Effects of high intensity interval training versus moderate intensity continuous training on exercise capacity and quality of life in patients with heart failure: A systematic review and meta-analysis.

INTRODUCTION AND AIMS: High intensity interval training (HIIT) is considered as an alternative exercise modality to moderate intensity continuous training (MICT) for heart failure (HF) patients. Yet a growing number of trials demonstrated inconsistent findings about the effectiveness of HIIT versus MICT until SMARTEX study and OptimEx-Clin study have made a consistent negative conclusion that HIIT was not superior to MICT. The aim of this study was to conduct a meta-analysis involving a subgroup analysis of total exercise time (TET) and disease categories of HF to investigate if TET could affect the superiority of HIIT when compared with MICT. METHODS AND RESULTS: An electronic literature search of Pubmed, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov was performed for this review. 16 studies of 661 patients were finally pooled into quantitative synthesis. The weighted mean difference (WMD) and standard mean difference (SMD) with 95% confidence interval (CI) were calculated for quantitative synthesis of outcomes. HIIT was superior to MICT in improving peak oxygen consumption (Peak VO2) (WMD: 1.68 ml · kg-1 · min-1 95% CI: 0.81 to 2.55 n = 661). The subgroup analysis of TET showed that HIIT was superior to MICT in improving Peak VO2 in "short time" subgroup (WMD: 1.61 ml · kg-1 · min-1 95% CI: 0.45 to 2.77 n = 166) and in "medium time" subgroup (WMD: 1.74 ml · kg-1 · min-1 95% CI: 0.53 to 2.95 n = 420), and that there was no significant difference between HIIT and MICT in improving Peak VO2 in "long time" subgroup (WMD: 0.62 ml · kg-1 · min-1 95% CI: -1.34 to 2.58 n = 75). CONCLUSIONS: The superiority of HIIT to MICT in improving Peak VO2 arose in a short to medium length of TET whereas it was effaced by an increment of TET. This "paradox" of TET on HIIT versus MICT might be due to the increasing poor adherence to target exercise intensity over time. TRIAL REGISTRATION: PROSPERO registration number: CRD42022375076.

Focused acoustic vortex-mediated sonochemotherapy for the amplification of immunogenic cell death combined with checkpoint blockade to potentiate cancer immunotherapy.

Sonodynamic therapy (SDT) as an auxiliary modality of cancer immunotherapy enhances systemic anti-tumor immunity. However, the efficiency of SDT-mediated immunotherapy based on conventional focused ultrasound (FUS) is restricted by the tiny focal region of FUS. Focused acoustic vortex (FAV) possessing a larger focal region, can induce stronger cavitation and thermal effects than FUS with the same parameters, having the potential to overcome this issue. This research investigated the feasibility of FAV-mediated sonochemotherapy combined with the immune checkpoint blockade (ICB) to reshape immunosuppressive tumor microenvironment (TME), inhibit tumor growth and lung metastasis. Sonosensitizer chlorin e6 (Ce6) and chemotherapeutic agent doxorubicin (Dox) were co-loaded into microbubble-liposome complex to compose Ce6/Dox@Lip@MBs (CDLM) for "all-in-one" synergistic sonochemotherapy, whose main components were clinical approved. FAV-activated CDLM significantly enriched immunogenic cell death (ICD) inducers in tumors and amplified ICD of cancer cells compared with FUS-activated CDLM. Furthermore, the amplified-ICD combined with ICB increased the infiltration of cytotoxic T lymphocytes and natural killer cells, polarized M2 macrophages to M1 macrophages, and decreased regulatory T cells. This study provides a multifunctional strategy for enriching ICD inducers in tumors and amplifying ICD to ameliorate immunosuppressive TME and potentiate systemic anti-tumor immunity.

Passive acoustic mapping with absolute time-of-flight information and delay-multiply-sum beamforming.

