Photoswitchable dynamics and RNAi synergist with tailored interface and controlled release reprogramming tumor immunosuppressive niche.

Immunosuppressive tumor microenvironment (ITM) severely limited the efficacy of immunotherapy against triple-negative breast cancer (TNBC). Herein, Apt-LPR, a light-activatable photodynamic therapy (PDT)/RNAi immune synergy-enhancer was constructed by co-loading miR-34a and photosensitizers in cationic liposomes (in phase III clinical trial). Interestingly, the introduction of tumor-specific aptamers creates a special "Liposome-Aptamer-Target" interface, where the aptamers are initially in a "lying down" state but transform to "standing up" after target binding. The interfacing mechanism was elaborately revealed by computational and practical experiments. This unique interface endowed Apt-LPR with neutralized surface potential of cationic liposomes to reduce non-specific cytotoxicity, enhanced DNase resistance to protect aptamers, and preserved target-binding ability for selective drug delivery. Upon near-infrared irradiation, the generated reactive oxygen species would oxidize unsaturated phospholipids to destabilize both liposomes and lysosomes, realizing stepwise lysosomal escape of miR-34a for tumor cell apoptosis and downregulation of PD-L1 to suppress immune escape. Together, tumor-associated antigens released from PDT-damaged mitochondria and endoplasmic reticulum could activate the suppressive immune cells to establish an "immune hot" milieu. The collaborative immune-enhancing strategy effectively aroused systemic antitumor immunity and inhibited primary and distal tumor progression as well as lung metastasis in 4T1 xenografted mouse models. The photo-controlled drug release and specific tumor-targeting capabilities of Apt-LPR were also visualized in MDA-MB-231 xenografted zebrafish models. Therefore, this photoswitchable PDT/RNAi immune stimulator offered a powerful approach to reprogramming ITM and reinforcing cancer immunotherapy efficacy.

Multicentre, randomized, double-blind, prospective study on the effects of ImmunoAdSorptiOn on cardiac function in patients with Dilated CardioMyopathy (IASO-DCM): Rationale and design.

AIMS: Pilot studies indicate that immunoadsorption with subsequent IgG substitution (IA/IgG) induces beneficial effects in patients with dilated cardiomyopathy (DCM) and heart failure. This placebo-controlled study investigates whether IA/IgG treatment enhances left ventricular (LV) systolic function as compared to a control group receiving pseudo-treatment. METHODS: This multicentre, randomized, double-blind, parallel-group trial aims to include 200 patients with heart failure due to DCM (LV ejection fraction [LVEF] <40%) on optimized guideline-directed heart failure medication. Participants are randomly assigned in a 1:1 ratio to IA/IgG using protein-A columns, or to pseudo-immunoadsorption followed by an intravenous infusion without IgG. Follow-up visits take place by telephone after 1 and 3 months and at the study centres after 6, 12 and 24 months. The primary efficacy endpoint is the change in LVEF from baseline to 6 months determined by contrast echocardiography, analysed at a core lab. In addition, LV end-diastolic and end-systolic volumes will be analysed as secondary endpoints over the entire study period to assess whether IA/IgG affects LV remodelling. As main secondary outcome, a composite of all-cause death, cardiac resuscitation, hospitalization for heart failure, and need for cardiac surgery to improve myocardial pump function will be evaluated after 24 months. In addition, exploratory outcomes as well as safety endpoints related to the treatment will be assessed throughout the whole study period. CONCLUSION: IASO-DCM is a randomized study which will provide comprehensive insights into the effects of immunoadsorption with subsequent IgG substitution in patients with DCM.

Incidence of aortic valve reintervention in patients with aortic stenosis undergoing transcatheter aortic valve implantation versus surgical aortic valve replacement: a systematic review and updated meta-analysis of randomized studies.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) are established interventions for alleviating symptoms and enhancing survival in individuals with severe aortic stenosis (AS). However, the long-term outcomes and incidence of reintervention associated with TAVI and SAVR remain uncertain. METHODS: We conducted a systematic review and meta-analysis to compare the incidence of reintervention in TAVI versus SAVR. PubMed, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs). Risk ratios (RR) and 95% confidence intervals (CI) were pooled with a random-effects model. A p-value < 0.05 was considered statistically significant. RESULTS: Nine RCTs were included, with 5144 (50.9%) patients randomized to TAVI. Compared with SAVR, TAVI increased reinterventions (RR 1.89; 95% CI 1.29-2.76; p < 0.01) and the need for pacemakers (RR 1.91; 95% CI 1.49-2.45; p < 0.01). In addition, TAVI significantly reduced the incidence of new-onset atrial fibrillation (RR 0.43; 95% CI 0.32- 0.59; p < 0.01). There were no significant differences in all-cause mortality (RR 1.04; 95% CI 0.92-1.16; p = 0.55), cardiovascular mortality (RR 1.04; 95% CI 0.94-1.17; p = 0.44), stroke (RR 0.97; 95% CI 0.80-1.17; p = 0.76), endocarditis (RR 0.96; 95% CI 0.70-1.33; p = 0.82), and myocardial infarction (RR 1.06; 95% CI 0.79-1.41; p = 0.72) between groups. CONCLUSIONS: In patients with severe AS, TAVI significantly increased the incidence of reinterventions and the need for pacemakers as compared with SAVR.

