Multicenter proteome-wide Mendelian randomization study identifies causal plasma proteins in melanoma and non-melanoma skin cancers.

This study addresses the diagnostic and therapeutic challenges in malignant melanoma (MM) and non-melanoma skin cancers (NMSC). We aim to identify circulating proteins causally linked to MM and NMSC traits using a multicenter Mendelian randomization (MR) framework. We utilized large-scale cis-MR to estimate the impact of numerous plasma proteins on MM, NMSC, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). To ensure robustness, additional analyses like MR Steiger and Bayesian colocalization are conducted, followed by replication through meta-analytical methods. The associations between identified proteins and outcomes are also validated at the tissue level using Transcriptome-Wide Association Study methods. Furthermore, a protein-protein interaction analysis is conducted to explore the relationship between identified proteins and existing cancer medication targets. The MR analysis has identified associations of 13 plasma proteins with BCC, 2 with SCC, and 1 with MM. Specifically, ASIP and KRT5 are associated with BCC, with ASIP also potentially targeting MM. CTSS and TNFSF8 are identified as promising druggability candidates for BCC. This multidimensional approach nominates ASIP, KRT5, CTSS, and TNFSF8 as potential diagnostic and therapeutic targets for skin cancers.

Identification of plasma protein markers of allergic disease risk: a mendelian randomization approach to proteomic analysis.

BACKGROUND: While numerous allergy-related biomarkers and targeted treatment strategies have been developed and employed, there are still signifcant limitations and challenges in the early diagnosis and targeted treatment for allegic diseases. Our study aims to identify circulating proteins causally associated with allergic disease-related traits through Mendelian randomization (MR)-based analytical framework. METHODS: Large-scale cis-MR was employed to estimate the effects of thousands of plasma proteins on five main allergic diseases. Additional analyses including MR Steiger analyzing and Bayesian colocalisation, were performed to test the robustness of the associations; These findings were further validated utilizing meta-analytical methods in the replication analysis. Both proteome- and transcriptome-wide association studies approach was applied, and then, a protein-protein interaction was conducted to examine the interplay between the identified proteins and the targets of existing medications. RESULTS: Eleven plasma proteins were identified with links to atopic asthma (AA), atopic dermatitis (AD), and allergic rhinitis (AR). Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. MR analysis and extra validation revealed STAT6 and TNFRSF6B to be Tier 1 and IL1RL2 and IL6R to be Tier 2 proteins with the potential for AA treatment. Two Tier 1 proteins, CRAT and TNFRSF6B, and five Tier 2 proteins, ERBB3, IL6R, MMP12, ICAM1, and IL1RL2, were linked to AD, and three Tier 2 proteins, MANF, STAT6, and TNFSF8, to AR. CONCLUSION: Eleven Tier 1 and 2 protein targets that are promising drug target candidates were identified for AA, AD, and AR, which influence the development of allergic diseases and expose new diagnostic and therapeutic targets.

Causal association between sleep traits and autoimmune arthritis: Evidence from a bidirectional Mendelian randomization study.

OBJECTIVE: To explore whether there is a genetic causal relationship between sleep traits and the risk of autoimmune arthritis (AA). METHODS: Univariable and multivariable Mendelian randomization was employed using genome-wide association studies data to assess sleep traits' associations with AAs, including rheumatoid arthritis (RA), ankylosing spondylitis, and psoriatic arthritis. The inverse-variance weighted method served as the primary analysis, supplemented by the CAUSE method to improve power and mitigate false positives. Mediation Mendelian randomization was used to quantify direct and indirect effects. RESULTS: Significant associations were shown between insomnia symptoms and increased risk of overall RA (odds ratio = 2.75, 95% confidence interval 1.45-5.22) and seronegative RA (odds ratio = 6.95, 95% confidence interval 2.47-19.56). CAUSE results revealed an association of insomnia symptoms with overall RA and seronegative RA, as well as the sleep duration with overall RA. After the adjustment for body mass index, alcohol status, smoking status, and physical activity levels, multivariable analyses revealed that genetic predisposition to insomnia symptoms and prolonged sleep duration showed independent negative associations with the risk of overall RA and seropositive RA. In the reversed multivariable analyses, a borderline negative association was shown in the overall RA-sleep duration and a positive association of seropositive RA with the risk of insomnia symptoms. CONCLUSION: This study demonstrated a potential bidirectional causal relationship that genetic predisposition to insomnia symptoms and shorter sleep duration was associated with the risk of AA, especially RA. Genetic predisposition to RA was also associated with decreased sleep duration, as well as increased insomnia symptom risk.