BACKGROUND: Passive acoustic mapping (PAM) is showing increasing application potential in monitoring ultrasound therapy by spatially resolving cavitation activity. PAM with the relative time-of-flight information leads to poor axial resolution when implemented with ultrasound diagnostic transducers. Through utilizing the absolute time-of-flight information preserved by the transmit-receive synchronization and applying the common delay-sum (DS) beamforming algorithm, PAM axial resolution can be greatly improved in the short-pulse excitation scenario, as with active ultrasound imaging. However, PAM with the absolute time-of-flight information (referred as AtPAM) suffers from low imaging resolution and weak interference suppression when the DS algorithm is applied. PURPOSE: This study aims to propose an enhanced AtPAM algorithm based on delay-multiply-sum (DMS) beamforming, to address the shortcomings of the DS-based AtPAM algorithm. METHODS: In DMS beamforming, the element signals delayed by the absolute time delays are first processed with a signed square-root operation and then multiplied in pairs and finally summed, the resulting beamformed output is further band-pass filtered. The performances of DS- and DMS-based AtPAMs are compared by experiments, in which an ultrasound diagnostic transducer (a linear array) is employed to passively sense the wire signals generated by an unfocused ultrasound transducer and the cavitation signals generated by a focused therapeutic ultrasound transducer in a flow phantom. The AtPAM image quality is assessed by main-lobe width (MLW), intensity valley value (IVV), area of pixels (AOP), signal-to-interference ratio (SIR), and signal-to-noise ratio (SNR). RESULTS: The single-wire experimental results show that compared to the DS algorithm, the DMS algorithm leads to an enhanced AtPAM image with a decreased transverse MLW of 0.15 mm and an improved SIR and SNR of 31.50 and 18.77 dB. For the four-wire images, the transverse (axial) IVV is decreased by 18.37 dB (13.11 dB) and the SIR (the SNR) is increased by 26.13 dB (18.47 dB) when using the DMS algorithm. The cavitation activity is better highlighted by DMS-based AtPAM, which decreases the AOP by 0.81 mm2 (-10-dB level) and 4.43 mm2 (-20-dB level) and increases the SIR and SNR by 20.14 and 10.48 dB respectively. The pixel distributions of AtPAM images of both wires and cavitation activity also indicate a better suppression of the DMS algorithm in sidelobe and noise. CONCLUSIONS: The experimental results illustrate that the DMS algorithm can improve the image quality of AtPAM compared to the DS algorithm. DMS-based AtPAM is beneficial for detecting cavitation activity during short-pulse ultrasound exposure with high resolution, and further for monitoring short-pulse ultrasound therapy.

Retraction: Enhanced anti-tumor efficacy of hyaluronic acid modified nanocomposites combined with sonochemotherapy against subcutaneous and metastatic breast tumors.

Retraction of 'Enhanced anti-tumor efficacy of hyaluronic acid modified nanocomposites combined with sonochemotherapy against subcutaneous and metastatic breast tumors' by Pengying Wu et al., Nanoscale, 2019, 11, 11470-11483, https://doi.org/10.1039/C9NR01691K.

Focused Acoustic Vortex-Regulated Composite Nanodroplets Combined with Checkpoint Blockade for High-Performance Tumor Synergistic Therapy.

The combination of checkpoint blockade with focused ultrasound (FUS) physical therapy can enhance antitumor immune response by improving the precision and efficiency of immunotherapy. However, one of the major disadvantages of conventional FUS treatment is the small lesion size, which prolongs treatment duration. We constructed a focused acoustic vortex (FAV) system with a hollow cylindrical focal region, which exhibited a larger focal region compared to conventional FUS of the same frequency. We developed an all-in-one synergistic therapy against metastatic breast cancer based on integrated FAV double combination sequence-regulated phase-transformation nanodroplets (CPDA@PFH) with checkpoint blockade immunotherapy. A single treatment with FAV + CPDA@PFH resulted in 2.25-fold higher inhibition of tumor growth compared to that with FUS + CPDA@PFH. In addition, FAV-regulated CPDA@PFH combined with ICB induced a systemic immune response that not only inhibited the growth of primary (98.41% inhibition rate) and distal (80.71%) 4T1 tumors but also reduced the progression of lung metastasis. In addition, the synergistic therapy achieved long-term immune memory that effectively prevented tumor growth and improved the survival time of mice. The long-term survival rate of 4T1 tumor-bearing mice treated with FAV + CPDA@PFH + Anti-PD-L1 was 57.14% on day 60 after treatment. Our study is a proof-of-concept of cascade-amplified synergistic tumor therapeutics based on ultrasonic-hyperthermia, cavitation, sonodynamic therapy (SDT), and checkpoint blockade immunotherapy through FAV-regulated CPDA@PFH phase-transformation nanodroplets.

