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UNASSIGNED: Adverse childhood experiences (ACEs) have long-term effects on adult health, including unresolved trauma and substance use disorder (SUD). There are hypotheses of a mediating role of emotion regulation. This systematic literature review and narrative synthesis assessed the effectiveness of psychological interventions on emotion regulation, PTSD and SUD symptoms.
UNASSIGNED: Searches were conducted using the Cochrane Handbook for Systematic Reviews methodology. Eligible studies were randomised controlled trials (RCTs) and quasi-experimental psychological interventions published between 2009 and 2019. Study characteristics, results and methodological quality were systematically analysed.
UNASSIGNED: Thirteen studies, including nine RCTs, were selected. Integrated SUD and PTSD treatments consisted of Seeking Safety, exposure-based treatment, Trauma Recovery and Empowerment Model, and integrated cognitive behavioural therapy. Two studies reported emotion regulation. Five studies found a small to medium positive effect size of psychological interventions on PTSD outcomes. Two studies had a small positive effect size on SUD outcomes and two a small negative effect size. Attrition was high across most studies. Characteristics likely to affect the applicability of the review were described.
UNASSIGNED: The review found some evidence of a small inconsistent positive effect of psychological interventions on PTSD outcomes, and no evidence of effect on SUD outcomes. The range of theoretical models was narrow. Overall quality was low with high clinical heterogeneity and missing key information, particularly on emotion regulation, an important transdiagnostic feature. Further research is required to establish interventions that can treat these multiple conditions with a focus on effectiveness, acceptability, and implementation in real life clinical practice.

UNASSIGNED: Primary biliary cholangitis (PBC) is an autoimmune liver disease involving the small intrahepatic bile ducts; when untreated or undertreated, it may evolve to liver fibrosis and cirrhosis. Ursodeoxycholic Acid (UDCA) is the standard of care treatment, Obeticholic Acid (OCA) has been approved as second-line therapy for those non responder or intolerant to UDCA. However, due to moderate rate of UDCA-non responders and to warnings recently issued against OCA use in patients with cirrhosis, further therapies are needed.Areas covered. Deep investigations into the pathogenesis of PBC is leading to proposal of new therapeutic agents, among which peroxisome proliferator-activated receptor (PPAR) ligands seem to be highly promising given the preliminary, positive results in Phase 2 and 3 trials. Bezafibrate, the most evaluated, is currently used in clinical practice in combination with UDCA in referral centers. We herein describe completed and ongoing trials involving PPAR agonists use in PBC, analyzing pits and falls.
UNASSIGNED: Testing new therapeutic opportunities in PBC is challenging due to its low prevalence and slow progression. However, new drugs including PPAR agonists, are currently under investigation and should be considered for at-risk PBC patients.

UNASSIGNED: Immune thrombocytopenia is an autoimmune disease characterised by decreased platelet count. In recent years, novel therapeutic regimens have been investigated in randomised controlled trials (RCTs). We aimed to compare the efficacy and safety of different treatments in newly diagnosed adult primary immune thrombocytopenia.
UNASSIGNED: We did a systematic review and network meta-analysis of RCTs involving treatments for newly diagnosed primary immune thrombocytopenia. PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched up to April 31, 2022. The primary outcomes were 6-month sustained response and early response. Secondary outcome was grade 3 or higher adverse events. This study is registered with PROSPERO (CRD42022296179).
UNASSIGNED: Eighteen RCTs (n = 1944) were included in this study. Pairwise meta-analysis showed that the percentage of patients achieving early response was higher in the dexamethasone-containing doublet group than in the dexamethasone group (79.7% vs 68.7%, odds ratio [OR] 1.82, 95% CI 1.10-3.02). The difference was more profound for sustained response (60.5% vs 37.4%, OR 2.57, 95% CI 1.95-3.40). Network meta-analysis showed that dexamethasone plus recombinant human thrombopoietin ranked first for early response, followed by dexamethasone plus oseltamivir or tacrolimus. Rituximab plus prednisolone achieved highest sustained response, followed by dexamethasone plus all-trans retinoic acid or rituximab. Rituximab plus dexamethasone showed 15.3% of grade 3 or higher adverse events, followed by prednis(ol)one (4.8%) and all-trans retinoic acid plus dexamethasone (4.7%).
UNASSIGNED: Our findings suggested that compared with monotherapy dexamethasone or prednis(ol)one, the combined regimens had better early and sustained responses. rhTPO plus dexamethasone ranked top in early response, while rituximab plus corticosteroids obtained the best sustained response, but with more adverse events. Adding oseltamivir, all-trans retinoic acid or tacrolimus to dexamethasone reached equally encouraging sustained response, without compromising safety profile. Although this network meta-analysis compared all the therapeutic regimens up to date, more head-to-head RCTs with larger sample size are warranted to make direct comparison among these strategies.
UNASSIGNED: National Natural Science Foundation of China, Major Research Plan of National Natural Science Foundation of China, Shandong Provincial Natural Science Foundation and Young Taishan Scholar Foundation of Shandong Province.

