OBJECTIVE: We aimed to evaluate the effects of HP eradication on PD symptoms.

METHODS: In this parallel-group, double-blind, randomized placebo-controlled, single-center trial, patients with PD with positive HP urea breath test and serology were block randomized (1:1) to receive standard eradication triple therapy or identically appearing placebo capsules for 1 week. Prespecified motor (International Parkinson and Movement Disorder Society Unified PD Rating Scale [MDS-UPDRS], timed tests, and home-based wearable sensor measurements), nonmotor (Leeds Dyspepsia Questionnaire and Montreal Cognitive Assessment), and quality-of-life (Parkinson's Disease Questionnaire-39) outcome measures were assessed at weeks 6, 12, 24, and 52. The primary outcome was the baseline-to-week 12 change in ON medication MDS-UPDRS motor scores. Lactulose-hydrogen breath testing for concomitant small intestinal bacterial overgrowth was performed at baseline and repeated at week 24, together with the urea breath test.

RESULTS: A total of 310 patients were screened for eligibility and 80 were randomly assigned, of whom 67 were included in the full-analysis set (32 treatment group patients, 35 placebo patients). HP eradication did not improve MDS-UPDRS motor scores at week 12 (mean difference 2.6 points in favor of placebo, 95% confidence interval: -0.4 to 5.6, P = 0.089). There was no significant improvement in any motor, nonmotor, or quality-of-life outcome at weeks 12 and 52. Both the full-analysis and per-protocol analyses (based on eradication status) supported these conclusions. Small intestinal bacterial overgrowth status did not influence treatment results.

METHODS AND RESULTS: After the randomized treatment period (5.6 years), participants were invited to participate in 3.1 further years of observation (total 8.7 years). The first co-primary outcome for the entire length of follow-up was the composite of myocardial infarction, stroke, or CV death [major adverse cardiovascular event (MACE)-1], and the second was MACE-1 plus resuscitated cardiac arrest, heart failure, or coronary revascularization (MACE-2). In total, 9326 (78%) of 11 994 surviving Heart Outcomes Prevention Evaluation (HOPE)-3 subjects consented to participate in extended follow-up. During 3.1 years of post-trial observation (total follow-up of 8.7 years), participants originally randomized to rosuvastatin compared with placebo had a 20% additional reduction in MACE-1 [95% confidence interval (CI), 0.64-0.99] and a 17% additional reduction in MACE-2 (95% CI 0.68-1.01). Therefore, over the 8.7 years of follow-up, there was a 21% reduction in MACE-1 (95% CI 0.69-0.90, P = 0.005) and 21% reduction in MACE-2 (95% CI 0.69-0.89, P = 0.002). There was no benefit of BP lowering in the overall study either during the active or post-trial observation period, however, a 24% reduction in MACE-1 was observed over 8.7 years.

CONCLUSION: The CV benefits of rosuvastatin, and BP lowering in those with elevated systolic BP, compared with placebo continue to accrue for at least 3 years after cessation of randomized treatment in individuals without cardiovascular disease indicating a legacy effect.

METHODS: ALPHA is an ongoing, international, phase 3, randomised, double-blind, placebo-controlled trial evaluating danicopan as add-on therapy to ravulizumab or eculizumab. Eligible patients were adults (age ≥18 years) with PNH and clinically significant extravascular haemolysis (haemoglobin ≤9·5 g/dL; absolute reticulocyte count ≥120 × 109/L) on ravulizumab or eculizumab for at least 6 months. Patients were randomly assigned (2:1) to danicopan or placebo added to ravulizumab or eculizumab for 12 weeks using an interactive response technology system. Randomisation was stratified based on transfusion history, haemoglobin, and patients enrolled from Japan. The initial oral danicopan dose was 150 mg three times a day; escalation to 200 mg three times a day was permitted based on clinical response. The infusion dose level of eculizumab (every 2 weeks) ranged from 900 mg to 1500 mg, and for ravulizumab (monthly or every 8 weeks) ranged from 3000 mg to 3600 mg. The primary endpoint was change in haemoglobin concentration from baseline to week 12. Here we present the protocol-prespecified interim analysis, planned when approximately 75% of participants were randomly assigned to treatment and completed or discontinued at 12 weeks. This trial is registered with ClinicalTrials.gov (NCT04469465).

