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Background & Aims: The aim of the study was to evaluate the efficacy and safety of adjuvant sorafenib treatment compared with placebo in patients with hepatocellular carcinoma who underwent local ablation., Methods: The SORAMIC trial is a randomised controlled trial with diagnostic, local ablation, and palliative sub-study arms. After initial imaging within the diagnostic study, patients were assigned to local ablation or palliative arms. In the local ablation cohort, patients were randomised 1:1 to local ablation + sorafenib vs. local ablation + placebo. The primary endpoint was time-to-recurrence (TTR). Secondary endpoints were local control rate and safety in terms of adverse events and quality-of-life., Results: The recruitment was terminated prematurely after 104 patients owing to slow recruitment. One patient was excluded because of a technical failure. Fifty-four patients were randomised to local ablation + sorafenib and 49 to local ablation + placebo. Eighty-eight patients who underwent standardised follow-up imaging comprised the per-protocol population. The median TTR was 15.2 months in the sorafenib arm and 16.4 months in the placebo arm (hazard ratio 1.1; 95% CI 0.53-2.2; p  = 0.82). Out of 136 lesions ablated within the trial, there was no difference in local recurrence rate between sorafenib (6/69, 8.6%) and placebo groups (5/67, 5.9%; p  = 0.792).Overall (92.5% vs. 71.4%, p  = 0.008) and drug-related (81.4% vs. 55.1%, p  = 0.003) adverse events were more common in the sorafenib arm compared with the placebo arm. Dose reduction because of adverse events were common in the sorafenib arm (79.6% vs. 30.6%, p <0.001)., Conclusions: Adjuvant sorafenib did not improve in TTR or local control rate after local ablation in patients with hepatocellular carcinoma within the limitations of an early terminated trial., Impact and Implications: Local ablation is the standard of care treatment in patients with early stages of hepatocellular carcinoma, along with surgical therapies. However, there is a risk of disease recurrence during follow-up. Sorafenib, an oral medication, is a routinely used treatment for patients with advanced hepatocellular carcinoma. This study found that sorafenib treatment after local ablation in people with early hepatocellular carcinoma did not significantly improve the disease-free period compared with placebo., Clinical Trial Number: EudraCT 2009-012576-27, NCT01126645., Competing Interests: MS: Personal fees: Bayer, Sirtex. OÖ: Honoraria: Bayer. PM: Grants: Bayer, Sirtex. TB: Grants/research support: Abbvie, BMS, Gilead, MSD/Merck, Humedics, Intercept, Merz, Novartis, Sequana Medical. Honoraria or consultation fees: Abbvie, Alexion, Bayer, Gilead, Eisai, Humedics, Intercept, Ipsen, Janssen, MSD/Merck, Novartis, Roche, Sequana Medical, SIRTEX, SOBI, and Shionogi. ENdT: Consultant fees: AstraZeneca, Bayer, BMS, EISAI, Eli Lilly & Co, Pfizer, IPSEN, and Roche. Travel fees: Arqule, Astrazeneca, BMS, Bayer, Celsion, and Roche and lecture honoraria from BMS and Falk. Grants: Arqule, AstraZeneca, BMS, Bayer, Eli Lilly, and Roche. BS: Consultancy fees: Adaptimmune, Astra Zeneca, Bayer, BMS, Boston Scientific, BTG, Eisai, Eli Lilly, H3 Biomedicine, Ipsen, Novartis, Merck, Roche, Sirtex Medical and Terumo. Speaker fees: Astra Zeneca, Bayer, BMS, BTG, Eli Lilly, Ipsen, Novartis, Merck, Roche, Sirtex Medical and Terumo. Grants (to Institution): BMS and Sirtex Medical. MP: Grants: Sirtex, Bayer; Personal fees: Sirtex. JR: Grants: Sirtex, Bayer; Personal fees: Sirtex, Bayer. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Background & Aims: Transcatheter arterial chemoembolisation (TACE) is recommended for patients with hepatocellular carcinoma devoid of macrovascular invasion or extrahepatic spread but not eligible for curative therapies. We compared the efficacy and safety of the combination of a single TACE and external conformal radiotherapy (CRT) vs . classical TACE., Methods: TACERTE was an open-labelled, randomised controlled trial with a 1:1 allocation rate to two or three TACE (arm A) or one TACE + CRT (arm B). Participants had a mean age of 70 years, and 86% were male. The aetiology was alcohol in 85%. The primary endpoint was liver progression-free survival (PFS) in the intention-to-treat population. The typical CRT schedule was 54 Gy in 18 sessions of 3 Gy., Results: Of the 120 participants randomised, 64 were in arm A and 56 in arm B; 100 participants underwent the planned schedule and defined the 'per-protocol' group. In intention-to-treat participants, the liver PFS