Enhanced Sonothrombolysis Induced by High-Intensity Focused Acoustic Vortex.

High-intensity focused ultrasound (HIFU) thrombolysis provides a targeted and non-invasive therapy for thrombosis-related diseases. Rapid thrombolysis and restoration of blood flow are vital to reduce the disability and death rate. The objective of this study was to explore the feasibility of using a high-intensity focused acoustic vortex (HIFAV) to enhance sonothrombolysis. The in vitro clots were treated with HIFU with a peak negative pressure (PNP) of 2.86 MPa (HIFU A) or 3.27 MPa (HIFU B) or HIFAV with a PNP of 2.14 MPa. The results revealed that HIFAV thrombolysis could achieve a significantly higher efficiency than HIFU (HIFAV: 65.4%, HIFU A: 24.1%, HIFU B: 31.6%, p < 0.01), even at a lower intensity. The average size of the debris particles generated in HIFAV thrombolysis was similar to that in HIFU. Additionally, the cavitation activities were found to be more intense in HIFAV thrombolysis. Although the efficiency of HIFAV thrombolysis was higher when the pulse repetition frequency increased from 100 to 500 Hz (41.4% vs. 65.4%, p < 0.05), it decreased when the PRF reached 1000 Hz (29.9%). Lastly, it was found that increasing the duty cycle from 5% to 15% led to a higher efficiency in HIFAV thrombolysis (40.3% vs. 75.2%, p < 0.001). This study illustrated that HIFAV provided enhanced thrombolysis and that its efficiency could be further increased by optimizing the ultrasound parameters.

Computer-assisted cannulated screw internal fixation versus conventional cannulated screw internal fixation for femoral neck fractures: a systematic review and meta-analysis.

OBJECTIVE: To compare the effects between computer-assisted and traditional cannulated screw internal fixation on treating femoral neck fracture. METHODS: The search was conducted in Embase, Pubmed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang Database from the beginning to August 2020. RevMan5.4 software, which was provided by the International Cochrane Group, was used for the meta-analysis comparing the differences in operation time, intraoperative bleeding volume, fluoroscopy frequency, fracture healing time, total drilling times, Harris score, fracture healing rate, and femoral head necrosis rate between computer-assisted and traditional methods groups. RESULTS: A total of 1028 patients were included in 16 studies. Primary outcome indicators: Compared with the traditional method group, the computer-assisted group had less operative time (2RCTs, P < 0.00001; 8 non-RCTs, P = 0.009; Overall, P < 0.00001), intraoperative bleeding (1 RCTs, P < 0.00001; 9non-RCTs, P < 0.00001; Overall, P < 0.00001), femoral head necrosis rate (1 RCT, P = 0.11;7 non-RCTs, P = 0.09; Overall, P = 0.02) and higher Harris scores (1 RCT, P < 0.0001; 9 non-RCTs, P = 0.0002; Overall, P < 0.0001), and there were no significant differences in fracture healing rate between the two groups (5 non-RCTs, P = 0.17). Secondary outcomes indicators: The computer-assisted group had a lower frequency of intraoperative fluoroscopy and total number of drills compared with the traditional method group, while there was no significant difference in fracture healing time. CONCLUSION: Compared with the traditional hollow screw internal fixation on the treatment of femoral neck fracture, computer-assisted percutaneous cannulated screw fixation can shorten the operation time and improve the operation efficiency and reduce the X-ray injury of medical staff and help patients obtain a better prognosis. Therefore, computer-assisted percutaneous cannulated screw fixation is a better choice for the treatment of femoral neck fracture. Study registration PROSPERO registration number CRD42020214493.