Childhood sunburn and risk of melanoma and non-melanoma skin cancer: a Mendelian randomization study.

Previous evidence has suggested that childhood sunburn could be a risk factor for cutaneous malignant melanoma (MM) and non-melanoma skin cancer (NMSC). However, existing observational studies could not reveal the causal associations genetically. This study aimed to investigate whether there was a genetic causal relationship between childhood sunburn and skin cancers. Univariable Mendelian randomization (MR) and Causal Analysis Using Summary Effect analysis was carried out for causal estimates and evaluation for the horizontal pleiotropy. Multivariable MR and the mediation effects analysis were used to test whether the causal associations were mediated by potential confounders. A suggestively significant causal association between childhood sunburn and MM was indicated (OR = 4.74; 95% CI: 1.31-17.19; p = 1.79E-02). Genetically predicted childhood sunburn was significantly associated with increased risk of overall melanoma in situ (MIS) (OR = 4.02; 95% CI: 2.00-8.08; p = 9.40E-05), MIS of face (OR = 18.28; 95% CI: 5.28-63.35; p = 4.59E-06), and MIS of trunk (OR = 7.05; 95% CI: 2.06-24.13; p = 1.88E-03). Similar trends were found for childhood sunburn and NMSC (OR = 8.16; 95% CI: 6.07-10.99; p = 1.53E-20), including both basal cell carcinoma (BCC) (OR = 3.76; 95% CI:2.96-4.77; p = 2.19E-08) and squamous cell carcinoma (SCC) (OR = 7.44; 95% CI: 5.09-10.87; p = 2.19E-08). After adjustment for hair and skin color, facial ageing, vitamin D levels, body mass index, alcohol consumption, and smoking status, childhood sunburn showed an independent association with MIS, MIS of face, MIS of trunk, as well as NMSC, including both BCC and SCC. Mediation analysis showed no significant mediation effect. This study demonstrated a causal relationship between childhood sunburn and the risk of both MM and NMSC, which suggested that enhanced screening and prevention for childhood sunburn could contribute to the early detection and decreased risk of MM and NMSC.

The association of metabolic syndrome with rotator cuff tendinopathy: a two-sample Mendelian randomization study.

BACKGROUND: Observational research reported the underlying correlation of metabolic syndrome (MetS) and its components with rotator cuff tendinopathy (RCT), but their causality remained unclear. This study aimed to investigate whether genetically predicted MetS was related to the risk of RCT. METHODS: Both univariable and multivariable Mendelian randomization (MR) analysis was applied using summary-level data from the most comprehensive genome-wide association studies to estimate the associations of MetS and its component with RCT, with the inverse variance weighted (IVW) as the primary method, and the method of Causal Analysis Using Summary Effect Estimates (CAUSE) as a supplement for false positives detection. The mediation analysis was furtherly used for the assessment of direct and indirect effects. RESULTS: Univariable analysis revealed that genetically predicted MetS (OR: 1.0793; 95% CI 1.0311 to 1.1297), body mass index (BMI) (OR 1.2239; 95% CI 1.1357 to 1.3189), and waist circumference (WAC) (OR 1.3177; 95% CI 1.2015 to 1.4451) had a significant positive association with the risk of RCT. Triglycerides and systolic blood pressure were suggestively associated with RCT risk. These associations were also identified by CAUSE. There was independent causality of BMI (OR: 1.1806; 95% CI 1.0788 to 1.2920) and WAC (OR 1.3716; 95% CI 1.2076 to 1.5580) on RCT after adjustment for confounders. No mediator was found in the causal associations. CONCLUSION: Our study revealed the genetic causality of MetS and its components, especially BMI and WAC, with RCT risk. Early prevention and diagnosis of excess central adiposity contributing to MetS are significant in the RCT risk management.