at 12 and 18 months were 59% and 19% in arm A and 61% and 36% in arm B (hazard ratio [HR] 0.69; 95% CI 0.40-1.18; p  = 0.17), respectively. In the per-protocol population, treated liver PFS tended to be better in arm B (HR 0.61; 95% CI 0.34-1.06; p  = 0.081) than in arm A. Liver-related grade III-IV adverse events were more frequent in arm B than in arm A. Median overall survival reached 30 months (95% CI 23-35) in arm A and 22 months (95% CI 15.7-26.2) in arm B., Conclusions: Although TACE + CRT tended to improve local control, this first Western randomised controlled trial showed that the combined strategy failed to increase PFS or overall survival and led more frequently to liver-related adverse effects., Impact and Implications: Hepatocellular carcinoma is frequently treated by arterial embolisation of the tumour and more recently by external radiotherapy. We tried to determine whether combination of the two treatments (irradiation after embolisation) might produce interesting results. Our results in this prospective randomised study were not able to demonstrate a beneficial effect of combining embolisation and irradiation in these patients. On the contrary, we observed more adverse effects with the combined treatment., Clinical Trials Registration: NCT01300143., Competing Interests: CF, LC, IA, XM, ER, CP, LM, FO, YT, JG, HR, JE, AR, PH, JFB, ENK, DA, AGP, EF-P, and HA did not receive any grants or funding. P Merle reports grants or funding from Roche, AstraZeneca, MSD, Eisai, Bayer, and Ipsen. P Mathurin reports grants or funding from Ipsen, Eisai, Abbvie, Sanofi, Gilead Sciences, Pfizer, Evive Biotech, Novo Nordisk, Bayer Healthcare, Surrozen, and Intercept. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Authors.)

Background: Motor disturbances and non-motor disturbances such as constipation are the main factors affecting the quality of life in patients with Parkinson's disease (PD). We investigated the efficacy and safety of electroacupuncture combined with conventional pharmacological treatment on motor dysfunction and constipation in PD., Methods: In this multi-centre randomised controlled trial, we enrolled 166 eligible participants between September 19, 2018 and September 25, 2019 in four hospitals in China. Participants were randomly assigned (1:1) to the electroacupuncture (EA) group and the waitlist control group. Each participant in both groups received the conventional pharmacological treatment, EA group received 3 sessions of electroacupuncture per week for 12 weeks. The primary outcome was the change in the Unified Parkinson's Disease Rating Scale (UPDRS) score from baseline to week 12. The secondary outcomes included the evaluation of functional disability in motor symptoms and constipation, the adherence and adverse events were also recorded. Registered with Chictr.org.cn, ChiCTR1800019517., Findings: At week 12, the change in the UPDRS score of the EA group was significantly higher than that of the control group, with a difference of -9.1 points (95% CI, -11.8 to -6.4), and this difference continued into weeks 16 and 24. From baseline to week 12, the 39-item Parkinson Disease Question (PDQ-39) decreased by 10 points (interquartile range, IQR -26.0 to 0.0) in the EA group and 2.5 points (IQR: -11.0 to 4.0) in the control group, the difference was statistically significant. The time and steps for the 20-m walk at week 12, as well as the changes from baseline in the EA group, were comparable with that in the control group. But the EA group had a greater decrease than the control group from baseline in the times for 20-m walks at weeks 16 and 24. From week 4 to week 24, the median values of spontaneous bowel movements (SBMs) per week in the EA group were higher than that in the control group, the differences were all statistically significant. The incidence of EA-related adverse events during treatment was low, and they are mild and transient., Interpretation: The findings of our study suggested that compared with conventional pharmacological treatment, conventional pharmacological treatment combined with electroacupuncture significantly enhances motor function and increased bowel movements in patients with PD, electroacupuncture is a safe and effective treatment for PD., Funding: Shanghai "Science and Technology Innovation Action Plan" Clinical Medicine Field Project (18401970700), Shanghai Special Project on Aging and Women's and Children's Health Research (020YJZX0134), Shanghai Clinical Research Centre for Acupuncture and Moxibustion (20MC1920500)., Competing Interests: We declare no competing interests., (© 2022 The Authors.)