FINDINGS: Individuals were randomly assigned between Dec 16, 2020, and Aug 29, 2022. At data cutoff (June 28, 2022), 73 individuals were randomly assigned, received treatment, and were analysed for safety (danicopan, n=49; placebo, n=24). The protocol-prespecified interim efficacy analysis set included the first 63 participants (danicopan, n=42; placebo, n=21). At week 12, danicopan plus ravulizumab or eculizumab increased haemoglobin versus placebo plus ravulizumab or eculizumab (least squares mean [LSM] change from baseline: danicopan, 2·94 g/dL [95% CI 2·52 to 3·36]; placebo, 0·50 g/dL [-0·13 to 1·12]; LSM difference, 2·44 g/dL [1·69 to 3·20]; p<0·0001). Grade 3 adverse events in the danicopan group were increased alanine aminotransferase (two [4%] of 49 patients), leukopenia (one [2%]), neutropenia (two [4%]), cholecystitis (one [2%]), COVID-19 (one [2%]), increased aspartate aminotransferase (one [2%]), and increased blood pressure (one [2%]), and in the placebo group were anaemia (one [4%] of 24 patients), thrombocytopenia (one [4%]), and asthenia (one [4%]). The serious adverse events reported in the danicopan group were cholecystitis (one [2%] patient) and COVID-19 (one [2%]) and in the placebo group were anaemia and abdominal pain, both in one (4%) patient. There were no serious adverse events related to study drug or deaths reported in the study.

INTERPRETATION: These primary efficacy and safety results show that danicopan as add-on treatment to ravulizumab or eculizumab significantly improved haemoglobin concentrations at week 12 with no new safety concerns, suggesting an improved benefit-risk profile in patients with PNH and clinically significant extravascular haemolysis.

METHODS: In this double-blind randomized clinical trial study, 50 NAFLD patients were divided into two groups of 25 participants who were treated with 520 mg/day of GSE or the placebo group for 2 months. The parameters of glycemic, lipid profile, blood pressure and steatohepatitis were measured before and after the intervention.

METHODS: Participants enrolled in TICH-2 were randomized to placebo or TXA. Participants randomized to either TXA or placebo were analyzed for whether they received neurosurgery within 7 days and their characteristics, outcomes, hematoma volumes (HVs) were compared. Characteristics and outcomes of participants who received surgery were also compared with those who did not.

RESULTS: Neurosurgery was performed in 5.2% of participants (121/2325), including craniotomy (57%), hematoma drainage (33%), and external ventricular drainage (21%). The number of patients receiving surgery who received TXA vs placebo were similar at 4.9% (57/1153) and 5.5% (64/1163), respectively (odds ratio [OR] 0.893; 95% CI 0.619-1.289; P -value = .545). TXA did not improve outcome compared with placebo in either surgically treated participants (OR 0.79; 95% CI 0.30-2.09; P = .64) or those undergoing hematoma evacuation by drainage or craniotomy (OR 1.19 95% 0.51-2.78; P -value = .69). Postoperative HV was not reduced by TXA (mean difference -8.97 95% CI -23.77, 5.82; P -value = .45).

METHODS: This was a randomized, double-blind, controlled study of 66 eligible neonates with PICCs inserted for the administration of TPN. Infants were randomized to receive TPN containing either 1 IU ml(-1) of heparin (n = 35) or no heparin (n = 31).

RESULTS: There was no significant difference in the incidence of blocked catheters between the two groups of infants (heparin: 14.3%; no-heparin: 22.6%, p = 0.4). Although a higher percentage (62.9%) of infants in the heparin group received a complete course of TPN successfully via PICC than those in the no-heparin group (48.4%), the difference was not statistically significant (p = 0.3). There were no significant differences in the incidence of catheter-related sepsis, hypertriglyceridaemia, hyperbilirubinaemia, coagulopathy or intraventricular haemorrhage between the two groups.