Feasibility, safety, and efficacy of task-oriented mirrored robotic training on upper-limb functions and activities of daily living in subacute poststroke patients: a pilot study.

BACKGROUND: Robotic training with high repetitions facilitates upper-limb movements but provides fewer benefits for activities of daily living. Integrating activities of daily living training tasks and mirror therapy into a robot may enhance the functional gains of robotic training. AIM: The aim of this study was to investigate the feasibility, safety, and efficacy of the task-oriented mirrored upper-limb robotic training on the upper-limb functions and activities of daily living of subacute poststroke patients. DESIGN: This study is a single-blinded, active-controlled pilot study. SETTING: The study was carried out at rehabilitation outpatient clinic and ward. POPULATION: A total of 32 subacute poststroke patients were enrolled in the study. METHODS: The enrolled patients were allocated into two groups in a ratio of 1:1. The experimental group received 4 weeks of task-oriented mirrored upper-limb robotic training, consisting of five sessions of 30-minute duration, along with 30 minutes of conventional training. The control group only received 60 minutes of conventional training. The outcome measures were the Fugl-Meyer Assessment Scale for Upper Extremity, Modified Barthel Index, Stroke Self-Efficacy Scale, System Usability Scale, and Quebec User Evaluation with Assistive Technology. RESULTS: All patients completed the full training sessions without significant adverse events related to robotic training. The task-oriented mirrored upper-limb robotic training led to increased Fugl-Meyer Assessment Scale for Upper Extremity (difference: 10.38 points, P<0.001) and Modified Barthel Index (difference: 18.38 points, P<0.001) scores, both of which exceeded the minimal clinically important difference. Intergroup analysis showed significantly higher improvements in the Fugl-Meyer Assessment Scale for Upper Extremity total scores, shoulder, wrist, and hand scores; and Modified Barthel Index scores in the experimental group than in conventional training (all P<0.05). Both groups showed significant improvements in Stroke Self-Efficacy Scale scores after the intervention (both P<0.001), but without a statistically significant intergroup difference (P>0.05). Participants in the experimental group scored an average usability perception score of 74.74 (good) and an average satisfaction score of four or more out of five. CONCLUSIONS: In general, task-oriented mirrored upper-limb robotic training appears feasible and safe for subacute poststroke rehabilitation, facilitating the recovery of upper-limb functions and activities of daily living. CLINICAL REHABILITATION IMPACT: Task-oriented mirrored upper-limb robotic training shows promise for future clinical rehabilitation and clinical trials involving subacute poststroke patients.

Causal association of rheumatoid arthritis with obstructive lung disease: Evidence from Mendelian randomization study.

BACKGROUND: Observational studies have found an association between rheumatoid arthritis (RA) and risk of obstructive lung disease (ORDs). However, whether RA plays a role in ORDs development remains unclear. OBJECTIVES: This study aimed to explore the causal association of RA with ORDs. METHODS: Both univariable and multivariable Mendelian randomization (MR) analyses were employed. Summary statistics for RA were obtained from the genome-wide association study (GWAS) meta-analysis, and the GWAS data source of ORDs, including the chronic obstructive pulmonary disease (COPD) and asthma, was accessed from the FinnGen Biobank. Causal Analysis Using Summary Effect Estimates (CAUSE) method was used to improve statistical power. multivariable and two-step mediation MR was applied to calculate the independent and mediated effects. RESULTS: The causal estimates by univariable and CAUSE results indicated genetic predisposition to RA had an effect on the increased risk of asthma/COPD (A/C) (ORCAUSE = 1.03; 95% CI: 1.02-1.04), COPD/asthma related infections (ACI) (ORCAUSE = 1.02; 95% CI: 1.01-1.03) and COPD/asthma related pneumonia or pneumonia derived septicemia (ACP) (ORCAUSE = 1.02; 95% CI: 1.01-1.03). Genetic predisposition to RA was significantly associated with early onset COPD (ORCAUSE = 1.02; 95% CI: 1.01-1.03) and asthma (ORCAUSE = 1.02; 95% CI: 1.01-1.03) risk and suggestively associated with non-allergic asthma (nAA) risk. After adjustment for confounders, independent causal effects remained for the associations of RA with risk of A/C, ACI, and ACP, as well as COPD, early-onset COPD, and asthma [total, nAA and allergic asthma (AA)] risk. Mediation analyses revealed no potential mediator. CONCLUSION: This study indicates a causal effect of increased genetic predisposition to RA on an increased risk of ORDs, including COPD and asthma, especially early-onset COPD and nAA, and on asthma/COPD related infections, pneumonia or pneumonia derived septicemia.