Prospective case-control study on pain intensity after the use of promethazine in patients undergoing videothoracoscopy.

Objective: Effective and secure pain management following video-assisted thoracoscopic surgery (VATS) is crucial for rapid postoperative recovery. This study evaluated analgesic and sedative effects of sufentanil and promethazine in patient-controlled intravenous analgesia (PCIA) post-thoracic surgery, along with potential adverse reactions. Methods: In this prospective, randomized, controlled, double-blind, clinical study, 60 patients (American Society of Anesthesiologists status I-III) undergoing VATS were enrolled. The patients were randomized into experimental (Group P) or control (Group C) groups. PCIA was administered post-general anesthesia using a double-blind method. Group P received sufentanil (3 µg/kg) + promethazine (1 mg/kg) + 0.9% sodium chloride solution (100 mL total), while Group C received sufentanil (3 µg/kg) + 0.9% sodium chloride solution (100 mL total). PCIA settings included a 1-mL bolus and 15-min locking time. The primary outcomes were the visual analog scale (VAS) at rest and during coughing and sedation (Ramsay) scores at 6, 12, 24, and 48 h. The secondary outcomes were rescue drug use rate, hemodynamic parameters (mean arterial pressure and heart rate), percutaneous oxygen saturation, respiratory rate, and occurrence of adverse reactions. Results: Group P exhibited lower resting and coughing VAS scores at 6, 12, 24, and 48 h, plus decreased incidence of nausea and vomiting within 48 h post-surgery compared with Group C (p < 0.05). No significant differences were observed in pruritus, sedation (Ramsay) scores, mean arterial pressure, heart rate, oxygen saturation, or respiratory rate between the two groups (p > 0.05). Discussion: The combination of sufentanil and promethazine for postoperative intravenous analgesia could effectively reduce adverse effects such as nausea and vomiting, contributing to postoperative pain relief.

Efficacy and safety of chemoradiotherapy plus immune checkpoint inhibitors for the treatment of locally advanced cervical cancer: a systematic review and meta-analysis.

Background: Radiotherapy plus concurrent chemotherapy is a standard method for treating locally advanced cervical cancer (LACC). Immune checkpoint inhibitors (ICIs) are widely applied in the treatment of recurrent cervical cancer, metastatic cervical cancer or LACC. The efficacy and safety of radiotherapy plus immunotherapy for LACC require further investigation. The objective of this review and meta-analysis was to analyze the efficacy and safety of concurrent chemoradiotherapy (CCRT) combined with ICIs for treating LACC on the basis of the results of randomized controlled trials (RCTs). Methods: We comprehensively searched electronic databases to identify RCTs that focused on CCRT plus ICIs for LACC treatment. The outcomes included the objective response rate (ORR) and progression-free survival (PFS), overall survival (OS) and adverse events (AEs). A standard method for systematic review and meta-analysis was used. Review Manager 5.4 was used for data combination and analyses. Results: Three RCTs involving 1882 participants with LACC were identified and included in the systematic review and meta-analysis. CCRT plus ICIs improved the rates of PFS (hazard ratio [HR]: 0.76, 95% confidence interval [CI]: CI: 0.64, 0.91, P = 0.002) and OS (HR: 0.7695% CI (95% CI 0.58-0.99, P = 0.04) in patients with LACC. Compared with the control group, the CCRT plus immunotherapy group had an increased ORR (OR: 1.37, 95% CI: 1.02,1.85, P=0.04). The two methods had similar rates (HR=1.99, 95% CI: 0.99, 1.43; P=0.07) of treatment-related grade 3 or higher AEs. The CCRT plus immunotherapy group had a higher rate than did the control group (HR: 2.68, 95% CI: 1.38, 5.21; P=0.004) in terms of any grade immunotherapy-related AEs. Conclusions: CCRT plus ICIs is efficacious and safe for the management of LACC. The addition of ICIs to CCRT improved the rates of PFS and OS in patients with LACC. The adverse effects of immunotherapy-related AEs should be strictly examined and managed in a timely manner.