PCAT6 may be a new prognostic biomarker in various cancers: a meta-analysis and bioinformatics analysis.

BACKGROUND: LncRNA prostate cancer-associated transcript 6 (PCAT6) has been reported to be dysregulated in several cancers and is associated with tumor progression. Here, we have performed a meta-analysis to assess the general prognostic role of PCAT6 in malignancies. METHODS: Four public databases (Embase, Pubmed, Web of Science, Cochrane Library) were used to identify eligible studies, then data was extracted and associations between prognostic indicators and clinical characteristics were combined to estimate hazard ratio (HR) or odds ratio (OR) with a 95% confidence interval (CI). Publication bias was measured using the Begg's test, and the stability of the combined results was measured using sensitivity analysis. Subsequently, results were validated using Gene Expression Profiling Interactive Analysis (GEPIA) and the National Genomics Data Center (NGDC). RESULTS: Ten studies were considered eligible for inclusion. In total, 937 patients and eight types of cancer were included. Our results revealed that overexpression of PCAT6 was significantly associated with a shorter OS (HR = 1.82; 95% CI, [1.40, 2.38]; P < 0.0001) and progression-free survival (PFS) (HR = 1.66; 95% CI, [1.22, 2.25]; P < 0.0001) in cancer patients, and that PCAT6 overexpression was significantly associated with individual tumor clinicopathological parameters, including TNM stage (OR = 0.29; 95% CI, [0.09, 0.94]; P = 0.04), gender (OR = 1.84; 95% CI, [1.31, 2.59]; P = 0.0005), and whether the tumor was metastatic (OR = 5.02; 95% CI, [1.36, 18.57]; P = 0.02). However, PCAT6 overexpression was not correlated with patient age and tumor differentiation. PCAT6 expression was significantly up-regulated in four types of cancer, which was validated using the GEPIA cohort. Combining OS and disease-free survival (DFS) of these four types of cancer revealed a shorter OS and DFS in patients with PCAT6 overexpression. PCAT6 expression in various types of cancer was also validated in NGDC. A total of eight cancers were analyzed and PCAT6 was highly expressed in all eight cancers. Further functional predictions suggest that PCAT6 is correlated with tumor prognosis, and that PCAT6 may be useful as a new tumor-specific marker. CONCLUSIONS: LncRNA PCAT6 is highly expressed in multiple cancer types and its upregulation was significantly associated with patient prognosis and poorer clinical features, thereby suggesting that PCAT6 may be a novel prognostic factor in multiple cancer types.

Role of microRNAs in intervertebral disc degeneration (Review).

The incidence of lower back pain caused by intervertebral disc degeneration (IDD) is gradually increasing. IDD not only affects the quality of life of the patients, but also poses a major socioeconomic burden. There is currently no optimal method for delaying or reversing IDD, mainly due to its unknown pathogenesis. MicroRNAs (miRNAs/miRs) participate in the development of a number of diseases, including IDD. Abnormal expression of miRNAs in the intervertebral disc is implicated in various pathological processes underlying the development of IDD, including nucleus pulposus (NP) cell (NPC) proliferation, NPC apoptosis, extracellular matrix remodeling, inflammation and cartilaginous endplate changes, among others. The focus of the present review was the advances in research on the involvement of miRNAs in the mechanism underlying IDD. Further research is expected to identify markers for early diagnosis of IDD and new targets for delaying or reversing IDD.

Plasmid-loadable magnetic/ultrasound-responsive nanodroplets with a SPIO-NP dispersed perfluoropentane core and lipid shell for tumor-targeted intracellular plasmid delivery.