Causal association of leisure sedentary behavior with arthritis: A Mendelian randomization analysis.

OBJECTIVES: This study aimed at exploring the potential causal effects of leisure sedentary behavior (LSB) on common types of arthritis. METHOD: Two-sample Mendelian randomization (MR), including both univariable MR (UVMR) and multivariable MR (MVMR) analysis, was performed to explore the effects of LSB on the risk of several common types of arthritis, including osteoarthritis, rheumatoid arthritis (RA), and psoriatic arthritis (PsA). Genetic variants from genome-wide association studies (GWAS) of LSBs for time spent on television watching, computer use, and driving were obtained from the UK Biobank. Summarized GWAS data of OA [overall, OA of the hip (HOA), and OA of the knee (KOA)], RA [overall, seronegative RA (nRA) and seropositive RA], and PsA was also acquired from the FinnGen Biobank Analysis. Causal Analysis Using Summary Effect Estimates (CAUSE) were further applied to verify the causality. RESULTS: UVMR results provided evidence for the causal relationship of time spent on watching TV with overall OA [odds ratio (OR) = 1.80, 95% confidence interval (CI) = 1.45-2.23], KOA (OR = 1.86, 95% CI = 1.45-2.39) and HOA (IVW-fixed: OR = 1.65, 95% CI =1.20-2.26). Similar associations were observed in the TV-overall RA and TV-pRA, and TV-PsA, but the CAUSE method results only supported the causal association of time spent TV watching with OA and KOA. Moreover, MVMR results showed indicated an independent causal effect of TV watching on OA (overall, KOA, and HOA). CONCLUSION: This study demonstrated the genetic causal association of prolonged TV watching time with overall OA and KOA risks.

Spondylodiscitis of lumbar complicated with spinal epidural abscess caused by Parvimonas micra: A case report and literature review. / å¾®å°å°å•èƒžèŒè °æ¤Žé—´ç›˜ç‚Žå¹¶æ¤Žç®¡å† ç¡¬è†œå¤–è„“è‚¿1例及文献回顾.

Spinal infection caused by Parvimonas micra (P. micra) is a rare infection. The characteristic imageology includes spondylodiscitis, spondylitis, paravertebral abscess, and epidural abscess. One case of spondylodiscitis of lumbar complicated with spinal epidural abscess caused by P. micra was admitted to the Department of Spinal Surgery, Xiangya Hospital, Central South University on February, 2023. This case is a 60 years old man with lower back pain and left lower limb numbness. MRI showed spondylitis, spondylodiscitis, and epidural abscess. The patient underwent debridement, decompression and fusion surgery. The culture of surgical sample was negative. P. micra was detected by metagenomic next-generation sequencing (mNGS). The postoperative antibiotic treatment included intravenous infusion of linezolid and piperacillin for 1 week, then intravenous infusion of ceftazidime and oral metronidazole for 2 weeks, followed by oral metronidazole and nerofloxacin for 2 weeks. During the follow-up, the lower back pain and left lower limb numbness was complete remission. Spinal infection caused by P. micra is extremely rare, when the culture is negative, mNGS can help the final diagnosis.

A time-dependent offset field approach to simulating realistic interactions between beating hearts and surgical devices in virtual interventional radiology.