A randomized phase III study evaluating dexamethasone-based mouthwash to prevent chemotherapy-induced stomatitis in patients with breast cancer.

Stomatitis, which is a common side effect of chemotherapy, currently lacks a standardized approach for its prevention. Therefore, this multicenter, randomized, open-label, controlled phase III trial aims to assess the efficacy and safety of a dexamethasone-based mouthwash for preventing chemotherapy-induced stomatitis in patients with early breast cancer. We will randomly assign 230 patients with early breast cancer scheduled to receive chemotherapy in a 1:1 ratio to either the dexamethasone-based mouthwash group (10 ml, 0.1 mg/ml; swish for 2 min and spit 4 times daily for 8 weeks) or the mouthwash-with-tap-water group. The incidence of stomatitis, measured using electronic patient-reported outcomes, is the primary endpoint.

Efficacy of vitamin D supplementation in the treatment of patients with COVID-19: a systematic review and meta-analysis of randomized controlled trials.

Context: COVID-19 has substantial effects on respiratory health and overall well-being. Recent studies suggest vitamin D as a potential treatment, but the results are inconclusive. Objective: The authors conducted a systematic review of randomized controlled trials (RCTs) to examine the link between vitamin D and patients with COVID-19. Data sources: The authors searched electronic databases PubMed, Cochrane, CINAHL, EMBASE and Google Scholar from their inception till August 2023. Study selection: Inclusion criteria used in our systematic review include: (1) patients who tested positive for COVID-19, (2) intervention was vitamin D supplementation, (3) the comparator was either a placebo, standard care of treatment, or, no treatment, (4) at least one of the clinical outcomes of interest were investigated, (5) study design being RCTs. Data extraction: Two independent reviewers manually extracted information from selected articles, including study characteristics, patient characteristics, and the primary outcomes: all-cause mortality, ICU and hospital stay length and secondary outcomes: mechanical ventilation, supplemental oxygen, ICU admission, and adverse events. Risk ratios or mean differences and 95% CIs were calculated using a random-effects model. Data synthesis: The authors' analysis included 14 RCTs with 2165 patients. Vitamin D significantly reduced ICU admissions and lowered the need for mechanical ventilation compared to placebo. However, it did not significantly affect hospital stay length, ICU stay length, mechanical ventilation duration, mortality, or the need for supplemental oxygen. Conclusion: Vitamin D does not significantly improve certain clinical outcomes, such as hospital and ICU stay length, for patients with COVID-19. However, it still may be significantly beneficial in decreasing the burden on intensive care services.

Utility of Acquire 22G-fine needle biopsy (FNB) needle vs the standard 22G needle during Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA): A Randomized Controlled Trial (RCT).

BACKGROUND: Various types of needles are available to perform endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). A relatively new needle for EBUS-TBNA, the Acquire Fine Needle Biopsy (FNB) device, has recently become available. METHODS: Consecutive subjects with lymphadenopathy >1 cm undergoing EBUS-TBNA were randomized to the Acquire 22-G EBUS-FNB needle and the standard 22-G EBUS-TBNA needle groups. RESULTS: A total of 86 subjects were randomized (43 in each group). The diagnostic yield of EBUS-TBNA was similar between the two groups: (36/43) 83.7% in the 22-G EBUS-FNB group and (34/43) 79.1% in the standard 22-G EBUS group (p = 0.58). The sampling adequacy, stations sampled, number of stations sampled, number of needle passes, and mean duration of the procedure between the two groups were also similar. Visible tissue clot core was obtained in a significantly greater proportion of subjects in the 22-G EBUS-FNB group (93.0% vs 46.5%, p < 0.001). Visibly bloody samples were more frequent in the 22-G EBUS-FNB group (74.4% vs 51.2%, p = 0.03). There was no difference in the complication rates between the two groups (p = 0.15). CONCLUSION: We did not observe a difference in the diagnostic yield of the Acquire 22-G EBUS-FNB needle compared with the standard 22-G EBUS needle. CLINICAL TRIAL REGISTRATION: Clinical Trial Registry of India (CTRI) https://ctri.nic.in/ (CTRI/2021/08/035589).

Antidepressants for pain management in adults with chronic pain: a network meta-analysis.