METHODS: Studies were identified from 4 electronic databases up to June 2019. Randomized clinical trials (RCTs) comparing the anesthetic success rate of GG, VA, and MI NBs with IANBs in mandibular premolars and molars with irreversible pulpitis were included. The quality of selected RCTs was appraised using the revised Cochrane risk of bias tool. Random-effects meta-analyses of risk ratio (RR) and 95% confidence intervals (CIs) were calculated, and random errors were evaluated by TSA. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach.

RESULTS: Five RCTs were included; 2 of them were classified as low risk of bias. No significant difference was observed in the anesthesia success rate compared between GG and IA NBs (RR = 1.10; 95% CI, 0.82-1.48; I2 = 0%). Similarly, no difference was evident between MINB and IANB (RR = 1.15; 95% CI, 0.97-1.36; I2 = 0%). Overall, the cumulative success rates for the 3 anesthetic techniques were low. TSA showed a lack of firm evidence for the results of the meta-analysis between GG NB and IANB. The Grading of Recommendations, Assessment, Development and Evaluation approach evaluation showed that the evidence was of moderate quality for GG NB and IANB compared with low quality for MI and IA NBs. Because only 1 study was available comparing VA NB and IANB, a meta-analysis was not performed. The adverse effect associated with MI NB was swelling, whereas it was prolonged numbness for IANB.

METHODS: A prospective, randomized, controlled trial was carried out at two tertiary hospitals. 32 patients diagnosed with chronic rhinosinusitis and had underwent endoscopic sinus surgery were enrolled. The study group received 2 mL of Tualang honey nasal dressing and the control group received nasal dressing with 2 mL of triamcinolone 20 mg/mL as positive control. A 2 cm nasal dressing was placed longitudinally into the middle meatuses of both nasal cavities. Postoperative healing assessments of edema, crusting, secretions, scarring and symptoms were performed at postoperative day 7, 14, 28 and at 3 months using Sinonasal Outcome Test 22 questionnaire and modified Lund-Kennedy scoring system.

RESULTS: There were no significant differences noted in the scores of Sinonasal Outcome Test 22 and modified Lund-Kennedy at Day 7, 14 and 28 (p>0.05) for both groups. At 3rd month, patients in the triamcinolone group had lesser symptoms and better endoscopic findings (p<0.05).

MATERIALS AND METHODS: Eighty patients for laparoscopic surgery with at least one of the determined risks (nonsmoker, female, previous PONV/motion sickness, or postoperative opioid use) were randomized into either an active or sham group. At the end of surgery, Reletex electrical acustimulation was placed at the P6 acupoint. The active group had grade 3 strength and the sham group had inactivated electrodes covered by silicone. It was worn for 24 h following surgery. PONV scores were recorded.

RESULTS: The active group had significantly shorter durations of surgery and lower PONV incidence over 24 h (35.1% versus 64.9%, P = 0.024) and this was attributed to the lower incidence of nausea (31.4% versus 68.6%, P = 0.006). The overall incidence of vomiting was not significantly different between the groups, but it was higher in the sham group of patients with PONV risk score 3 (23.9%, P = 0.049).

METHODS: Data were pooled from 2 multicenter, double-blind, placebo-controlled, parallel-group, 14-week treatment studies of mirogabalin conducted at ∼350 study sites (Japan, South Korea, Taiwan, Singapore, Malaysia, and Thailand). Eligible patients in both studies were randomized in a 2:1:1:1 ratio, stratified according to a baseline average daily pain score (ADPS) of <6 or ≥6, to placebo, mirogabalin 15-mg once daily (QD), mirogabalin 10-mg twice daily (BID), or mirogabalin 15-mg BID treatment groups. Safety was assessed based on treatment-emergent adverse events identified from the adverse events collected throughout both studies. The primary efficacy end point of both studies was the change from baseline in ADPS at week 14.