Endovascular interventional radiology (IR) is a minimally invasive procedure for the treatment of vascular diseases. This procedure requires physicians to be highly skilled at manipulating interventional devices under the guidance of two-dimensional X-ray imaging. By offering a non-error-sensitive and radiation-free environment, a virtual reality-based simulator provides a promising alternative for surgical skills training and surgery planning. Building a realistic and interactive simulator is a challenging task. To achieve better realism, this paper proposes a novel method of simulating the heartbeat for both standard and patient-specific anatomical data. A time-dependent offset field approach is proposed to efficiently and stably simulate the interactive behavior between the dynamic heart mesh and surgical devices. For medical imaging simulation, we propose a GPU-based linear depth subtraction method to approximate fluoroscopic images based on the attenuation of the X-ray. On this basis, a topology-based flow map method is proposed to simulate the propagation of the contrast medium in angiography. Experimental results show that the proposed algorithm can simulate heartbeat stably for meshes with varying geometrical shapes and complexities. In efficiency, the dynamic heart mesh can interact with surgical devices stably at 60 frames/s. Under the simulated fluoroscopic imaging effect, the injected contrast medium can realistically visualize both dynamic and static vessels. In a face validity by medical students and clinicians, the category of effectiveness score 8.35 out of 10 on average, demonstrating that our simulator is useful in surgical skills training and surgery planning.

Automated assessment of balance: A neural network approach based on large-scale balance function data.

Balance impairment (BI) is an important cause of falls in the elderly. However, the existing balance estimation system needs to measure a large number of items to obtain the balance score and balance level, which is less efficient and redundant. In this context, we aim at building a model to automatically predict the balance ability, so that the early screening of large-scale physical examination data can be carried out quickly and accurately. We collected and sorted out 17,541 samples, each with 61-dimensional features and two labels. Moreover, using this data a lightweight artificial neural network model was trained to accurately predict the balance score and balance level. On the premise of ensuring high prediction accuracy, we reduced the input feature dimension of the model from 61 to 13 dimensions through the recursive feature elimination (RFE) algorithm, which makes the evaluation process more streamlined with fewer measurement items. The proposed balance prediction method was evaluated on the test set, in which the determination coefficient (R2) of balance score reaches 92.2%. In the classification task of balance level, the metrics of accuracy, area under the curve (AUC), and F1 score reached 90.5, 97.0, and 90.6%, respectively. Compared with other competitive machine learning models, our method performed best in predicting balance capabilities, which is especially suitable for large-scale physical examination.

The causal association of polyunsaturated fatty acids with allergic disease: A two-sample Mendelian randomization study.

Objectives: Previous studies have reported a potential association of polyunsaturated fatty acids (PUFAs) levels with allergic disease risk and the possible benefit of PUFAs supplementation on allergic disease prevention. This study was performed to estimate the genetic association between PUFAs and allergic diseases using the method of both univariable and multivariable two-sample Mendelian randomization (MR). Methods: As indicators of the PUFAs levels, we included the omega-3, omega-6, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), linoleic acid (LA), and the ratio of omega-6 to omega-3 (omega-6:3). Summarized statistics of genome-wide association studies (GWASs) for these PUFAs were obtained from the United Kingdom Biobank and the Twins United Kingdom cohort. Genetic data relating to allergic diseases, including atopic dermatitis (AD), allergic rhinitis (AR), allergic conjunctivitis (AC), allergic urticaria (AU) and asthma, were accessed from the FinnGen biobank analysis. Odds ratios and 95% CIs were used to express the impact. Results: The MR results denoted a genetic association between the genetically determined increase in omega-3 levels and the decreased risk of some allergic diseases including AD (OR: 0.863; 95% CI: 0.785 to 0.949; p = 3.86E-03), AC (OR:0.720; 95% CI: 0.547 to 0.947; p = 1.87E-02) and AU (OR:0.821; 95% CI: 0.684 to 0.985; p = 3.42E-02), while omega-6 and DHA level was only found to have negatively correlation with risk of AC with ORs of 0.655 (95% CI: 0.445 to 0.964; p = 3.18E-02) and 0.671 (95% CI 0.490 to 0.918; p = 1.25E-02), respectively. Omega-6:3 were causally significantly associated with the increased risk of AD (OR:1.171; 95% CI: 1.045 to 1.312; p = 6.46E-03) and AC (IVW: OR:1.341; 95% CI: 1.032 to 1.743; p = 2.83E-02). After adjustment of age, economic level, BMI, smoking and alcohol behaviors in the multivariable MR analysis, a direct causal protective effect of omega-3 on AD and AC, as well as a direct causal association between DHA and AD were observed. Omega-6:3 was also found to be directly associated with an increased risk of AD and AC. No association was found of EPA or LA with allergic diseases. Conclusion: Higher PUFA concentrations (omega-3, omega-6, DHA) and lower omega-6:3 ratios were genetically associated with a lower risk of some allergic diseases.

