Epidemiology, Clinical, and Microbiological Characteristics of Multidrug-Resistant Gram-Negative Bacteremia in Qatar.

Antimicrobial resistance is a global healthcare threat with significant clinical and economic consequences peaking at secondary and tertiary care hospitals where multidrug-resistant Gram-negative bacteria (MDR GNB) lead to poor outcomes. A prospective study was conducted between January and December 2019 for all invasive bloodstream infections (BSIs) secondary to MDR GNB in Qatar identified during routine microbiological service to examine their clinical, microbiological, and genomic characteristics. Out of 3238 episodes of GNB BSIs, the prevalence of MDR GNB was 13% (429/3238). The predominant MDR pathogens were Escherichia coli (62.7%), Klebsiella pneumoniae (20.4%), Salmonella species (6.6%), and Pseudomonas aeruginosa (5.3%), while out of 245 clinically evaluated patients, the majority were adult males, with the elderly constituting almost one-third of the cohort and with highest observed risk for prolonged hospital stays. The risk factors identified included multiple comorbidities, recent healthcare contact, previous antimicrobial therapy, and admission to critical care. The in-hospital mortality rate was recorded at 25.7%, associated with multiple comorbidities, admission to critical care, and the acquisition of MDR Pseudomonas aeruginosa. Resistant pathogens demonstrated high levels of antimicrobial resistance but noticeable susceptibility to amikacin and carbapenems. Genomic analysis revealed that Escherichia coli ST131 and Salmonella enterica ST1 were the predominant clones not observed with other pathogens.

Mutual Information Guided Diffusion for Zero-shot Cross-modality Medical Image Translation.

Cross-modality data translation has attracted great interest in medical image computing. Deep generative models show performance improvement in addressing related challenges. Nevertheless, as a fundamental challenge in image translation, the problem of zero-shot learning cross-modality image translation with fidelity remains unanswered. To bridge this gap, we propose a novel unsupervised zero-shot learning method called Mutual Information guided Diffusion Model, which learns to translate an unseen source image to the target modality by leveraging the inherent statistical consistency of Mutual Information between different modalities. To overcome the prohibitive high dimensional Mutual Information calculation, we propose a differentiable local-wise mutual information layer for conditioning the iterative denoising process. The Local-wise-Mutual-Information-Layer captures identical cross-modality features in the statistical domain, offering diffusion guidance without relying on direct mappings between the source and target domains. This advantage allows our method to adapt to changing source domains without the need for retraining, making it highly practical when sufficient labeled source domain data is not available. We demonstrate the superior performance of MIDiffusion in zero-shot cross-modality translation tasks through empirical comparisons with other generative models, including adversarial-based and diffusion-based models. Finally, we showcase the real-world application of MIDiffusion in 3D zero-shot learning-based cross-modality image segmentation tasks.

Epilepsy and demyelination: Towards a bidirectional relationship.

Demyelination stands out as a prominent feature in individuals with specific types of epilepsy. Concurrently, individuals with demyelinating diseases, such as multiple sclerosis (MS) are at a greater risk of developing epilepsy compared to non-MS individuals. These bidirectional connections raise the question of whether both pathological conditions share common pathogenic mechanisms. This review focuses on the reciprocal relationship between epilepsy and demyelination diseases. We commence with an overview of the neurological basis of epilepsy and demyelination diseases, followed by an exploration of how our comprehension of these two disorders has evolved in tandem. Additionally, we discuss the potential pathogenic mechanisms contributing to the interactive relationship between these two diseases. A more nuanced understanding of the interplay between epilepsy and demyelination diseases has the potential to unveiling the molecular intricacies of their pathological relationships, paving the way for innovative directions in future clinical management and treatment strategies for these diseases.

Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer.

