was therefore an appropriate condition to study the effects of modulating sympathetic activity on Achilles tendon and musculoskeletal symptoms. Method(s): A secondary analysis of a double-blinded, randomised controlled trial on women with polycystic ovarian syndrome was conducted. Participants received 12 weeks of moxonidine (n = 14) or placebo (n = 18). Musculoskeletal symptom and Victorian Institute of Sport Assessment - Achilles (VISA-A) questionnaires were distributed, and ultrasound tissue characterisation quantified tendon structure at 0 and 12 weeks. 2-way ANOVA was used for multiple comparisons. Result(s): There was no difference in mean change in musculoskeletal symptoms (- 0.6 +/- 1.7 vs - 0.4 +/- 1.8, p = 0.69) or VISA-A (moxonidine - 0.2 +/- 8.8 vs placebo + 4.2 +/- 14.6, p = 0.24) attributable to the intervention. There was no difference in any measures of Achilles structure. Moxonidine did not reduce sympathetic drive when compared to placebo. Conclusion(s): This was the first study to investigate the effects of blocking sympathetic drive on musculoskeletal and Achilles tendon symptoms in a metabolically diverse population. While the study was limited by small sample size and lack of sympathetic modulation, moxonidine did not change tendon pain/structure or musculoskeletal symptoms. Trial registration: ClinicalTrials.gov, NCT01504321. Registered 5 January 2012.Copyright © 2020 The Author(s).

Background Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain. Methods To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate.1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism. Results A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m2; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings. Conclusions In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia. Clinical Trial r

Aim: This paper describes the use of the single patient therapy plan (SPTP). The SPTP has been designed to assess the efficacy at an individual level of a commercially available cannabinoid product, cannabidiol, in reducing seizure frequency in paediatric patients with intractable epilepsy. Method(s): The SPTP is a randomised, double-blind, placebo-controlled N-of-1 trial designed to assess the efficacy of treatment in a neurology outpatient setting. The primary objective of the SPTP is to assess the efficacy of cannabidiol in reducing seizure frequency in each patient with intractable epilepsy, with change in seizure frequency being the primary outcome of interest. The analysis adopts a Bayesian approach, which provides results in the form of posterior probabilities that various levels of benefit (based on the primary outcome measure, seizure frequency) have been achieved under active treatment compared to placebo, accompanied by decision rules that provide thresholds for deciding whether treatment has been successful in the individual patient. The SPTP arrangement is most accurately considered part of clinical practice rather than research, since it is aimed at making clinical treatment decisions for individual patients and is not testing a hypothesis or collecting aggregate data. Therefore, Human Research Ethics Committee approval was considered not to be required, although it is recommended that hospital Clinical Ethics Committees provide ethical oversight. Conclusion(s): These SPTP resources are made available so that they may inform clinical practice in the treatment of severe epilepsy or adapted for use in other conditions.Copyright © 2020, Commonwealth of Australia. Journal of Paediatrics and Child Health © 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

Rationale: Recent evidence has demonstrated that the combination of atomoxetine (selective norepinephrine reuptake inhibitor) and oxybutynin (antimuscarinic inhibitor) greatly reduced OSA severity. Conversely, trials using serotonergic agonists have had poor success in reducing OSA severity despite previous studies demonstrating potential mechanistic pathways for improving upper airway patency. Notably, atomoxetine and oxybutynin also did not improve OSA severity when taken alone. It is therefore possible that serotonergic agents also need to be delivered in combination therapy to be efficacious. Moreover, adding a serotonergic component to the noradrenergic and antimuscarinic drug combination may further reduce OSA severity. We therefore aimed to assess the impact that (1) milnacipran and (2) duloxetine (two noradrenergic/serotonergic reuptake inhibitors), in combination with oxybutynin has on OSA severity. Method(s): A randomized, double-blind, 4 way cross-over, placebo-controlled trial in 10 OSA patients was performed with the following drug conditions administered as oral capsules prior to bedtime: 1) milnacipran/oxybutynin combination 50/5mg, 2) duloxetine/oxybutynin combination 60/5mg, 3) oxybutynin 5mg, 4) placebo. Patients received each drug condition separately across four overnight in-lab polysomnography (PSG) studies ~1-week apart. The primary outcome was OSA severity measured by the Apnea/Hypopnea Index (AHI) from overnight PSG. In order to understand how each drug combination altered OSA pathophysiology four key OSA traits (collapsibility, muscle compensation, arousal threshold, loop gain) were measured non-invasively from the PSG validated techniques. Values reported as mean+/-SD Results: All drug combinations did not significantly reduce the overall AHI compared to placebo (p=0.24). Total sleep time was consistent across each condition (p=0.92), although duloxetine/oxybutynin significantly reduced time spent in REM sleep (3.5 [4.15] vs 9.11 [7.71] %to