Strategy and Efficacy of Surgery for Congenital Cervicothoracic Scoliosis with or without Hemivertebra Osteotomy.

OBJECTIVE: Cervicothoracic scoliosis will cause severe deformities in the early stage, and its structure is complex and the surgical methods are varied. The purpose of this research is to explore the indication and analyze the corrective effect of the two different posterior approach surgical strategies, including correction with fusion and hemivertebra osteotomy, for congenital cervicothoracic scoliosis deformities in children and adolescents. METHODS: This was a retrospective study of 21 patients with cervicothoracic scoliosis who received surgical treatment from January 2010 to June 2020, including nine cases of posterior hemivertebra osteotomy and fusion surgery and 12 cases of posterior correction and fusion alone. The Cobb angle, T1 tilt angle, clavicular angle, neck tilt angle, radiographic shoulder height, sagittal vertical axis, coronal balance distance, and local kyphosis angle were measured preoperatively, postoperatively, and at the last follow-up. Posterior approach hemivertebra resection or correction with fusion surgery was adopted based on the different individual characteristics of deformity such as main curve Cobb angle, growth potential, and flexibility. Patients were divided into two groups (osteotomy group and nonosteotomy group) according to whether a hemivertebra osteotomy was performed, and the corrective results in the two groups were compared. Paired-sample t tests or independent-sample t tests were used. RESULTS: The median follow-up after surgery of the 21 patients was 36 months (range, 18-72 months). The Cobb angle was corrected from 45.81° ± 14.23° preoperatively to 10.48° ± 5.56° postoperatively (correction rate, 77.78% ± 8.93%). The T1 tilt angle decreased from 15.26° ± 7.08° preoperatively to 3.33° ± 2.14° postoperatively (correction rate,73.42% ± 21.86%). The radiographic shoulder height was corrected from 1.13 ± 0.74 cm preoperatively to 0.52 ± 0.42 cm postoperatively (correction rate, 39.51% ± 35.65%). The clavicular angle improved from 2.52° ± 1.55° preoperatively to 1.16° ± 0.96° postoperatively (correction rate, 47.18% ± 35.84%). No significant differences were found at the last follow-up (p > 0.05). The Cobb angle of the main curve, T1 tilt angle, clavicular angle, cervical tilt angle, and shoulder height difference were similar in the two groups (p > 0.05). CONCLUSIONS: Posterior approach hemivertebra resection or correction with fusion surgery can be used in the treatment of congenital cervicothoracic scoliosis with satisfactory results, and the surgeon can make an individualized surgical plan according to individual characteristics of deformity.

Optimal Surgical Treatment Method for Anterior Cruciate Ligament Rupture: Results from a Network Meta-Analysis.

BACKGROUND Previous studies have shown that primary repair (PR) and anterior cruciate ligament reconstruction (ACLR) can effectively treat ACL injuries. Our study aimed to compare different treatments of ACL tears, including autograft, allograft, hybrid graft ACLR, and PR, by assessing clinical outcomes and adverse events. MATERIAL AND METHODS PubMed, Cochrane Library, Embase, and CNKI databases were searched and a frequentist-framework network meta-analysis was used. RESULTS Overall, PR with augmentation was superior to ACLR only for activity recovery (WMD 0.28 95%CI [0.07 to 0.49]), and there was no significant difference shown between PR without augmentation and ACLR. ACLR with irradiated allograft was a poor option for the treatment of ACL rupture, showing the weakest subjective evaluations and functional outcomes and worst safety profile. PR with or without augmentation provided fairly good postoperative efficacy results and produced less postoperative knee laxity than irradiated allograft ACLR (PR: standardized mean difference [SMD] -1.27 [-1.80 to -0.74]; ACLR: SMD -1.36 [-1.88 to -0.83]). However, PR without augmentation showed a high failure rate compared with autograft ACLR (autograft vs PR without augmentation: risk ratio 0.29 [0.10 to 0.85]). CONCLUSIONS For surgical treatment of ACL rupture, irradiated allograft ACLR had the worst efficacy and safety and is not recommended. PR may be an ideal treatment method in terms of efficacy but it is related to a significantly higher revision risk if without augmentation. Autograft ACLR may be the preferred method currently available for most patients requiring surgical treatment of ACL rupture.