WEE1 and CHEK1 (CHK1) kinases are critical regulators of the G2/M cell cycle checkpoint and DNA damage response pathways. The WEE1 inhibitor AZD1775 and the CHK1 inhibitor SRA737 are in clinical trials for various cancers, but have not been thoroughly examined in prostate cancer, particularly castration-resistant (CRPC) and neuroendocrine prostate cancers (NEPC). Our data demonstrated elevated WEE1 and CHK1 expressions in CRPC and NEPC cell lines and patient samples. AZD1775 resulted in rapid and potent cell killing with comparable IC50s across different prostate cancer cell lines, while SRA737 displayed time-dependent progressive cell killing with 10- to 20-fold differences in IC50s. Notably, their combination synergistically reduced the viability of all CRPC cell lines and tumor spheroids in a concentration- and time-dependent manner. Importantly, in a transgenic mouse model of NEPC, both agents alone or in combination suppressed tumor growth, improved overall survival, and reduced the incidence of distant metastases, with SRA737 exhibiting remarkable single agent anticancer activity. Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC.

In Vivo Analysis of Acromioclavicular Kinematics and Distance During Multiplanar Humeral Elevation.

BACKGROUND: Knowledge of acromioclavicular (AC) joint kinematics and distance may provide insight into the biomechanical function and development of new treatment methods. However, accurate data on in vivo AC kinematics and distance between the clavicle and acromion remain unknown. PURPOSE/HYPOTHESIS: The purpose of this study was to investigate 3-dimensional AC kinematics and distance during arm elevation in abduction, scaption, and forward flexion in a healthy population. It was hypothesized that AC kinematics and distance would vary with the elevation angle and plane of the arm. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 19 shoulders of healthy participants were enrolled. AC kinematics and distance were investigated with a combined dual fluoroscopic imaging system and computed tomography. Rotation and translation of the AC joint were calculated. The AC distance was measured as the minimum distance between the medial border of the acromion and the articular surface of the distal clavicle (ASDC). The minimum distance point (MDP) ratio was defined as the length between the MDP and the posterior edge of the ASDC divided by the anterior-posterior length of the ASDC. AC kinematics and distance between different elevation planes and angles were compared. RESULTS: Progressive internal rotation, upward rotation, and posterior tilt of the AC joint were observed in all elevation planes. The scapula rotated more upward relative to the clavicle in abduction than in scaption (P = .002) and flexion (P = .005). The arm elevation angle significantly affected translation of the AC joint. The acromion translated more laterally and more posteriorly in scaption than in abduction (P < .001). The AC distance decreased from the initial position to 75° in all planes and was significantly greater in flexion (P < .001). The MDP ratio significantly increased with the elevation angle (P < .001). CONCLUSION: Progressive rotation and significant translation of the AC joint were observed in different elevation planes. The AC distance decreased with the elevation angle from the initial position to 75°. The minimum distance between the ASDC and the medial border of the acromion moved anteriorly as the shoulder elevation angle increased. CLINICAL RELEVANCE: These results could serve as benchmark data for future studies aiming to improve the surgical treatment of AC joint abnormalities to restore optimal function.

A simplicial epidemic model for COVID-19 spread analysis.

Networks allow us to describe a wide range of interaction phenomena that occur in complex systems arising in such diverse fields of knowledge as neuroscience, engineering, ecology, finance, and social sciences. Until very recently, the primary focus of network models and tools has been on describing the pairwise relationships between system entities. However, increasingly more studies indicate that polyadic or higher-order group relationships among multiple network entities may be the key toward better understanding of the intrinsic mechanisms behind the functionality of complex systems. Such group interactions can be, in turn, described in a holistic manner by simplicial complexes of graphs. Inspired by these recently emerging results on the utility of the simplicial geometry of complex networks for contagion propagation and armed with a large-scale synthetic social contact network (also known as a digital twin) of the population in the U.S. state of Virginia, in this paper, we aim to glean insights into the role of higher-order social interactions and the associated varying social group determinants on COVID-19 propagation and mitigation measures.

Light and Humidity Dual-Responsive Anti-Counterfeiting Films Based on Hydrogen-Bonded Cholesteric Liquid Crystal Polymers with Spiropyran.