Objectives: Regular Baduanjin exercise training has been shown to be beneficial to the physical and cognitive health of older adults, but the underlying mechanisms remain to be investigated. This study examined the influence of Baduanjin on cerebral hemodynamics in community-dwelling older adults with cognitive frailty., Design: Randomized controlled trial., Methods: A total of 102 eligible participants were randomly allocated into the Baduanjin exercise intervention group (BEG) or usual physical activity control group (CG) for 24 weeks. Cerebral hemodynamic parameters of bilateral middle/anterior cerebral artery and basilar artery, cognitive ability and physical frailty were assessed using Transcranial Doppler (TCD), Montreal Cognitive Assessment (MoCA) and Edmonton Frailty Scale (EFS) at baseline and 24 weeks post-intervention., Results: After 24 weeks intervention, the changes in peak systolic velocity (PSV), mean blood flow velocity (MBFV), and end diastolic velocity (EDV) in the right middle cerebral artery and basilar artery were better in the BEG than in the CG; the increase in MoCA scores and the decrease in EFS scores were significantly higher in the BEG than in the CG. Moreover, the interaction of exercise and time on those variables showed obvious significance., Conclusions: The 24 weeks Baduanjin exercise training had a positive beneficial effect on cerebral blood flow in community-dwelling older adults with cognitive frailty. This may be a potential mechanism by which Baduanjin exercise improves the cognitive frailty in older adults., Trial Registration: Chinese Clinical Trial Registry, ChiCTR1800020341., Date of Registration: December 25, 2018, http://www.chictr.org.cn/showproj.aspx?proj=29846., Competing Interests: No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication., (© 2022 The Society of Chinese Scholars on Exercise Physiology and Fitness. Published by Elsevier (Singapore) Pte Ltd.)

Background & Aims: EASL guidelines recommend 8 weeks of treatment with sofosbuvir plus velpatasvir (SOF/VEL) for the treatment of acute or recently acquired HCV infection, but only 6- and 12-week data are available. Therefore, the aim of this study was to evaluate the safety and efficacy of a shortened 8-week SOF/VEL treatment for acute HCV monoinfection., Methods: In this investigator-initiated, prospective, multicentre, single-arm study, we recruited 20 adult patients with acute HCV monoinfection from nine centers in Germany. Patients received SOF/VEL (400/100 mg) as a fixed-dose combination tablet once daily for 8 weeks. The primary efficacy endpoint was the proportion of patients with sustained virological response 12 weeks after the end of treatment (SVR12)., Results: The median HCV RNA viral load at baseline was 104,307 IU/ml; the distribution of HCV genotypes was as follows: GT1a/1b/2/3/4: n = 12/1/1/3/3. Thirteen (65%) of the 20 patients were taking medication for HIV pre-exposure prophylaxis. SVR12 was achieved in all patients who complied with the study protocol (n = 18/18 [100%], per protocol analysis), but the primary endpoint was not met in the intention-to-treat analysis (n = 18/20 [90%]) because two patients were lost to follow-up. One serious adverse event (unrelated to study drug) occurred during 12 weeks of post-treatment follow-up., Conclusions: The 8-week treatment with SOF/VEL was well tolerated and highly effective in all adherent patients with acute HCV monoinfection. Early treatment of hepatitis C might effectively prevent the spread of HCV in high-risk groups., Clinical Trial Number: NCT03818308., Impact and Implications: The HepNet acute HCV-V study (NCT03818308), an investigator-initiated, single-arm, multicenter pilot study, demonstrates the efficacy and safety of 8 weeks of daily treatment with the fixed-dose combination sofosbuvir/velpatasvir (400/100 mg) in patients with acute hepatitis C virus (HCV) infection. All patients who completed therapy and were followed-up achieved sustained virologic response. Thus, early treatment with SOF/VEL which might effectively prevent the spread of HCV in high-risk groups can be recommended for patients with acute HCV monoinfection., Competing Interests: The authors declare no conflict of interest concerning the content of this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Background: Bifidobacterium longum BB536 supplementation can be used to regulate bowel movements in various people, including healthy subjects and patients with irritable bowel syndrome (IBS); however, individuals vary in their responses to B. longum BB536 treatment. One putative factor is the gut microbiota; recent studies have reported that the gut microbiota mediates the effects of diet or drugs on the host. Here, we investigated intestinal features, such as the microbiome and metabolome, related to B. longum BB536 effectiveness in increasing bowel movement frequency., Results: A randomized, double-blind controlled crossover trial was conducted with 24 adults who mainly tended to be constipated. The subjects received a two-week dietary intervention consisting of B. longum BB536 in acid-resistant seamless capsules or similarly encapsulated starch powder as the placebo control. Bowel movement frequency was recorded daily, and fecal samples were collected at several time points, and analyzed by metabologenomic approach that consists of an integrated analysis of metabolome data obtained