Video 1Successful endoscopic resection using gel immersion for a tumor adjacent to the papilla of Vater.

UNASSIGNED: The safety and feasibility of preoperative pembrolizumab combined with chemoradiotherapy (PPCT) for resectable esophageal squamous cell carcinoma have been confirmed by the prior Preoperative Anti-PD-1 Antibody combined with Chemoradiotherapy for Locally Advanced Squmous Cell Carcinoma of Esophageus (PALACE)-1 trial. Potential therapeutic benefit was also observed with a pathologic complete response rate of 55.6% after PPCT. We will conduct the multicenter single-arm PALACE-2 study to investigate the efficacy and to further confirm the safety of PPCT (ClinicalTrials.gov ID: NCT04435197).
UNASSIGNED: A total of 143 patients with previously untreated, locally advanced, and surgically resectable esophageal squamous cell carcinoma (T2 through T4a, N0 through N+, M0) will be enrolled in PALACE-2. Main exclusion criteria are autoimmune disease, interstitial lung disease, ongoing immunosuppressive therapy, and having received chemotherapy, radiotherapy, target therapy, or immune therapy for this or any other malignancies. Positive programmed cell death ligand 1 expression is not mandatory for enrollment. Patients will receive PPCT, which includes concurrent pembrolizumab (200 mg on day 1 and day 22), carboplatin (area under the curve = 2, once a week for 5 weeks), nab-paclitaxel (50 mg/m2, once a week for 5 weeks), and radiotherapy (23 fractions of 1.8 Gy, 5 fractions a week). Esophagectomy will be performed within 4 to 6 weeks after the completion of PPCT.
UNASSIGNED: The primary end point is the rate of pathologic complete response. Secondary outcome measures are 3-year disease-free survival rate, 3-year overall survival rate, R0 resection rate, and adverse events during neoadjuvant and perioperative periods.
UNASSIGNED: PPCT was preliminarily demonstrated to be safe, feasible, and to provide potential therapeutic benefits by the PALACE-1 trial. The subsequent multicenter PALACE-2 study will investigate the efficacy and further confirm the safety of PPCT for locally advanced, resectable esophageal squamous cell carcinoma.

Patients with Gaucher disease type 3 (GD3), especially those with GBA p.L444P homozygous mutation, often suffer from complications including lymphadenopathy even under regular enzyme replacement therapy (ERT). In order to improve their outcome, we administrated eliglustat, a substrate reduction therapy (SRT), in combination with ERT to four patients, age ranged 9-18 years, for two years. The results revealed that patients\' plasma glucosylsphingosine (lyso-GL1) level and chitotriosidase activity both decreased after adding eliglustat. In three patients who completed follow-up MRI scanning, sizes of lymph nodes all decreased. No severe adverse events were attributed to eliglustat. Therefore, our data suggest that a combined SRT and ERT treatment may improve the ERT-resistant symptoms in patients with GD3.