Using ultrasound activating contrast agents to induce sonoporation is a potential strategy for effective lesion-targeted gene delivery. Previous reports have proven that submicron nanodroplets have a better advantage than microbubbles in that they can pass through tumor vasculature endothelial gaps by passive targeting; however, they cannot achieve an adequate dose in tumors to facilitate ultrasound-enhanced gene delivery. Additionally, a few studies focused on delivering macromolecular genetic materials (i.e. overexpression plasmid and CRISPR plasmid) have presented more unique advantages than small-molecular genetic materials (i.e. miRNA mimics, siRNA and shRNA etc.), such as enhancing the expression of target genes with long-term effectiveness. Thereby, we constructed novel plasmid-loadable magnetic/ultrasound-responsive nanodroplets, where superparamagnetic iron oxide nanoparticle dispersed perfluoropentane was encapsulated with lipids to which plasmids could be adhered, and branched polyethylenimine was used to protect the plasmids from enzymolysis. Furthermore, in vitro and in vivo studies were performed to verify the magnetic tumor-targeting ability of the plasmid-loadable magnetic/ultrasound-responsive nanodroplets and focused ultrasound enhanced intracellular plasmid delivery. The plasmid-loadable magnetic/ultrasound-responsive nanodroplets, carrying 16-19 plasmids per droplet, had desirable diameters less than 300 nm, and integrated the merits of excellent magnetic targeting capabilities and phase transition sensitivity to focused ultrasound. Under programmable focused ultrasound exposure, the plasmid-loadable magnetic/ultrasound-responsive nanodroplets underwent a phase-transition into echogenic microbubbles and the subsequent inertial cavitation of the microbubbles achieved an ∼40% in vitro plasmid delivery efficiency. Following intravenous administration, T2-weighted magnet resonance imaging, scanning electron microscopy and inductively coupled plasma optical emission spectrometry of the tumors showed significantly enhanced intratumoral accumulation of the plasmid-loadable magnetic/ultrasound-responsive nanodroplets under an external magnetic field. And a GFP ELISA assay and immunofluorescence staining indicated that focused ultrasound-induced inertial cavitation of the plasmid-loadable magnetic/ultrasound-responsive nanodroplets significantly enhanced the intracellular delivery of plasmids within the tumor after magnet-assisted accumulation, while only lower GFP levels were observed in the tumors on applying focused ultrasound or an external magnet alone. Taken together, utilizing the excellent plasmid-loadable magnetic/ultrasound-responsive nanodroplets combined with magnetism and ultrasound could efficiently deliver plasmids to cancer cells, which could be a potential strategy for macromolecular genetic material delivery in the clinic to treat cancer.

Multipotent miRNA Sponge-Loaded Magnetic Nanodroplets with Ultrasound/Magnet-Assisted Delivery for Hepatocellular Carcinoma Therapy.

Gene therapy is likely to be the most promising way to tackle cancer, while defects in molecular strategies and delivery systems have led to an impasse in clinical application. Here, it is found that onco-miRNAs of the miR-515 and -449 families were upregulated in hepatocellular carcinoma (HCC), and the sponge targeting miR-515 family had a significant probability to suppress cancer cell proliferation. Then, we constructed non-toxic sponge-loaded magnetic nanodroplets containing 20% C6F14 (SLMNDs-20%) that are incorporated with fluorinated superparamagnetic iron oxide nanoparticles enhancing external magnetism-assisted targeting and enabling a direct visualization of SLMNDs-20% distribution in vivo via magnetic resonance imaging monitoring. SLMNDs-20% could be vaporized by programmable focused ultrasound (FUS) activation, achieving ∼45% in vitro sponge delivery efficiency and significantly enhancing in vivo sponge delivery without a clear apoptosis. Moreover, the sponge-1-carrying SLMNDs-20% could effectively suppress proliferation of xenograft HCC after FUS exposure because sponge-1-suppressing onco-miR-515 enhanced the expression of anti-oncogenes (P21, CD22, TIMP1, NFKB, and E-cadherin) in cancer cells. The current results indicated that ultrasonic cavitation-inducing sonoporation enhanced the intracellular delivery of sponge-1 using SLMNDs-20% after magnetic-assisted accumulation, which was a therapeutic approach to inhibit HCC progression.

Barbed suture versus traditional suture in primary total knee arthroplasty: A systematic review and meta-analysis of randomized controlled studies.