Background: Melatonin is a potent oxygen scavenger and is capable of altering blood flow in various vascular beds. Aim(s): We aimed to determine the effect of melatonin on ovarian vascular indices during ovarian stimulation for in vitro fertilisation (IVF). Material(s) and Method(s): This is a pilot double-blind placebo-controlled randomised trial. Sixty-nine women (mean age 35.8 +/- 4.3 years) undergoing their first cycle of IVF were randomised to receive either placebo, 2, 4 or 8 mg of melatonin, twice a day. Each participant underwent a transvaginal ultrasound at days 6-10 assessing follicular number and size. The vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI) were measured. These indices were then correlated with embryological outcomes. Informed consent was obtained from participants. This trial was registered with the Australia New Zealand Clinical Trials Registry (ACTRN12613001317785). Result(s): The number of follicles did not differ between groups (P = 0.4). There were no differences in the VI (P = 0.4), FI (P = 0.1) or VFI (P = 0.3) in the right ovary or the FI (P = 0.3) or VFI (P = 0.3) in the left ovary between groups. When comparing placebo to any dose of melatonin, there were no differences in any measured parameter. While there was correlation between the number of follicles on ultrasound and all measured embryological outcomes, there was no correlation between ovarian vascular indices and these important clinical outcomes. Conclusion(s): Melatonin does not appear to change ovarian vascular indices during ovarian stimulation. In addition, such vascular indices cannot predict the number or quality of oocytes or embryos obtained in an IVF cycle. These findings require confirmation in future larger studies.Copyright © 2019 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists

Background: In NASH, disease progression results from a complex interplay of intra- and extra-hepatic processes encompassing metabolic (adipose tissue dysfunction, insulin resistance), inflammatory and fibrogenic pathways. Successful treatment most likely needs a multi-targeted approach Peroxisome proliferator-activated receptors (PPAR) are nuclear receptors with key regulatory functions in metabolism, inflammation and fibrogenesis. Lanifibranor is a well-balanced agonist of the 3 PPAR isotypes with a broader and superior efficacy over single and dual PPAR agonists in various pre-clinical models Methods: NATIVE (NCT03008070) was a phase 2b double-blind randomisedcontrolled trial of lanifibranor in patients with biopsy proven, non-cirrhotic, highly active NASH (a SAF Activity score of 3-4) Patients were randomised 1:1:1 to receive once daily placebo, 800 or 1200 mg of lanifibranor for 24 weeks. The primary endpoint was a >=2 point reduction in SAF Activity score. Secondary endpoints were NASH resolution and fibrosis regression Results: 247 patients were randomised: mean age 54y, mean BMI 32 9 kg/m2, 42% males, 42% diabetes, 76% F2/F3 and 73% NAFLD Activity Score (NASH CRN) >=6. Lanifibranor met the primary endpoint at 1200 mg/day and also all key secondary endpoints including: NASH resolution without worsening of fibrosis and regression of >=1 stage of fibrosis without worsening of NASH (Table). The combined endpoint of resolution of NASH plus regression of fibrosis was also significantly met for both treatment arms. Both doses significantly and sustainably improved liver enzymes starting at week 4. In diabetics, both doses significantly reduced HbA1c by > 0.5%. Both doses also equally and significantly increased HDL cholesterol and decreased serum triglycerides Lanifibranor showed a favourable safety profile with a low dropout rate (<5%) of for adverse events comparable to placebo A mean weight increase of 2 4 and 2 7 kg in the 800 and 1200 mg arms respectively was