using mass spectrometry and microbiome data obtained using high-throughput sequencing. There were differences among subjects in B. longum intake-induced bowel movement frequency. The responders were predicted by machine learning based on the microbiome and metabolome features of the fecal samples collected before B. longum intake. The abundances of eight bacterial genera were significantly different between responders and nonresponders., Conclusions: Intestinal microbiome and metabolome profiles might be utilized as potential markers of improved bowel movement after B. longum BB536 supplementation. These findings have implications for the development of personalized probiotic treatments., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Among Chinese college students, the burden of depression is considerably high, affecting up to 30 % of the population. Despite this burden, few Chinese students seek mental health treatment. In addition, depression is highly comorbid with other mental health disorders, such as anxiety. Scalable, transdiagnostic, evidence-based interventions are needed for this population., Objective: The study will evaluate the effectiveness of a World Health Organization transdiagnostic digital mental health intervention, Step-by-Step, to reduce depressive and anxiety symptoms and improve well-being compared with enhanced care as usual and its implementation in a Chinese university community., Methods: A type 1 effectiveness-implementation two-arm, parallel, randomized controlled trial will be conducted. The two conditions are 1) the 5-session Step-by-Step program with minimal guidance by trained peer-helpers and 2) psychoeducational information on depression and anxiety and referrals to local community services. A total of 334 Chinese university students will be randomized with a 1:1 ratio to either of the two groups. Depression, anxiety, wellbeing, and client defined problems will be assessed at pre-intervention, post-intervention, and 3-month follow-up. Endline qualitative interviews and focus group discussions will be conducted to explore SbS implementation among service users, university staff, and stakeholders. Data will be analysed based on the intent-to-treat principle., Discussion: Step-by-Step is an innovative approach to address common mental health problems in populations with sufficient digital literacy. It is a promising intervention that can be embedded to scale mental health services within a university setting. It is anticipated that after successful evaluation of the program and its implementation in the type 1 hybrid design RCT study, Step-by-Step can be scaled and maintained as a low-intensity treatment in universities, and potentially extended to other populations within the Chinese community., Trial Registration: ChiCTR2100050214., Competing Interests: HFS declared no conflict of interest (and other authors)., (© 2022 The Author(s).)

Purpose: Faricimab is a novel anti-angiopoietin-2 and anti-vascular endothelial growth factor (VEGF) bispecific antibody with high affinities and specificities for both VEGF and angiopoietin-2. It is postulated that targeting angiogenic factors and inflammatory pathways in addition to the VEGF pathway will increase treatment durability and improve outcomes. The phase 3 YOSEMITE (ClinicalTrials.gov identifier, NCT03622580) and RHINE (ClinicalTrials.gov identifier, NCT03622593) trials are designed to assess efficacy, safety, and durability of faricimab compared with aflibercept in patients with diabetic macular edema (DME). The trials evaluate a personalized treatment interval (PTI) approach to address heterogeneity in treatment response among patients with DME., Design: Two identically designed, global, double-masked, randomized, controlled phase 3 trials (YOSEMITE and RHINE)., Participants: Adults with center-involving DME secondary to type 1 or 2 diabetes mellitus., Methods: These studies were designed to evaluate 3 treatment groups: faricimab 6.0 mg dosed either at fixed dosing every 8 weeks after initial treatment with 6 intravitreal doses at 4-week intervals, or faricimab 6.0 mg dosed according to PTI after initial treatment with 4 every-4-week doses, compared with aflibercept 2.0 mg dosed every 8 weeks after 5 initial every-4-week doses. The primary end point of the studies was change from baseline in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Secondary end points included anatomic, durability, and patient-reported outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. The PTI is a protocol-defined flexible regimen based on the treat-and-extend concept, which allowed up to every-16-week adjustable dosing based on objective and standardized criteria. The PTI design aimed to maximize therapeutic results while minimizing treatment burden., Main Outcome Measures: We describe the rationale for the study design and the novel PTI (up to every-16-week adjustable dosing) approach for treatment with faricimab., Results: YOSEMITE and RHINE enrolled 940 and 951 patients, respectively. Results from each study will be reported separately., Conclusions: YOSEMITE and RHINE were the first registrational trials in retinal disease to incorporate an objective PTI regimen, allowing for up to every-16-week adjustable dosing with a dual angiopoietin-2 and VEGF-A inhibitor, faricimab 6.0 mg, for treatment of DME., (© 2021 by the American Academy of Ophthalmology.)