Background: Chronic pain is common and costly. Antidepressants are prescribed to reduce pain. However, there has not been a network meta-analysis examining all antidepressants across all chronic pain conditions, so effectiveness and safety for most antidepressants for pain conditions remain unknown. Objective: To assess the efficacy and safety of antidepressants for chronic pain (except headache) in adults. Our primary outcomes were as follows: substantial pain relief (50%), pain intensity, mood and adverse events. Our secondary outcomes were as follows: moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change, serious adverse events and withdrawal. Design: This was a systematic review with a network meta-analysis. We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials of antidepressants for chronic pain conditions up until 4 January 2022. The review was registered in PROSPERO (CRD42020171855), and the protocol was published in the Cochrane Library (https://doi.org/10.1002/14651858.CD014682). Setting: We analysed trials from all settings. Participants: We included trials in which participants had chronic pain, defined as longer than 3 months, from any condition excluding headache. Interventions: We included all antidepressants. Main outcome measures: Our primary outcome was substantial pain relief, defined as a reduction ˃ 50%. We also measured pain intensity, mood and adverse events. Secondary measures included moderate pain relief (above 30% reduction), physical function, sleep, quality of life, Global Impression of Change, serious adverse events, and withdrawal from trial. Results: We identified 176 studies with a total of 28,664 participants. Most studies were placebo-controlled (n = 83) and parallel armed (n = 141). The most common pain conditions examined were fibromyalgia (59 studies), neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of randomised controlled trials was 10 weeks. Most studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. Standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that for duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Limitations: The evidence for antidepressants other than duloxetine is poor. For duloxetine, it is not clear whether the effect applies to groups with both pain and low mood, since these groups were excluded from trials. There is also insufficient evidence on long-term outcomes and on adverse effects. Conclusions: There is only reliable evidence for duloxetine in the treatment of chronic pain. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Data for all other antidepressants were of low certainty. However, the findings should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. Future work: There is a need for large, methodologically sound trials testing the effectiveness of antidepressants for chronic pain. These trials should examine long-term outcomes (> 6 months) and include people with low mood. There should also be better reporting of adverse events, tolerance of drugs, and long-term compliance. Study registration: This study is registered as PROSPERO CRD42020171855. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128782) and is published in full in Health Technology Assessment; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information.

Chronic pain is pain that lasts for more than 3 months. Over one-third of people across the world experience chronic pain. This often has a detrimental impact on people's mood, disability and well-being. Antidepressants are often prescribed to reduce pain, but we are not sure which antidepressants work best for different types of pain, or whether they are safe. We wanted to find out whether antidepressants were effective and safe for management of chronic pain. We searched for studies that had compared any antidepressant with any other treatment for any type of chronic pain (except headache). We compared all the treatments against each other using a statistical method called network meta-analysis. This method allows us to rank the treatments in order of best to worst for each outcome. We found 176 studies that included a total of 28,664 people with chronic pain. Most of the studies (83/176) compared an antidepressant with a placebo (which looks like the real medicine but does not have any medicine in it). The evidence from our analysis suggests that: Duloxetine is the antidepressant that we have the most confidence in. It was the best antidepressant for reducing pain and improving physical function. A standard dose of duloxetine was equally as effective for reducing pain as a high dose of duloxetine. Milnacipran was also effective at reducing pain, but we are not as confident in this result as in the one for duloxetine because there were fewer studies with fewer people involved. Aside from duloxetine and milnacipran, we do not have confidence in the results from any other antidepressant included in this review, and even for duloxetine and milnacipran, we do not know the long-term effects. It is important to recognise that the lack of evidence for the majority of antidepressants in this review does not necessarily equal a lack of benefit. Rather, this means that the large, high-quality trials required for us to be certain of an antidepressant's effectiveness have not been undertaken. Altogether, although duloxetine and milnacipran are effective, the results of this review should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety. These conclusions were informed by our patient and public involvement group.

Reporting of patient-reported outcomes amongst randomized clinical trials in plastic surgery: a systematic review using CONSORT-PRO.