There is still significant room for improvement when combining structural color with fluorescence patterns in dual anti-counterfeiting and dynamic anti-counterfeiting labels. In this study, we achieved significant breakthroughs under dual anti-counterfeiting conditions by using the structural color properties of the hydrogen-bonded cholesteric liquid crystal (HBCLC) and combining them with the fluorescence dye spiropyran (SP) to create anti-counterfeiting patterns. The anti-counterfeiting label can only display storage information after meeting the conditions of humidity and ultraviolet light (UV) and has the functions of dynamic encryption and repeated reading. We adjusted the center of the reflection band of the HBCLC film to transition from red to infrared under 40-90% relative humidity (RH) conditions and used it as a background film to draw anti-counterfeiting patterns with SP. Since these fluorescence dyes can switch between merocyanine (MC) (red) and SP (colorless) under UV and visible light conditions, when combined with the HBCLC, orthogonal dynamic encryption was achieved. Additionally, with the adsorption of SP, the reflection band of HBCLC films under the same humidity range increased from around 160 nm to around 260 nm, greatly improving the sensitivity to humidity changes. Furthermore, under UV conditions, it can still emit red fluorescence, demonstrating a polymorphic encryption feature, which greatly increased the complexity of the anti-counterfeiting pattern with significant significance to dynamic anti-counterfeiting and information storage.

Synthetic lethal combination of CHK1 and WEE1 inhibition for treatment of castration-resistant prostate cancer.

WEE1 and CHEK1 (CHK1) kinases are critical regulators of the G2/M cell cycle checkpoint and DNA damage response pathways. The WEE1 inhibitor AZD1775 and the CHK1 inhibitor SRA737 are in clinical trials for various cancers, but have not been examined in prostate cancer, particularly castration-resistant (CRPC) and neuroendocrine prostate cancers (NEPC). Our data demonstrated elevated WEE1 and CHK1 expressions in CRPC/NEPC cell lines and patient samples. AZD1775 resulted in rapid and potent cell killing with comparable IC50s across different prostate cancer cell lines, while SRA737 displayed time-dependent progressive cell killing with 10- to 20-fold differences in IC50s. Notably, their combination synergistically reduced the viability of all CRPC cell lines and tumor spheroids in a concentration- and time-dependent manner. Importantly, in a transgenic mouse model of NEPC, both agents alone or in combination suppressed tumor growth, improved overall survival, and reduced the incidence of distant metastases, with SRA737 exhibiting remarkable single agent anticancer activity. Mechanistically, SRA737 synergized with AZD1775 by blocking AZD1775-induced feedback activation of CHK1 in prostate cancer cells, resulting in increased mitotic entry and accumulation of DNA damage. In summary, this preclinical study shows that CHK1 inhibitor SRA737 alone and its combination with AZD1775 offer potential effective treatments for CRPC and NEPC.

Comparison of the mid-term clinical efficacy of different fixtaion methods combined with oblique lumbar interbody fusion in treating lumbar degenerative diseases.