BACKGROUND: Barbed suture has been widely used in some surgical fields, and it has achieved good results, but the application in total knee arthroplasty is still controversial. OBJECTIVE: Literature is collected for statistical analysis so as to provide evidence for the use of barbed suture in Total knee arthroplasty. METHODS: We searched PubMed, the Cochrane library and EMBASE database for randomized controlled trials (RCTs) using barbed suture and conventional suture to close incisions after primary total knee arthroplasty, and the retrieval time was from July 2019 to the establishment of the database. Literature was screened according to inclusion and exclusion criteria, quality evaluation and data extraction were conducted for the final included literature, and statistical analysis was conducted using RevMan 5.3 software. RESULTS: A total of six RCTs (826 knees) were included in our meta-analysis. The results showed that the re-negative conversion could shorten the wound closure time (MD -4.41, 95% CI -5.11 to -3.72, P < .00001) and reduce the wound closure total cost (MD -282.61, 95% CI -445.36 to -119.85, P = .0007) and acupuncture injury (RR 0.14, 95% CI 0.03-0.78, P = .02), and did not significantly increasing the incidence of complications (RR 0.80, 95% CI 0.05-0.96, P = .38) or suture breakages (RR 4.58, 95% CI 0.16-128.29, P = .37). There were no significant differences in ROM at postoperative 6 weeks and 3 months (MD -0.74, 95% CI -4.19 to 2.71, P = .67; MD -0.30, 95% CI -2.62 to 2.02, P = .80) and no significant differences in KSS at postoperative 6 weeks (MD -0.22, 95% CI -3.10 to 2.66, P = .88). CONCLUSIONS: Our study shows that barbed suture is a fast, low-cost, safe and effective suture method in total knee arthroplasty compared with traditional suture, we also need more literature and longer follow-up to confirm this conclusion.

ROS-Responsive Blended Nanoparticles: Cascade-Amplifying Synergistic Effects of Sonochemotherapy with On-demand Boosted Drug Release During SDT Process.

Sonodynamic therapy (SDT) not only has greater tissue-penetrating depth compared to photo-stimulated therapies, but also can also trigger rapid drug release to achieve synergistic sonochemotherapy. Here, reactive oxygen species (ROS)-responsive IR780/PTL- nanoparticles (NPs) are designed by self-assembly, which contain ROS-cleavable thioketal linkers (TL) to promote paclitaxel (PTX) release during SDT. Under ultrasound (US) stimulation, IR780/PTL-NPs produce high amounts of ROS, which not only induces apoptosis in human glioma (U87) cells but also boosts PTX released by decomposing the ROS-sensitive TL. In the U87 tumor-bearing mouse model, the IR780/PTL-NPs releases the drug at the target sites in a controlled manner upon US irradiation, which significantly inhibits tumor growth and induces apoptosis in the tumor tissues with no obvious toxicity. Taken together, the IR780/PTL-NPs are a novel platform for sonochemotherapy, and can control the spatio-temporal release of chemotherapeutic drugs during SDT.

circRNA_0006393 promotes osteogenesis in glucocorticoid­induced osteoporosis by sponging miR­145­5p and upregulating FOXO1.

Glucocorticoids are the most common cause of glucocorticoid­induced osteoporosis (GIOP). Moreover, the role of circular RNAs (circRNAs) in the regulation of bone metabolism remains unclear. Therefore, in the present study, it was hypothesized that hsa_circ_0006393 may play an important role in GIOP. To investigate the role of circRNAs in GIOP, treatment with dexamethasone or transfection with a vector overexpressing hsa_circ_0006393 were performed using in vitro cell and in vivo mouse models. Reverse transcription­quantitative PCR, fluorescence in situ hybridization and western blotting were performed to investigate the function of hsa_circ_0006393 in vitro. In addition, the effects of hsa_circ_0006393 on osteogenesis were investigated. Dual­energy X­ray absorptiometry analysis was performed to examine the osteogenic potential of hsa_circ_0006393 in vivo. Moreover, the mechanism underlying hsa_circ_0006393­mediated bone metabolism regulation via the microRNA (miR)­145­5p/forkhead box O1 (FOXO1) pathway was investigated. The present results suggested that the expression level of hsa_circ_0006393 was decreased in patients with GIOP. Furthermore, the overexpression of hsa_circ_0006393 increased the expression level of genes associated with osteogenesis. Moreover, hsa_circ_0006393 was identified to be localized mainly in the cytoplasm and nucleus of bone marrow mesenchymal stem cells. miR­145­5p was found to be directly targeted by hsa_circ_0006393. Collectively, hsa_circ_0006393 increases the expression levels of osteogenic genes during bone remodeling by sponging miR­145­5p and upregulating FOXO1.