BACKGROUND: Patient-reported outcomes (PROs) are key to investigating patient perspectives in randomized controlled trials (RCTs). Standardization of PRO reporting is critical for trial generalizability and the application of findings to clinical practice. This systematic review aimed to evaluate the reporting quality of RCTs published in the top plastic surgery journals according to the consolidated standards of reporting trials (CONSORT)-PRO extension. METHODS: We completed a comprehensive search of MEDLINE, Embase, and Cochrane Central Register of Controlled Trials. All RCTs with a validated PRO endpoint published in the top 10 plastic surgery journals (based on the 2021 Web of Science Impact Factor) from 2014 to 2023 were included. Two reviewers independently extracted data and scored the included studies using the CONSORT-PRO checklist. Univariate regression was applied to assess factors associated with reporting adherence. Studies were assessed for their risk of bias using the Cochrane Risk of Bias 2.0 tool. RESULTS: A total of 88 RCTs were included. PROs were the primary endpoint in 50 (57%) and the secondary endpoint of 38 (43%) studies. Mean overall reporting adherence was poor (39% (±12) and 36% (±13) in studies with PRO as primary and secondary endpoints, respectively). The presence of industry support was significantly associated with greater adherence. CONCLUSIONS: There is low adherence to the CONSORT-PRO extension among plastic surgery RCTs published in the top 10 plastic surgery journals. We encourage journals and authors to endorse and apply the CONSORT-PRO extension. This may optimize the dissemination of clinical findings from RCTs and assist patient-centered care.

A randomized trial of pharmacological ascorbate, gemcitabine, and nab-paclitaxel for metastatic pancreatic cancer.

BACKGROUND: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have poor 5-year survival. Pharmacological ascorbate (P-AscH-, high dose, intravenous, vitamin C) has shown promise as an adjunct to chemotherapy. We hypothesized adding P-AscH- to gemcitabine and nab-paclitaxel would increase survival in patients with metastatic PDAC. METHODS: Patients diagnosed with stage IV pancreatic cancer randomized 1:1 to gemcitabine and nab-paclitaxel only (SOC, control) or to SOC with concomitant P-AscH-, 75 g three times weekly (ASC, investigational). The primary outcome was overall survival with secondary objectives of determining progression-free survival and adverse event incidence. Quality of life and patient reported outcomes for common oncologic symptoms were captured as an exploratory objective. Thirty-six participants were randomized; of this 34 received their assigned study treatment. All analyses were based on data frozen on December 11, 2023. RESULTS: Intravenous P-AscH- increased serum ascorbate levels from micromolar to millimolar levels. P-AscH- added to the gemcitabine + nab-paclitaxel (ASC) increased overall survival to 16 months compared to 8.3 months with gemcitabine + nab-paclitaxel (SOC) (HR = 0.46; 90 % CI 0.23, 0.92; p = 0.030). Median progression free survival was 6.2 (ASC) vs. 3.9 months (SOC) (HR = 0.43; 90 % CI 0.20, 0.92; p = 0.029). Adding P-AscH- did not negatively impact quality of life or increase the frequency or severity of adverse events. CONCLUSIONS: P-AscH- infusions of 75 g three times weekly in patients with metastatic pancreatic cancer prolongs overall and progression free survival without detriment to quality of life or added toxicity (ClinicalTrials.gov number NCT02905578).

Do prospective randomized controlled trials comply with filed protocols? Spin study of 206 trials from 2010 to 2023.

INTRODUCTION: Prospective randomized controlled trials (RCT) have a robust methodology, but some distortions may occur during the course of study. Some protocols may not be available at the time an article is reading. Some authors may change the methodology between the time the protocol was submitted and when the trial results are actually published. Others may distort results to favor more attractive findings and draw conclusions that support prior hypotheses. This has rarely been investigated and none explored the RCTs published in the Journal of Bone and Joint Surgery (JBJS). Therefore, we did a retrospective investigation aiming to determine: (1) the proportion of trials with a protocol deposited and accessible to the reader, (2) whether the trials scrupulously followed the filed protocols. HYPOTHESIS: Protocols were available in over 80% of cases, and these protocols were followed in over 80% of trials for the primary endpoint. PATIENTS AND METHODS: This was a retrospective study of articles published in the JBJS between January 2010 and November 2023. Differences in primary and secondary endpoints between protocols and articles were sought. RESULTS: Of the 206 RCT articles studied, 113 (54.9%) described clear and identifiable endpoints, and 93 (45.1%) were not identifiable and were inferred in the results; 184 (89.3%) articles identified a trial protocol. For the 184 articles (89.3%) declaring a trial protocol in the text, 23 (11.1%) protocols were not accessible. In all, 45 articles (21.8%) thus had no protocol available on the Internet (i.e., not available to the reader either because it was not cited in the text or because it was not accessible) so we analyzed 161 articles. The primary endpoint remained unchanged in 97 articles (60.2%) out of the 161 studied, was changed in 64 articles (39.8%), and was lacking (protocol not accessible) in 45 articles (21.8% of all articles). The secondary endpoints of the articles were unchanged in 61 articles (37.9%) out of the 161 studied. DISCUSSION: Like other leading journals, JBJS publishes RCT articles containing a significant proportion of inconsistencies between preoperative trial protocols and the methods actually used in the research. LEVEL OF EVIDENCE: III; retrospective comparative study non randomized.