BACKGROUND: To compare the mid-term follow-up clinical efficacy among three treatment approaches for lumbar degenerative diseases (LDD): standalone oblique lumbar interbody fusion (SF), oblique lumbar interbody fusion combined with lateral screw fixation (LF), and oblique lumbar interbody fusion combined with posterior screw fixation (PF). METHOD: This retrospective study included a total of 71 cases of single level LDD that underwent OLIF in Hospital of Chengdu University of Traditional Chinese Medicine were retrospectively collected between March 2016 and September 2017. Patients were divided into three groups: 24 cases in the SF group, 24 cases in the LF group and 23 cases in the PF group. Various parameters, such as operation time, hospitalization time, and complications, were recorded. The fusion condition was assessed at last follow up. Clinical outcomes were evaluated using the Visual Analogue Scale (VAS) and Oswestry Disability Index (ODI) from pre-operation to 5 years post-surgery. RESULTS: Significantly lower mean operation time and hospitalization time were observed in the SF and LF groups compared to the PF group (p < .05). However, no significant difference in fusion rate was found among the three groups. Regarding clinical outcomes, there was no statistically significant difference in VAS scores between the three groups during all follow-up periods. At the 6th month and 1st year after surgery, the SF and LF groups had significantly lower Oswestry Disability Index (ODI) scores compared to the PF group (p < .05). There was no significant difference in perioperative complication rates among the three groups (p > .05). In the LF group, one case of instrument displacement and urethra injury were reported, while in the SF, LF, and PF groups, 10, 9, and 3 cases of cage subsidence were reported, respectively. CONCLUSION: The study findings suggest that oblique lumbar interbody fusion (OLIF) is a safe and effective treatment for mid-term management of lumbar degenerative diseases (LDD). Compared to the posterior screw fixation (PF) group, both the standalone OLIF (SF) and OLIF combined with lateral screw fixation (LF) groups showed advantages in terms of reduced operation time, shorter hospitalization, and faster symptom alleviation in the short-term. However, OLIF combined with PF demonstrated comparable symptom relief in the mid-term and had the additional benefit of lower cage subsidence rates while improving fusion rates as well.

Liquid-crystal-based fiber laser sensor for non-invasive gas detection.

This Letter reports a new optical fiber gas sensor for measuring breath acetone. The sensor is based on photonic bandgap (PBG) mode laser emission sensing technology using liquid crystal (LC), which is combined with silica fiber and chiral nematic liquid crystal (CNLC), thus providing an ultra-compact, fast-response and simple-to-produce sensing system with a fast response that can accurately and quantitatively determine the concentration of respiratory acetone within the normal oral temperature range (35-38°C). Since LCs are affected by temperature, we propose a method that eliminates the influence of the temperature to solve the problem of the temperature influence when measuring gas. The detection of acetone leads to splitting of the dual laser peaks, with a linear correlation of 0.99. The sensor has a limit of detection of 65 ppm for acetone vapor and thus is suitable for breath acetone detection in diabetic patients.

Protein kinase D2 confers neuroprotection by promoting AKT and CREB activation in ischemic stroke.

Ischemic stroke, constituting 80-90% of all strokes, is a leading cause of death and long-term disability in adults. There is an urgent need to discover new targets and therapies for this devastating condition. Protein kinase D (PKD), as a key target of diacylglycerol involved in ischemic responses, has not been well studied in ischemic stroke, particularly PKD2. In this study, we found that PKD2 expression and activity were significantly upregulated in the ipsilateral side of the brain after transient focal cerebral ischemia, which coincides with the upregulation of PKD2 in primary neurons in response to in vitro ischemia, implying a potential role of PKD2 in neuronal survival in ischemic stroke. Using kinase-dead PKD2 knock-in (PKD2-KI) mice, we examined whether loss of PKD2 activity affected stroke outcomes in mice subjected to 1 h of transient middle cerebral artery occlusion (tMCAO) and 24 h of reperfusion. Our data demonstrated that PKD2-KI mice exhibited larger infarction volumes and worsened neurological scores, indicative of increased brain injury, as compared to the wild-type (WT) mice, confirming a neuroprotective role of PKD2 in ischemia/reperfusion (I/R) injury. Mouse primary neurons obtained from PKD2-KI mice also exhibited increased cell death as compared to the WT neurons when subjected to in vitro ischemia. We have further identified AKT and CREB as two main signaling nodes through which PKD2 regulates neuronal survival during I/R injury. In summary, PKD2 confers neuroprotection in ischemic stroke by promoting AKT and CREB activation and targeted activation of PKD2 may benefit neuronal survival in ischemic stroke.

Suppressed Akt/GSK-3ß/ß-catenin signaling contributes to excessive adipogenesis of fibro-adipogenic progenitors after rotator cuff tears.