Enhanced anti-tumor efficacy of hyaluronic acid modified nanocomposites combined with sonochemotherapy against subcutaneous and metastatic breast tumors.

Sonochemotherapy is a promising strategy for inhibiting tumor growth. However, achieving highly targeted and effective sonochemotherapy is still an enormous challenge. In this study, a novel chemotherapeutic-carrying nanocomposite (HPCID) was developed, which can effectively target metastatic cancer cells and provide an enhanced therapeutic effect. In detail, HPCID was composed of hyaluronic acid (HA), carboxyl-terminated PAMAM dendrimer, fluorochrome indocyanine green (ICG), and doxorubicin hydrochloride (Dox). The efficacy of this drug delivery system (DDS) in sonochemotherapy was assessed on the CD44-overexpressing metastatic breast cancer cell line 4T1 both in vitro and in vivo. The HA modification significantly improved the cellular internalization of HPCID, and the degradation of the HA shell by hyaluronidase that is abundant in the 4T1 cells resulted in enzyme-responsive drug release. Under ultrasound (US) stimulation, HPCID produced a high amount of reactive oxidant species (ROS), which induced significant cell apoptosis when combined with chemotherapy. In addition, the administration of HPCID in 4T1 xenograft-bearing mice combined with ultrasonic exposure significantly inhibited tumor growth and pulmonary metastasis, with no systemic toxicity. Taken together, the proposed HPCID-mediated sonodynamic therapy (SDT) is a novel strategy against breast cancer progression and metastasis.

Reduced clot debris size in sonothrombolysis assisted with phase-change nanodroplets.

Thrombosis-related diseases such as stroke, deep vein thrombosis, and others represent leading causes of mortality and morbidity around the globe. Current clinical thrombolytic treatments are limited by either slow reperfusion (drugs) or invasiveness (catheters) and carry significant risks of bleeding. High intensity focused ultrasound (HIFU) has been demonstrated to be a non-pharmacological, non-invasive but yet efficient thrombolytic approach. However, clinical concerns still remain related to the clot debris produced via fragmentation of the original clot potentially being too large and hence occluding downstream vessels, causing hazardous emboli. In this study, we introduced phase-change nanodroplets into pulse HIFU-mediated thrombolysis. The size distribution of the clot debris generated in sonothrombolysis with and without nanodroplets was compared. The effects of nanodroplet concentration, acoustic power and pulse repetition frequency on the clot debris size were further evaluated. It was found that the volume percentage of the large clot debris particles (above 10 µm in diameter) was smaller and the average diameter of the clot debris reduced significantly in nanodroplets-assisted sonothrombolysis. The stable cavitation dose was higher in sonothrombolysis without nanodroplets but the inertial cavitation dose showed no significant differences under two conditions. Besides, the average diameter decreased with increasing nanodroplet concentration and acoustic power when calculated by number percentage, but was found to be similar when calculated by volume percentage. In addition, the number percentage of the clot debris above 30 µm was demonstrated to be larger upon applying a higher pulse repetition frequency. Taken in concert, this study demonstrated that the introduction of phase-change nanodroplets could provide a safer sonothrombolysis method by reducing the overall clot debris size.

Efficacy of intravenous acetaminophen in multimodal management for pain relief following total knee arthroplasty: a meta-analysis.