FINDINGS: In total, 1587 patients (824 with diabetic peripheral neuropathic pain; 763 with post-herpetic neuralgia) who received at least 1 dose of study drug were analyzed (633 received placebo, 954 treated with mirogabalin). Treatment-emergent adverse events included somnolence (3.8%, 10.8%, 14.5%, and 19.1%) and dizziness (2.7%, 5.7%, 9.1%, and 13.1%) in patients receiving placebo, mirogabalin 15 mg QD, mirogabalin 10 mg BID, and mirogabalin 15 mg BID, respectively. In patients treated with mirogabalin 15 mg QD, 2 (0.6%) of 316 patients discontinued due to somnolence. In the mirogabalin 10-mg BID group, somnolence, edema, and peripheral edema each resulted in 3 (0.9%) of 318 patient discontinuations. In the mirogabalin 15-mg BID group, 6 (1.9%) of 320 patients discontinued due to dizziness and 3 (0.9%) due to somnolence. At week 14, mirogabalin 10 mg BID and 15 mg BID statistically significantly improved ADPS versus placebo, with least squares mean changes (95% CI) of -0.31 (-0.55, -0.08) and -0.63 (-0.86, -0.40). Post hoc analysis showed a statistically significant difference 2 days after administration in the mirogabalin 10-mg and 15-mg BID groups compared with placebo. Female sex, age ≥65 years, and baseline weight <60 kg may influence the safety of mirogabalin, particularly regarding the incidence of somnolence and dizziness, but had no notable impact on efficacy. ClinicalTrials.gov identifiers: NCT02318706 and NCT02318719.

OBJECTIVE: To establish whether tranexamic acid compared with placebo increased the prevalence or number of remote cerebral DWIHLs within 2 weeks of ICH onset.

DESIGN, SETTING, AND PARTICIPANTS: This prospective nested magnetic resonance imaging (MRI) substudy of a randomized clinical trial (RCT) recruited participants from the multicenter, double-blind, placebo-controlled, phase 3 RCT (Tranexamic Acid for Hyperacute Primary Intracerebral Hemorrhage [TICH-2]) from July 1, 2015, to September 30, 2017, and conducted follow-up to 90 days after participants were randomized to either the tranexamic acid or placebo group. Participants had acute spontaneous ICH and included TICH-2 participants who provided consent to undergo additional MRI scans for the MRI substudy and those who had clinical MRI data that were compatible with the brain MRI protocol of the substudy. Data analyses were performed on an intention-to-treat basis on January 20, 2020.

INTERVENTIONS: The tranexamic acid group received 1 g in 100-mL intravenous bolus loading dose, followed by 1 g in 250-mL infusion within 8 hours of ICH onset. The placebo group received 0.9% saline within 8 hours of ICH onset. Brain MRI scans, including DWI, were performed within 2 weeks.

MAIN OUTCOMES AND MEASURES: Prevalence and number of remote DWIHLs were compared between the treatment groups using binary logistic regression adjusted for baseline covariates.

RESULTS: A total of 219 participants (mean [SD] age, 65.1 [13.8] years; 126 men [57.5%]) who had brain MRI data were included. Of these participants, 96 (43.8%) were randomized to receive tranexamic acid and 123 (56.2%) were randomized to receive placebo. No baseline differences in demographic characteristics and clinical or imaging features were found between the groups. There was no increase for the tranexamic acid group compared with the placebo group in DWIHL prevalence (20 of 96 [20.8%] vs 28 of 123 [22.8%]; odds ratio [OR], 0.71; 95% CI, 0.33-1.53; P = .39) or mean (SD) number of DWIHLs (1.75 [1.45] vs 1.81 [1.71]; mean difference [MD], -0.08; 95% CI, -0.36 to 0.20; P = .59). In an exploratory analysis, participants who were randomized within 3 hours of ICH onset or those with chronic infarcts appeared less likely to have DWIHLs if they received tranexamic acid. Participants with probable cerebral amyloid angiopathy appeared more likely to have DWIHLs if they received tranexamic acid.

CONCLUSIONS AND RELEVANCE: This substudy of an RCT found no evidence of increased prevalence or number of remote DWIHLs after tranexamic acid treatment in acute ICH. These findings provide reassurance for ongoing and future trials that tranexamic acid for acute ICH is unlikely to induce cerebral ischemic events.