Muscular fatty infiltration is a common and troublesome pathology after rotator cuff tears (RCT), which mainly derives from fibro-adipogenic progenitors (FAPs). Compared to the RCT, fatty infiltration is not so severe in Achilles tendon tears (ATT). The knowledge of why fatty infiltration is more likely to occur after RCT is limited. In this study, more severe fatty infiltration was verified in supraspinatus than gastrocnemius muscles after tendon injury. Additionally, we revealed higher adipogenic differentiation ability of RCT-FAPs in vitro. Activation of Akt significantly stimulated GSK-3ß/ß-catenin signaling and thus decreased PPARγ expression and adipogenesis of RCT-FAPs, while the inhibition effect was attenuated by ß-catenin inhibitor. Furthermore, Wnt signaling activator BML-284 limited adipogenesis of RCT-FAPs, alleviated muscular fatty infiltration, and improved parameters in gait analysis and treadmill test for RCT model. In conclusion, our study demonstrated that suppressed Akt/GSK-3ß/ß-catenin signaling increased PPARγ expression and thus contributed to excessive adipogenesis in RCT-FAPs. Modulation of Akt/GSK-3ß/ß-catenin signaling ameliorated excessive fatty infiltration of rotator cuff muscles and improved shoulder function after RCT.

A systematic review and meta-analysis of risk factors for reoperation after degenerative lumbar spondylolisthesis surgery.

BACKGROUND: Considering the high reoperation rate in degenerative lumbar spondylolisthesis (DLS) patients undergoing lumbar surgeries and controversial results on the risk factors for the reoperation, we performed a systematic review and meta-analysis to explore the reoperation rate and risk factors for the reoperation in DLS patients undergoing lumbar surgeries. METHODS: Literature search was conducted from inception to October 28, 2022 in Pubmed, Embase, Cochrane Library, and Web of Science. Odds ratio (OR) was used as the effect index for the categorical data, and effect size was expressed as 95% confidence interval (CI). Heterogeneity test was performed for each outcome effect size, and subgroup analysis was performed based on study design, patients, surgery types, follow-up time, and quality of studies to explore the source of heterogeneity. Results of all outcomes were examined by sensitivity analysis. Publication bias was assessed using Begg test, and adjusted using trim-and-fill analysis. RESULTS: A total of 39 cohort studies (27 retrospective cohort studies and 12 prospective cohort studies) were finally included in this systematic review and meta-analysis. The overall results showed a 10% (95%CI: 8%-12%) of reoperation rate in DLS patients undergoing lumbar surgeries. In surgery types subgroup, the reoperation rate was 11% (95%CI: 9%-13%) for decompression, 10% (95%CI: 7%-12%) for fusion, and 9% (95%CI: 5%-13%) for decompression and fusion. An increased risk of reoperation was found in patients with obesity (OR = 1.91, 95%CI: 1.04-3.51), diabetes (OR = 2.01, 95%CI: 1.43-2.82), and smoking (OR = 1.51, 95%CI: 1.23-1.84). CONCLUSIONS: We found a 10% of reoperation rate in DLS patients after lumbar surgeries. Obesity, diabetes, and smoking were risk factors for the reoperation.

Laser emission from tapered fiber-based liquid-crystal microsphere for sensing.

This Letter introduces a novel laser emission probe for liquid-crystal microspheres based on a tapered fiber. A cholesteric liquid crystal (CLC) is injected into a hollow glass microsphere (HGM) attached at the front end of a tapered fiber in order to produce laser. Tapered fibers are preferable to rectangular fibers for liquid-crystal microsphere laser emission. The whispering gallery mode (WGM) laser is significantly suppressed by the tapered fiber-based liquid-crystal microsphere, which also displays an apparent single-mode photonic bandgap (PBG) laser peak. The stimulation response of tapered fiber-based liquid-crystal microspheres to organic vapors causes a modification of the laser peak wavelength with increasing gas concentration. In addition, laser emission generated by tapered fiber-based liquid-crystal microspheres is expected to be used in fields such as microenvironmental biosensing.