Background: The COVID-19 pandemic has had a detrimental effect on the mental health of older adults living in nursing homes. Very few studies have examined the effects of Internet-based Cognitive Behavioral Therapy (ICBT) on older adults living in nursing homes during the pandemic. We conducted a feasibility study using a single-group design, to explore the effectiveness of ICBT on psychological distress in 137 older adults (without cognitive impairment) from 8 nursing homes in 4 southeast cities in China, between January and March 2020., Methods: Symptoms of depression, anxiety, general psychological distress, and functional disability were measured at baseline, post-treatment (5 weeks) and at a 1-month follow-up. Mixed-effects model was used to assess the effects of ICBT., Results: Statistically significant changes with large effect sizes were observed from pre- to post-treatment on the PHQ-9 ( p  < .001, Cohen's d  = 1.74), GAD-7 ( p  < .001, d  = 1.71), GDS ( p  < .001, d  = 1.30), K-10 ( p  < .001, d  = 1.93), and SDS ( p  < .001, d  = 2.03). Furthermore, improvements in treatment outcomes were sustained at 1-month follow-up, and high levels of adherence and satisfaction were indicated., Conclusion: ICBT was effective in reducing psychological distress in older adults without cognitive impairments living in nursing homes during the COVID-19 pandemic. Thus, it could be applied in improving the mental health of this vulnerable group during the pandemic., Competing Interests: None., (© 2021 The Authors.)

Depression is a debilitating disorder associated with poor health outcomes, including increased comorbidity and early mortality. Despite the advent of new digital health interventions, few have been tested among patients with more severe forms of depression. As such, in an intent-to-treat study we examined whether 218 patients with at least moderately severe depressive symptoms (PHQ-9 ≥ 15) experienced significant reductions in depressive symptoms after participation in a therapist-supported, evidence-based mobile health (mHealth) program, Meru Health Program (MHP). Patients with moderately severe and severe depressive symptoms at pre-program assessment experienced significant decreases in depressive symptoms at end-of treatment (mean [standard deviation] PHQ-9 reduction = 8.30 [5.03], Hedges' g  = 1.64, 95% CI [1.44, 1.85]). Also, 34% of patients with at least moderately severe depressive symptoms at baseline and 29.9% of patients with severe depressive symptoms (PHQ-9 ≥ 20) at baseline responded to the intervention at end-of-treatment, defined as experiencing ≥50% reduction in PHQ-9 score and a post-program PHQ-9 score lower than 10. Limitations include use lack of a control group and no clinical diagnostic information. Future randomized trials are warranted to test the MHP as a scalable solution for patients with more severe depressive symptoms., Competing Interests: Dr. Forman-Hoffman is employed as the Chief Research Officer at Meru Health, Inc., receives salary from the company and owns options of the company. Dr. Nelson is an employee of Meru Health, Inc. Mr. Ranta serves as the Chief Executive Officer (CEO) at Meru Health, Inc., owns a large share of stocks, and raises salary from the company. Dr. Hilgert is employed as Director of Therapy Development and Clinical Operations at Meru Health Inc., receives salary from the company, and owns stocks and options of the company. Mr. Nazander serves as the Chief Technology Office (CTO) at Meru Health Inc., owns a large share of stocks, and raises salary from the company. Dr. de Quevedo has no competing financial interests., (© 2021 The Authors.)