Background: ENZA, a potent androgen receptor inhibitor, provides benefit in men with castration-resistant prostate cancer (CRPC). In post hoc analyses, the role of ENZA+ ADT inmHSPC patients (pts) randomized within the multinational, doubleblind, PBO-controlled, Phase 3 ARCHES study (NCT02677896) was determined by disease volume and risk group stratification. Method(s): mHSPC pts were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints included prostate-specific antigen (PSA) progression and radiographic responses, overall survival (OS), and quality of life (QoL). Analyses were completed by CHAARTED-defined disease volume and LATITUDE-defined risk groups. Result(s): 1150 pts were randomized (ENZA +ADT, n=574; PBO +ADT, n=576). Median follow-up was 14.4 months. ENZA + ADT significantly improved rPFS (hazard ratio [95% CI] 0.39 [0.30, 0.50]; p<0.0001). ENZA+ ADT pts significantly benefited from prolonged rPFS in all subgroups (Table). Significant treatment benefits were observed with ENZA + ADT in several secondary clinical endpoints in the overall population and in both high and low disease volume and risk groups (Table). High QoL at baseline was maintained over time. OS data are immature. Adverse events (AEs) were reported in 85.1% of ENZA + ADT vs. 85.9% of PBO +ADT pts, with no unexpected AEs. Conclusion(s): ENZA+ ADT treatment showed efficacy benefit across all mHSPC pts, irrespective of disease volume and risk group. Similar delays in rPFS, symptomatic skeletal events, PSA progression, castration resistance, and improvements in radiographic responses and PSA declines, with maintenance of high QoL over time, were observed. Preliminary safety analysis appears consistent with the safety profile of ENZA in previous CRPC clinical trials.

BACKGROUND: Elevated serum urate levels are associated with progression of chronic kidney disease. Whether urate-lowering treatment with allopurinol can attenuate the decline of the estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease who are at risk for progression is not known. METHOD(S): In this randomized, controlled trial, we randomly assigned adults with stage 3 or 4 chronic kidney disease and no history of gout who had a urinary albumin: creatinine ratio of 265 or higher (with albumin measured in milligrams and creatinine in grams) or an eGFR decrease of at least 3.0 ml per minute per 1.73 m2 of body-surface area in the preceding year to receive allopurinol (100 to 300 mg daily) or placebo. The primary outcome was the change in eGFR from randomization to week 104, calculated with the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. RESULT(S): Enrollment was stopped because of slow recruitment after 369 of 620 intended patients were randomly assigned to receive allopurinol (185 patients) or placebo (184 patients). Three patients per group withdrew immediately after randomization. The remaining 363 patients (mean eGFR, 31.7 ml per minute per 1.73 m2; median urine albumin: creatinine ratio, 716.9; mean serum urate level, 8.2 mg per deciliter) were included in the assessment of the primary outcome. The change in eGFR did not differ significantly between the allopurinol group and the placebo group (-3.33 ml per minute per 1.73 m2 per year [95% confidence interval {CI}, -4.11 to -2.55] and -3.23 ml per minute per 1.73 m2 per year [95% CI, -3.98 to -2.47], respectively; mean difference, -0.10 ml per minute per 1.73 m2 per year [95% CI, -1.18 to 0.97]; P = 0.85). Serious adverse events were reported in 84 of 182 patients (46%) in the allopurinol group and in 79 of 181 patients (44%) in the placebo group. CONCLUSION(S): In patients with chronic kidney disease and a high risk of progression, urate-lowering treatment