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BACKGROUND: Lipid nanoparticle (LNP) encapsulated self-amplifying RNA (saRNA) is a novel technology formulated as a low dose vaccine against COVID-19.
METHODS: A phase I first-in-human dose-ranging trial of a saRNA COVID-19 vaccine candidate LNP-nCoVsaRNA, was conducted at Imperial Clinical Research Facility, and participating centres in London, UK, between 19th June to 28th October 2020. Participants received two intramuscular (IM) injections of LNP-nCoVsaRNA at six different dose levels, 0.1-10.0μg, given four weeks apart. An open-label dose escalation was followed by a dose evaluation. Solicited adverse events (AEs) were collected for one week from enrolment, with follow-up at regular intervals (1-8 weeks). The binding and neutralisation capacity of anti-SARS-CoV-2 antibody raised in participant sera was measured by means of an anti-Spike (S) IgG ELISA, immunoblot, SARS-CoV-2 pseudoneutralisation and wild type neutralisation assays. (The trial is registered: ISRCTN17072692, EudraCT 2020-001646-20).
RESULTS: 192 healthy individuals with no history or serological evidence of COVID-19, aged 18-45 years were enrolled. The vaccine was well tolerated with no serious adverse events related to vaccination. Seroconversion at week six whether measured by ELISA or immunoblot was related to dose (both p<0.001), ranging from 8% (3/39; 0.1μg) to 61% (14/23; 10.0μg) in ELISA and 46% (18/39; 0.3μg) to 87% (20/23; 5.0μg and 10.0μg) in a post-hoc immunoblot assay. Geometric mean (GM) anti-S IgG concentrations ranged from 74 (95% CI, 45-119) at 0.1μg to 1023 (468-2236) ng/mL at 5.0μg (p<0.001) and was not higher at 10.0μg. Neutralisation of SARS-CoV-2 by participant sera was measurable in 15% (6/39; 0.1μg) to 48% (11/23; 5.0μg) depending on dose level received.
CONCLUSIONS: Encapsulated saRNA is safe for clinical development, is immunogenic at low dose levels but failed to induce 100% seroconversion. Modifications to optimise humoral responses are required to realise its potential as an effective vaccine against SARS-CoV-2.
BACKGROUND: This study was co-funded by grants and gifts from the Medical Research Council UKRI (MC_PC_19076), and the National Institute Health Research/Vaccine Task Force, Partners of Citadel and Citadel Securities, Sir Joseph Hotung Charitable Settlement, Jon Moulton Charity Trust, Pierre Andurand, Restore the Earth.

OBJECTIVE: To investigate the effects of a 12-week movement-to-music (M2M) intervention on physical and psychosocial outcomes in people poststroke.
METHODS: Two-arm randomized controlled trial.
METHODS: A community-based fitness facility.
METHODS: Participants (N=47) with stroke between 18 and 65 years old were randomized to M2M (n=23) or waitlist control (n=24).
METHODS: Participants in M2M completed 3 60-minute exercise sessions per week for 12 weeks. Controls received biweekly educational newsletters via mail.
METHODS: Primary outcomes included Six-Minute Walk Test (6MWT, in meters), Five Times Sit-to-Stand Test (FTSST, in seconds) and Timed Up and Go (TUG, in seconds). Secondary outcomes were self-reported measures using Patient-Reported Outcomes Measurement Information System Fatigue and Pain Interference Short Form 8a. Outcomes were collected at baseline and postintervention. Analyses involved descriptive statistics and adjusted linear mixed models.
RESULTS: Mixed models adjusted for the respective baseline values and demographic variables showed that M2M participants had longer 6MWT distance (least square mean difference [LSM], 14.5; 95% confidence interval [CI], -12.9 to 42.0), more FTSST time (LSM, 2.0; 95% CI, -4.5 to 8.5), and less fatigue (LSM, -3.0; 95% CI, -7.2 to 1.2) compared with controls postintervention. When controlling for baseline TUG and demographic variables, there was a larger increase in 6MWT distance (LSM, 37.9; 95% CI, -22.7 to 98.6), lower FTSST time (LSM, -6.1; 95% CI, -18.5 to 6.2), and decrease in fatigue (LSM, -6.5; 95% CI, -13.1 to 0.2) in the M2M group compared with controls. Moderate effect sizes were observed for improving 6MWT (d=0.6), FTSST (d=-0.6), and fatigue (d=-0.6). There was no group difference in change in TUG time and pain interference, with trivial effect sizes (d=-0.1).
CONCLUSIONS: M2M may be a valuable exercise form for adults with stroke. Future studies are needed to determine optimal exercise doses for improving health and function in this population.