Despite the high prevalence of comorbid depression in people living with coronary artery disease (CAD), uptake of psychological treatment is generally low. This study was designed to investigate the feasibility of an internet-based cognitive-behavioral (iCBT) depression intervention for people with CAD and depressive symptoms., Methods: People with CAD and depressive symptoms (PHQ-9 ≥ 5) were randomly assigned to the eight modules comprising iCBT ( N  = 18), or waitlist-control ( N  = 16). Measures were taken at baseline (t1) and at post-treatment (eight weeks after randomization, t2). Feasibility-related outcomes were recruitment strategy, study attrition, intervention dropout, satisfaction, negative effects as well as the potential of the intervention to affect likely outcomes in a future full-scale trial (depression, anxiety, quality of life, fear of progression). Data analyses were based on intention-to-treat principles. Linear regression models were used to detect between group differences. Linear Mixed Models were used to model potential changes over time., Results: This trial was terminated prior to a-priori defined sample size has been reached given low recruitment success as well as high intervention dropout (88%) and study attrition (23%). On average, participants in the intervention group completed M  = 2.78 ( SD  = 3.23) modules. Participants in the waitlist control group barely started one module ( M  = 0.82, SD  = 1.81). The satisfaction with the intervention was low ( M  = 20.6, SD  = 0.88). Participants reported no negative effects attributed to the iCBT. Differences between groups with regard to depression, anxiety, fear of progression and quality of life remained non-significant ( p  > 0.05)., Conclusion: This trial failed to recruit a sufficient number of participants. Future work should explore potential pitfalls with regards to the reach and persuasiveness of internet interventions for people living with CAD. The study gives important indications for future studies with regard to the need for new ideas to reach and treat people with CAD and depression., Competing Interests: HB received consultancy fees, reimbursement of congress attendance and travel costs as well as payments for lectures from Psychotherapy and Psychiatry Associations as well as Psychotherapy Training Institutes in the context of E-Mental-Health topics. He has been the beneficiary of study support (third-party funding) from several public funding organizations. DDE possess shares in the GET.On Institute GmbH, which works to transfer research findings on Internet- and mobile-phone-based health interventions into routine care. DDE has received payments from several companies and health insurance providers for advice on the use of Internet-based interventions. He has received payments for lectures from Psychotherapy and Psychiatry Associations and has been the beneficiary of third-party funding from health insurance providers., (© 2021 The Authors.)

Background & Aims: Despite limitations, platelet transfusion has been used to minimise bleeding risk in patients with thrombocytopaenia. Lusutrombopag is an oral, thrombopoietin receptor agonist approved for treatment of thrombocytopaenia associated with chronic liver disease in patients undergoing planned invasive procedures. This post-hoc analysis assessed the magnitude of platelet count change based on the integrated per-protocol population from 2 similar phase III multicentre, randomised, double-blind, placebo-controlled trials., Methods: Adults with chronic liver disease-induced thrombocytopaenia and platelet count <50 (× 10 9 /L) received lusutrombopag 3 mg or placebo ≤7 days before invasive procedure scheduled 9-14 days after randomisation. Platelet transfusion was required per protocol if the platelet count remained <50 no more than 2 days before the planned invasive procedure. Post-hoc analysis included: proportion of patients with platelet count ≥50, ≥1.5-fold increase, and a doubling of platelet count; maximum and maximum change in platelet count; and platelet count time course., Results: Platelet count ≥50, a platelet count increase ≥1.5-fold, and at least a doubling in platelet count were achieved in 88.3%, 86.9%, and 52.6% of patients in the lusutrombopag group (n = 137) vs. 58.6%, 32.3%, and 6.0% of patients in the placebo group (n = 133), respectively. In the lusutrombopag group, median maximum platelet count across baseline platelet counts of <30, ≥30 to <40, and ≥40 was 46, 76, and 87, respectively. Median maximum change in platelet count by baseline platelet count was +24, +42, and +40, respectively. Patients who received lusutrombopag without platelet transfusion achieved a median platelet count ≥50 for 3 weeks., Conclusions: Patients treated with lusutrombopag experienced a clinically relevant response in platelet count for a substantial duration of time., Lay Summary: Patients with low platelet counts caused by chronic liver disease may not receive planned invasive procedures or surgeries because of an increased risk of bleeding. Lusutrombopag has previously demonstrated efficacy in raising platelet counts and is approved to treat chronic liver disease patients with low platelet counts in advance of a planned surgery. Physicians need to understand more clearly what to expect in terms of platelet count change when using lusutrombopag; this integrated analysis provides data to help guide its clinical application., Competing Interests: Robert S. Brown, Jr: Consultant and research support from AbbVie, Shionogi, Dova, Gilead, Intercept. Michio Imawari: Advisor for Shionogi, Japan Bio Products and EA Pharma. Namiki Izumi: Funding for speakers bureau from AbbVie, Shionogi, Bayer, Gilead, Otsuka, and Eisai. Yukio Osaki: Speaking and teaching for Gilead, Bayer Yakuhin, MSD, Shionogi, AbbVie GK, and Eisai. Roy Bentley: Shionogi employee. Toshimitsu Ochiai: Shionogi employee. Takeshi Kano: Shionogi employee. Markus Peck-Radosavljevic: Personal fees from Shionogi during the conduct of this study. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2021 The Authors.)