Hydrogel Applications in the Diagnosis and Treatment of Glioblastoma.

Glioblastoma multiforme (GBM), a common malignant neurological tumor, has boundaries indistinguishable from those of normal tissue, making complete surgical removal ineffective. The blood-brain barrier (BBB) further impedes the efficacy of radiotherapy and chemotherapy, leading to suboptimal treatment outcomes and a heightened probability of recurrence. Hydrogels offer multiple advantages for GBM diagnosis and treatment, including overcoming the BBB for improved drug delivery, controlled drug release for long-term efficacy, and enhanced relaxation properties of magnetic resonance imaging (MRI) contrast agents. Hydrogels, with their excellent biocompatibility and customizability, can mimic the in vivo microenvironment, support tumor cell culture, enable drug screening, and facilitate the study of tumor invasion and metastasis. This paper reviews the classification of hydrogels and recent research for the diagnosis and treatment of GBM, including their applications as cell culture platforms and drugs including imaging contrast agents carriers. The mechanisms of drug release from hydrogels and methods to monitor the activity of hydrogel-loaded drugs are also discussed. This review is intended to facilitate a more comprehensive understanding of the current state of GBM research. It offers insights into the design of integrated hydrogel-based GBM diagnosis and treatment with the objective of achieving the desired therapeutic effect and improving the prognosis of GBM.

Understanding Iron-Doping Modulating Domain Orientation and Improving the Device Performance of Monolayer Molybdenum Disulfide.

Domain orientation modulation and controlled doping of two-dimensional (2D) transition-metal dichalcogenides (TMDCs) are two pivotal tasks for synthesizing wafer-scale single crystals and boosting device performances. However, realizing two such targets and uncovering internal physical mechanisms remain daunting challenges. We develop an accurate Fe doping strategy, which enables domain orientation control and electron mobility improvement of monolayer MoS2. By tuning of the Fe dopant dosages, parallel steps with different heights are formed, which induce edge-nucleation of unidirectionally aligned monolayer MoS2. In parallel, Fe doping induces the down shift of the conduction band minimum of monolayer MoS2 and matches well with the work function of an electrode, which reduces Schottky barrier height and delivers ultralow contact resistance (561 Ω µm) and excellent electron mobility (37.5 cm2 V-1 s-1). The modulation mechanism is clarified by combining theory calculations and electronic structure characterizations. This work hereby provides a new paradigm for synthesizing wafer-scale 2D TMDC single crystals and constructing high-performance devices.

Comparable bleeding and inflammation outcomes between heparin-coated and uncoated minimal invasive extracorporeal circuits in isolated coronary artery bypass surgery - A double-blinded randomized control trial.

OBJECTIVE: Minimally invasive extracorporeal circulation has been shown to be non-inferior or even superior to conventional cardiopulmonary bypass circuits in isolated coronary artery bypass grafting, but there is little evidence whether the addition of a heparin-coated circuit can further reduce the inflammatory response and amount of bleeding in these patients. METHODS: A single-center randomized control trial enrolled 49 adult patients scheduled to undergo isolated coronary artery bypass grafting with minimally invasive extracorporeal circulation (MiECC) between January 2015 and December 2018. Patients were randomized 1:1 to either the heparin-coated circuit group, or the uncoated (control) circuit group. The primary outcome was chest tube output 18 h after weaning from MiECC, and secondary outcomes included inflammatory (TNF-α, IL-6, IL-8, IL-10) and complement (C3a, C4d, C5a, sC5b-9) biomarkers, platelet count and function (D2D, TAT, SDC1, PF4), number of transfused blood products, and 30-day survival. RESULTS: Patients were randomized to undergo myocardial revascularization using heparin-coated circuits (n = 25), and to the uncoated MiECC circuit (n = 24), with comparable baseline demographics. No significant difference was observed in chest tube output and for all secondary outcomes. IL-6 and IL-8 were increased from baseline at 18 h after weaning (effect size 0.29 and 0.05, respectively) and sC5b-9 was lower (effect size 0.11) in the heparin-coated than in the uncoated MiECC, although not significantly different. CONCLUSIONS: Compared with an uncoated MiECC circuit, heparin-coated MiECC circuit was not associated with a reduction in postoperative bleeding, transfusion, inflammation, complement activation, and platelet biomarkers, following isolated coronary artery bypass grafting.