Research progress of colon-targeted oral hydrogel system based on natural polysaccharides.

The quality of life is significantly impacted by colon-related diseases. There have been a lot of interest in the oral colon-specific drug delivery system (OCDDS) as a potential carrier to decrease systemic side effects and protect drugs from degradation in the upper gastrointestinal tract (GIT). Hydrogels are effective oral colon-targeted drug delivery carriers due to their high biodegradability, substantial drug loading, and great biocompatibility. Natural polysaccharides give the hydrogel system unique structure and function to effectively respond to the complex environment of the GIT and deliver drugs to the colon. In this paper, the physiological factors of colonic drug delivery and the pathological characteristics of common colonic diseases are summarized, and the latest advances in the design, preparation and characterization of natural polysaccharide hydrogels are reviewed, which are expected to provide new references for colon-targeted oral hydrogel systems using natural polysaccharides as raw materials.

LaserNet: a method of laser stripe center extraction under non-ideal conditions.

The extraction of the center of a laser stripe is a key step in line-structure measurement, where noise interference and changes in the surface color of an object are the main factors affecting extraction accuracy. To obtain sub-pixel level center coordinates under such non-ideal conditions, we propose LaserNet, a novel deep learning-based algorithm, to the best of our knowledge, which consists of a laser region detection sub-network and a laser position optimization sub-network. The laser region detection sub-network is used to determine potential stripe regions, and the laser position optimization sub-network uses the local image of these regions to obtain the accurate center position of the laser stripe. The experimental results show that LaserNet can eliminate noise interference, handle color changes, and give accurate results under non-ideal conditions. The three-dimensional reconstruction experiments further demonstrate the effectiveness of the proposed method.

Spatio-temporally deciphering peripheral nerve regeneration in vivo after extracellular vesicle therapy under NIR-II fluorescence imaging.

Extracellular vesicles (EVs) show potential as a therapeutic tool for peripheral nerve injury (PNI), promoting neurological regeneration. However, there are limited data on the in vivo spatio-temporal trafficking and biodistribution of EVs. In this study, we introduce a new non-invasive near-infrared fluorescence imaging strategy based on glucose-conjugated quantum dot (QDs-Glu) labeling to target and track EVs in a sciatic nerve injury rat model in real-time. Our results demonstrate that the injected EVs migrated from the uninjured site to the injured site of the nerve, with an increase in fluorescence signals detected from 4 to 7 days post-injection, indicating the release of contents from the EVs with therapeutic effects. Immunofluorescence and behavioral tests revealed that the EV therapy promoted nerve regeneration and functional recovery at 28 days post-injection. We also found a relationship between functional recovery and the NIR-II fluorescence intensity change pattern, providing novel evidence for the therapeutic effects of EV therapy using real-time NIR-II imaging at the live animal level. This approach initiates a new path for monitoring EVs in treating PNI under in vivo NIR-II imaging, enhancing our understanding of the efficacy of EV therapy on peripheral nerve regeneration and its mechanisms.

Functional and Structural Outcomes After Arthroscopic Rotator Cuff Repair With or Without Preoperative Corticosteroid Injections.