Background: Jingshu Keli (or Jingshu granules), a traditional Chinese medicine, are widely used for treating cervical spondylotic radiculopathy in China; however, no randomized, double-blind, controlled study has verified their effectiveness., Purpose: To evaluate the efficacy and safety of Jingshu Keli for the treatment of cervical spondylotic radiculopathy in a randomized controlled trial., Design: From August 2015 to July 2017, a multicenter, randomized, double-blind, placebo-controlled trial was conducted at 13 large- and medium-sized hospitals in China., Patient Sample: A total of 360 and 120 patients were initially enrolled in the Jingshu and control groups, respectively; 386 patients completed the study, with 299 in the Jingshu group and 87 in the control group., Outcome Measures: The main index for evaluating the curative effect was the pain score on a visual analogue scale (VAS; 0-100 points)., Methods: All patients were administered a bag of Jingshu Keli or placebo 3 times a day for 4 weeks, and were interviewed at the second and fourth weeks. The decrease in pain scores and rate of change in pain scores after treatment were calculated, related laboratory indices were reviewed, and adverse reactions were recorded., Results: In the Per Protocol Set (PPS) analysis, the baseline pain VAS scores in the control and Jingshu groups were 49.31 ​± ​6.97 and 50.06 ​± ​7.33, respectively, with no significant difference between the groups (P ​> ​0.05). While there were no differences at 2 weeks between groups, at four weeks the pain VAS scores in the control and Jingshu groups decreased by 12.86 ​± ​13.45 and 22.72 ​± ​15.08, respectively relative to the values at baseline, with significant group differences (P ​< ​0.0001). While there were similar significant differences between the groups (P ​< ​0.0001) in the Full Analysis Set (FAS) analyses neither group achieved the minimal clinically important difference at any time point., Conclusions: Jingshu Keli are effective for the treatment of cervical spondylotic radiculopathy., Translational Potential Statement: This is the first prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial that confirmed the clinical efficacy and safety of Jingshu Keli for treating cervical spondylotic radiculopathy, which can provide evidence for clinical treatment., Competing Interests: The authors have no conflicts of interest to disclose in relation to this article., (© 2020 Published by Elsevier (Singapore) Pte Ltd on behalf of Chinese Speaking Orthopaedic Society.)

Background: Scientific support for Thai traditional medicine (TTM) practice is warranted for reintroduction into modern healthcare systems. A promising TTM practice for treatment of pressure ulcers was selected to conduct a clinical trial. This study aimed to evaluate the efficacy of the TTM practice for the treatment of pressure ulcers using honey or a Thai Herbal Oil preparation (THO) based on the TTM wound diagnosis comparing with the standard practice., Methods: The study design was an open-label randomized controlled trial. Sixty-six participants, with pressure ulcers at least stage II-IV or unstageable, were allocated to two groups via minimization. A TTM practice group received honey or THO depending on the TTM diagnosis via the Thai Traditional Medicine Pressure Ulcer Assessment Tool (TTM-PUAT). A standard practice group received advanced dressings, including hydrogel, alginate, silver-impregnated, or hydrocolloid dressings. The primary outcome was the Pressure Ulcer Scale for Healing (PUSH)., Results: Both TTM practice and standard practice showed a significant reduction in PUSH scores after treatments. However, there was no significant difference in PUSH score reduction between the groups. The mean PUSH score reduction over the 6-week period was 2.58 ± 3.38 (95% CI 1.34-3.82) in the TTM practice group and 3.24 ± 3.49 (95% CI 1.91-4.57) in the standard practice group (p = 0.284). The TTM practice and standard practice accelerated pressure ulcer healing without statistically significant difference between the practices, during 6 weeks in a home-based care setting. This finding supported the TTM practice as an alternative treatment for pressure ulcer., Competing Interests: The authors declare that they have no competing interests., (© 2020 The Authors.)