Different peripheral nerve blocks for patients undergoing total knee arthroplasty: a network meta-analysis of randomized controlled trials.

INTRODUCTION: To comprehensively compare the effect of different peripheral nerve blocks for patients undergoing total knee arthroplasty (TKA). MATERIALS AND METHODS: PubMed, Embase, Cochrane Library, and Web of Science were comprehensively searched. The outcomes included postoperative pain, postoperative function, adverse events, oral morphine equivalent (OME), and perioperative indicators. Network plots, forest plots, league tables and rank probabilities were drawn for all outcomes. RESULTS: Totally 30 studies were included. For postoperative pain, continuous adductor canal block (cACB) + genicular nerve block (GNB) was most likely to be the most effective block regarding rest pain score at 24 h; cACB + GNB was most likely to result in the lowest rest pain score at 48 h; patients undergoing cACB + infiltration between the popliteal artery and the capsule of the knee (IPACK) + GNB was most likely to have the lowest motion pain score at 24 h; patients undergoing cACB + GNB was most likely to have the lowest motion pain score at 48 h. For postoperative function, patients undergoing cACB + IPACK + GNB had the highest likelihood to exhibit the shortest time in Timed Up and Go test (TUG); cACB + tibial nerve block (TNB) was most likely to be the most effective block in terms of range of motion (ROM); cACB + IPACK was most likely to be the optimal block concerning the ambulation distance. CONCLUSION: cACB combined with IPACK/GNB may be the most favorable block after TKA, continuous blocks may be better than single-shot blocks, and combined blocks may be better than separate blocks.

Dose-escalated Adaptive Radiotherapy for Bladder Cancer: Results of the Phase 2 RAIDER Randomised Controlled Trial.

BACKGROUND AND OBJECTIVE: Delivering radiotherapy to the bladder is challenging as it is a mobile, deformable structure. Dose-escalated adaptive image-guided radiotherapy could improve outcomes. RAIDER aimed to demonstrate the safety of such a schedule. METHODS: RAIDER is an international phase 2 noncomparative randomised controlled trial (ISRCTN26779187). Patients with unifocal T2-T4a urothelial bladder cancer were randomised (1:1:2) to standard whole bladder radiotherapy (WBRT), standard-dose adaptive radiotherapy (SART), or dose-escalated adaptive radiotherapy (DART). Two fractionation (f) schedules recruited independently. WBRT and SART dose was 55 Gy/20f or 64 Gy/32f, and DART dose was 60 Gy/20f or 70 Gy/32f. For SART and DART, a radiotherapy plan (small, medium, or large) was chosen daily. The primary endpoint was the proportion of patients with radiotherapy-related late Common Terminology Criteria for Adverse Events grade ≥3 toxicity; the trial was designed to rule out >20% toxicity with DART. KEY FINDINGS AND LIMITATIONS: A total of 345 patients were randomised between October 2015 and April 2020: 41/46 WBRT, 41/46 SART, and 81/90 DART patients in the 20f/32f cohorts, respectively. The median age was 72/73 yr; 78%/85% had T2 tumours, 46%/52% had neoadjuvant chemotherapy, and 70%/71% had radiosensitising therapy. The median follow-up was 42.1/38.2 mo. Sixty-six of 77 (86%) 20f and 74 of 82 (90%) 32f participants planned for DART met the mandatory medium plan dose constraints. Radiotherapy-related grade ≥3 toxicity was reported in one of 58 patients (90% confidence interval [CI] 0.1, 7.9) with 20f DART and zero of 56 patients with 32f DART. Two-year overall survival was 77% (95% CI 69, 82) for WBRT + SART and 80% (95% CI 73, 85) for DART (hazard ratio = 0.84, 95% CI 0.59, 1.21, p = 0.4). Thirteen of 345 (3.8%) participants had salvage cystectomy. CONCLUSIONS AND CLINICAL IMPLICATIONS: Grade ≥3 late toxicity was low. DART was safe and feasible to deliver, meeting preset toxicity thresholds. Disease-related outcomes are promising for dose-escalated treatments, with a low salvage cystectomy rate and overall survival similar to that seen in cystectomy cohorts.

Low-intensity extracorporeal shock wave therapy for Peyroniès disease: a systematic review and meta-analysis.