BACKGROUND: The efficacy of intravenous acetaminophen in multimodal pain management in patients undergoing total knee arthroplasty (TKA) is controversial. The purpose of this meta-analysis was to compare the efficacy of intravenous acetaminophen versus placebo in TKA. METHODS: Randomized controlled trials (RCTs) or retrospective cohort studies (RCSs) concerning related topics were retrieved from PubMed (1996-June 2018), Embase (1980-June 2018), and the Cochrane Library (CENTRAL June 2018). Any studies comparing intravenous acetaminophen with a placebo were included in this meta-analysis. Meta-analysis results were collected and analyzed by Stata 12.0. Subgroup analysis was performed according to the general characteristics of the patients. RESULTS: In total, the patients from six studies met the inclusion criteria. Our meta-analysis results indicated that compared with a control group, intravenous acetaminophen was associated with reductions in total morphine consumption and visual analogue scale (VAS) score at postoperative day (POD) 3. However, there was no significant difference in morphine consumption at POD 1 or in VAS at POD 1 or POD 2. Moreover, there was no significant difference in the length of hospital stay. CONCLUSIONS: Based on our results, intravenous acetaminophen in multimodal management has shown better efficacy in pain relief at POD 3 and has morphine-sparing effects. High-quality studies with more patients are needed in the future.

Acoustic droplet vaporization and inertial cavitation thresholds and efficiencies of nanodroplets emulsions inside the focused region using a dual-frequency ring focused ultrasound.

In this work, in order to develop a low-acoustic-intensity, high-efficiency and precise-treatment strategy, the vaporization of droplets and the inertial cavitation of vaporized microbubbles, using a dual-frequency focused ultrasound transducer, were investigated. The effect of a low frequency (LF), 1.1-MHz, sonication on droplet vaporization and the following inertial cavitation by the introduction of a high frequency (HF), 5-MHz, sonication was studied. It is shown that acoustic droplet vaporization (ADV) threshold is the lowest at dual-frequency sonication (LF of 18.9 W/cm2 and HF of 4.1 W/cm2); moreover, the ADV efficiency is the highest at intensity threshold. The ADV area can be minimized to 2 mm2 using a dual-frequency sonication (LF of 38.1 W/cm2 and HF of 8.5 W/cm2). The IC area and efficiency can also be modulated using a dual-frequency sonication. Consequently, it can be concluded that in contrast to the single-frequency sonication, using the dual-frequency ultrasound, the vaporization of nanodroplets and the following inertial cavitation of the vaporized microbubbles can be modulated. Besides, a dual-frequency can result in the minimum ADV/IC area, lowest ADV/IC threshold, and highest ADV/IC efficiency.

The association between risk of limb fracture and type 2 diabetes mellitus.

BACKGROUND: Recently, increasing reports showed that the risk of fracture may be correlated with type 2 diabetes mellitus (T2DM). However, their results still remained controversial. Thus we performed a meta-analysis including 11 studies to estimate the risk factor of limb fracture in type 2 diabetes mellitus. MATERIALS AND METHODS: Databases including PubMed, Embase, Cochrane Library and Web of Science were searched to September, 2017. Risk Ratio (RR) with its 95% confidence intervals (CI) was used to evaluate the association between risk of limb fracture and type 2 diabetes mellitus. Two reviewers assessed the quality of all the included studies and extracted data for analysis independently. RESULTS: A total of 11 studies including 663,923 participants were included in this meta-analysis. Our analysis results showed that patients with type 2 diabetes mellitus had a significant association with risk of limb fracture (RR 1.18; 95% CI 1.02-1.35), including leg or ankle fracture (RR 1.80; 95% CI 1.13-2.87). Subgroup analysis showed individuals with type 2 diabetes had almost two-fold excessive risk of leg/ankle fracture in women and the pooled RR of leg/ankle fracture was 2.03 (95% CI 1.36-3.05; P = 0.0006). CONCLUSIONS: The results of the present meta-analysis showed that individuals with type 2 diabetes mellitus had higher risk of limb fractures, and this relationship is more pronounced in leg or ankle fracture.