BACKGROUND: Corticosteroid injections (CSIs) are effective in alleviating pain in patients with rotator cuff tears, but controversy still exists regarding their potential adverse effects on clinical outcomes after rotator cuff repair. PURPOSE: To compare both the functional and the structural outcomes in patients who underwent arthroscopic rotator cuff repair with or without preoperative CSIs. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective cohort study was carried out among patients who underwent arthroscopic rotator cuff repair for partial- and full-thickness tears between 2015 and 2019. The patients who received preoperative CSIs were included in the CSI group and compared with a group without preoperative CSIs (non-CSI group), matched at a ratio of 1:2 based on tear size, age, and follow-up time. Both functional evaluation and structural assessments using magnetic resonance imaging (MRI) were performed at the final follow-up. Clinical outcomes-including retear rate as the primary outcome; pain; functional scores including the Constant-Murley score, American Shoulder and Elbow Surgeons score, and Fudan University Shoulder Score; range of motion (ROM); tendon integrity; tendon healing type; and cartilage thickness-were compared between the 2 groups with a statistical significance of P < .05 and power of 0.9. RESULTS: Thirty-one patients were included in the CSI group, and 62 were included in the non-CSI group. After a mean 3-year follow-up, the 2 groups demonstrated no significant differences in retear rate; visual analog scale for pain; shoulder functional scores; and active ROM including forward flexion, abduction, external rotation, and internal rotation. No significant differences were observed on postoperative MRI scans of the rotator cuff tendon (tendon integrity, healing type, residual tendon attachment area, etc), cartilage thickness, and muscle atrophy. CONCLUSION: No significant differences were found at a mean 3-year follow-up in the retear rates, pain, ROM, and glenohumeral structure on postoperative MRI scans after arthroscopic rotator cuff repair with or without preoperative CSIs.

Protein Kinase D2 and D3 Promote Prostate Cancer Cell Bone Metastasis by Positively Regulating Runx2 in a MEK/ERK1/2-Dependent Manner.

Advanced-stage prostate tumors metastasize to the bone, often causing death. The protein kinase D (PKD) family has been implicated in prostate cancer development; however, its role in prostate cancer metastasis remains elusive. This study examined the contribution of PKD, particularly PKD2 and PKD3 (PKD2/3), to the metastatic potential of prostate cancer cells and the effect of PKD inhibition on prostate cancer bone metastasis in vivo. Depletion of PKD2/3 by siRNAs or inhibition by the PKD inhibitor CRT0066101 in AR-positive and AR-negative castration-resistant prostate cancer cells potently inhibited colony formation and cell migration. Depletion or inhibition of PKD2/3 significantly blocked tumor cell invasion and suppressed the expression of genes related to bone metastasis in the highly invasive PC3-ML cells. The reduced invasive activity resulting from PKD2/3 depletion was in part mediated by the transcription factor Runx2, as its silencing decreased PKD2/3-mediated metastatic gene expression through the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 signaling axis. Furthermore, inhibition of PKD by CRT0066101 potently decreased the frequency of bone micrometastases in a mouse model of bone metastasis based on intracardiac injection of PC3-ML cells. These results indicate that PKD2/3 plays an important role in the bone metastasis of prostate cancer cells, and its inhibition may be beneficial for the treatment of advanced prostate cancer.

Effective interventions for gaming disorder: A systematic review of randomized control trials.

Objective: To identify effective intervention methods for gaming disorder (GD) through a rigorous assessment of existing literature. Methods: We conducted a search of six databases (PubMed, Embase, PsycINFO, CNKI, WanFang, and VIP) to identify randomized controlled trials (RCTs) that tested GD interventions, published from database inception to December 31, 2021. Standardized mean differences with 95% confidence intervals were calculated using a random effects model. Risk of bias was assessed with the Risk of Bias 2 (RoB 2) tool. Results: Seven studies met the inclusion criteria. Five interventions were tested in these studies: group counseling, craving behavioral intervention (CBI), transcranial direct current stimulation (tDCS), the acceptance and cognitive restructuring intervention program (ACRIP), and short-term cognitive behavior therapy (CBT). Four of the five interventions (the tDCS was excluded) were found to have a significant effect on GD. The results of the quality assessment showed that the included studies had a medium to high risk in the randomization process and a medium to high risk of overall bias. Conclusion: Rigorous screening identified that four interventions are effective for GD: group counseling, CBI, ACRIP, and short-term CBT. Additionally, a comprehensive review of the literature revealed that improvements could be made in the conceptualization of GD, experimental design, sample representativeness, and reporting quality. It is recommended that future studies have more rigorous research designs and be based on established standards to provide more credible evidence to inform the development of GD interventions.