The programmed cell death protein 1 (PD-1) pathway has received considerable attention due to its role in eliciting the immune checkpoint response of T cells, resulting in tumor cells capable of evading immune surveillance and being highly refractory to conventional chemotherapy. Application of anti-PD-1/PD-L1 antibodies as checkpoint inhibitors is rapidly becoming a promising therapeutic approach in treating tumors, and some of them have successfully been commercialized in the past few years. However, not all patients show complete responses and adverse events have been noted, suggesting a better understanding of PD-1 pathway mediated immunosuppression is needed to predict patient response and improve treatment efficacy. Here, we review the progresses on the studies of the mechanistic role of PD-1 pathway in the tumor immune evasion, recent clinical development and commercialization of PD-1 pathway inhibitors, the toxicities associated with PD-1 blockade observed in clinical trials as well as how to improve therapeutic efficacy and safety of cancer immunotherapy.

The present study examined whether a web-based intervention could promote weight-loss maintenance, after weight loss. The study was a two-phase, 27-month, randomized controlled trial conducted in Ibaraki, Japan, from 2014 to 2017; 133 participants were recruited through local newspaper advertisements. The eligibility criteria were as follows: age of 40-64 years, body mass index of 25-40 kg/m 2 , and having at least one metabolic syndrome component. In phase 1, a 3-month, group-based weight-loss program was provided to all eligible participants ( n  = 119). We then randomly assigned (1:1) participants who had lost 5% or more of their weight during phase 1 ( n  = 95) to either the self-help (mean 3-month weight loss 7.30 kg) or the web-support group (7.00 kg). Participants in the web-support group regularly reported their body weight and physical activity through a web-based system. They received monthly personalized feedback from a study staff for 24 months. The primary outcome, 27-month body-weight change (mean ± standard deviation), in the self-help and web-support groups were - 5.3 ± 5.0 kg and -4.5 ± 4.9 kg, respectively. There was no significant difference. An exploratory secondary analysis demonstrated that those with greater 27-month increases in their step count, assessed with an accelerometer, lost more weight with no difference in changes in energy intake. The mean 27-month body-weight change in the 4th quartile of changes in step count was -7.78 kg. Although web-based intervention using an activity monitor failed to promote weight-loss maintenance, increased physical activity was associated with successful weight-loss maintenance.

The objective of the present study was to evaluate the growth and tolerance in healthy, term infants consuming a synbiotic formula with daily weight gain as the primary outcome. In a randomised, controlled, double-blind, multicentre, intervention study infants were assigned to an extensively hydrolysed formula containing a specific combination of Bifidobacterium breve M-16V and a prebiotic mixture (short-chain galacto-oligosaccharides and long-chain fructo-oligosaccharides in a 9:1 ratio; scGOS/lcFOS; synbiotic group), or the same formula without this synbiotic concept for 13 weeks (control group). Anthropometry, formula intake, tolerance, stool characteristics, blood parameters, faecal microbiota and metabolic faecal profile were assessed. Medically confirmed adverse events were recorded throughout the study. Equivalence in daily weight gain was demonstrated for the intention-to-treat (ITT) population ( n 211). In the per-protocol (PP) population ( n 102), the 90 % CI of the difference in daily weight gain slightly crossed the lower equivalence margin. During the intervention period, the mean weight-for-age and length-for-age values were close to the median of the WHO growth standards in both groups, indicating adequate growth. The number of adverse events was not different between both groups. No relevant differences were observed in blood parameters indicative for liver and renal function. At 13 weeks, an increased percentage of faecal bifidobacteria (60 v . 48 %) and a reduced percentage of Clostridium lituseburense/C. histolyticum (0·2 v . 2·6 %) were observed in the synbiotic group ( n 19) compared with the control group ( n 27). In conclusion, this study demonstrates that an extensively hydrolysed formula with B. breve M-16V and the prebiotic mixture scGOS/lcFOS (9:1) supports an adequate infant growth.