BACKGROUND: A systematic review of the evidence was conducted to assess the efficacy of low-intensity extracorporeal shock wave therapy (LI-ESWT) for patients with Peyronie`s Disease (PD). METHODS: A comprehensive search of the Cochrane Registry, PubMed and Embase databases was conducted to identify all controlled trials, including randomised controlled trials (RCTs), cohort studies and case-control studies, focusing on the efficacy of LI-ESWT in treating PD, and published before February 2023. The size of plaques, curvature deviation, visual analog scale [VAS] and International Index of Erectile Function (IIEF) were the most commonly used tool to evaluate the treatment effectiveness of LI-ESWT. RESULTS: There were 7 studies including  475 patients from 1999 to 2023. The meta-analysis of the data revealed that LI-ESWT could considerably enhance the proportion of men experiencing a reduction in penile plaques (RD 0.27, 95% CI: 0.04-0.50, P = 0.02), improvement in penile curvature (RD: 0.13; 95% CI, 0-0.26; p = 0.05), alleviation of pain (RD 0.22, 95% CI: 0.01-0.42, P = 0.04), and complete remission (RD 0.38, 95% CI 0.23-0.52, P < 0.00001). However, there were no significant differences in improvement of sexual function (MD: 1.44; 95% CI, -3.10-5.97; p = 0.53) between LI-ESWT and the placebo group. CONCLUSIONS: According to these studies, LI-ESWT has the potential to decrease plaque size and improve penile curvature or pain in men with PD. The publication of robust evidence from additional well-designed long-term multicenter randomized controlled trials would provide more confidence regarding use of these devices in patients with PD.

Sexual Function and Discomfort in Women After Midurethral Sling Surgery.

INTRODUCTION AND HYPOTHESIS: The purpose of this study was to evaluate medium-term sexual function following midurethral sling (MUS) surgery. METHODS: This was an ambidirectional observational study with a nested matched case-control study performed in a tertiary urogynecology referral center. We assessed sexual discomfort and function using the Pelvi-Perineal Surgery Sexuality Questionnaire (PPSSQ), pre- and postoperatively, in a patient cohort that comprised patients who underwent an MUS procedure between January 2014 and December 2019. We recruited a group of volunteers without a previous history of MUS surgery. The nested case-control study comprised a subgroup of cases from the patients' cohort matched to controls from the volunteer's cohort. Cases and controls were matched for age and menopausal status at a 1:1 ratio. RESULTS: A total of 118 patients and 128 volunteers were recruited. Of these, 105 cases and 105 controls comprised the nested case-control study. There was no statistically significant difference in the mean discomfort and pain scores between cases and controls (19.8 ± 21.2 vs 15.4 ± 15.7 respectively; p = 0.19 primary outcome). Similarly, there was no difference in mean sexual health scores. However, the rate of reported sensation of an obstruction in the vagina was significantly more in cases (16%) than in controls (2.6%; p = 0.001). There were no significant differences between patient-reported sexual function at follow-up compared with their recollection before surgery. CONCLUSION: Midurethral sling surgery does not seem to impair the quality of sexual life in the medium term.

The Impact of the American Association of Thoracic Surgery on Clinical Trial Development by Cardiothoracic Surgeons.

OBJECTIVE: Clinical trials play a critical role in the rapidly evolving field of cardiothoracic surgery and the American Association of Thoracic Surgery (AATS) Clinical Trials Methods Course has provided a biannual symposium led by preeminent surgeons with vast experience in planning, conducting and analyzing surgical clinical trials. This study hypothesizes that participation in the course is associated with future success in clinical trial leadership. METHODS: A list of course attendees (2014-2022) was queried in "ClinicalTrials.gov", a database of clinical trials funded by the United States Health and Human Services and the National Institutes of Health. The type of clinical trial and publications from the trial were collected. Demographic information about the participants were collected from faculty pages. RESULTS: A total of 107 participants from various professional backgrounds attended the AATS Clinical Trials course and led 91 clinical trials. The average time to starting a clinical trial after attending the workshop was 3.04 years for participants who had not already been involved with a trial. Of the 107 participants, 36 (36/107; 33.6%) were either the principal investigator or a sub-investigator for 91 clinical trials. CONCLUSIONS: The AATS Clinical Trials course provides participants the tools for successfully leading surgical clinical trials. Although participation has been limited, those who attend the course and lead a clinical trial do so within approximately 3 years. The Clinical Trials course provides an excellent return on investment and the AATS should continue sponsorship of this program as it supports the develop of future leaders in cardiothoracic surgery.