Optimal administration strategies of tranexamic acid to minimize blood loss during spinal surgery: results of a Bayesian network meta-analysis.

BACKGROUND: Tranexamic acid (TXA) has been widely used for bleeding reduction in spinal surgery. Available evidence is insufficient to inform clinical decisions making and there remains a lack of comprehensive comparisons of dose regimens and delivery routes. This study is aimed to assess and compare different strategies regarding the involvement of TXA in spinal surgery for the optimal pathway of efficacy and safety. MATERIALS AND METHODS: Cochrane Library, PubMed, Embase, Scopus and CNKI were searched for the period from January 1990 to October 2021. A random-effect model was built in the Bayesian network meta-analysis. The surface under the cumulative ranking analysis (SUCRA) and clustering rank analysis was performed for ranking the effects. RESULTS: The current network meta-analysis incorporated data from 33 studies with 3302 patients. Combination administration showed superior effects on reducing intraoperative bleeding (SUCRA 78.78%, MD -129.67, 95% CI [(-222.33, -40.58)]) than placebo, and was ranked as top in reducing postoperative bleeding (SUCRA 86.91%, MD -169.92, 95% CI [(-262.71, -83.52)]), changes in haemoglobin (SUCRA 97.21%, MD -1.28, 95% CI [(-1.84, -0.73)]), and perioperative blood transfusion (SUCRA 93.23%, RR 0.10, 95% CI [(0.03, 0.25)]) simultaneously, and was shown as the best effectiveness and safety (cluster-rank value for IBL and VTE: 4057.99 and for TRF and VTE: 4802.26). CONCLUSIONS: Intravenous (IV) plus topical administration of TXA appears optimal in the reduction of perioperative bleeding and blood transfusion, while the local infiltration administration is not effective for blood conservation. Further studies are required to verify the current findings.

Optimal Biologic Drugs for the Treatment of Ankylosing Spondylitis: Results from a Network Meta-Analysis and Network Metaregression.

Background: Ankylosing spondylitis (AS) is a common immune-related systemic chronic inflammatory osteoarthropathy. Previous studies have proven that biologic agents, including IL-17A inhibitors (IL17Ai), TNF-α inhibitor FC fusion protein (TNFiFCP), or fully human monoclonal antibody (TNFiNMA) and JAK inhibitor (JAKi), are effective for AS treatment. Our study is aimed at comparing the clinical efficacy, tolerability, and safety of different biological agents, including novel IL-6 inhibitor (IL6i), IL-23 inhibitor (IL23i), and IL-17 A/F dual variable domain inhibitor (IL17AFi) in AS. Method: PubMed, Scopus, Embase, CNKI, and the Cochrane Library were systematically searched. A frequentist framework network meta-analysis with a random-effects model was performed. Ranking effects were calculated by surface under the cumulative ranking analysis (SUCRA) and cluster-rank analysis. Results: IL17AFi reported both the highest ASAS40 (SUCRA = 91.4%) and ASAS20 (SUCRA = 92.5%) response, while IL6i and IL23i reported the lowest responses (SUCRA = 6.6% and 19.9%, respectively). With the exceptions of IL6i (RR 0.60, 95% CI (0.22 to 1.67) for ASAS40 and 1.36 (0.71 to 2.58) for ASAS20) and IL23i (0.98 (0.68 to 1.40) for ASAS40 and 0.91 (0.70 to 1.19) for ASAS20), all biological drugs demonstrated statistically superior ASAS responses than placebo. TNFiFMA performed best in the suppression of disease activity (SUCRA = 77.4%, SMD 2.35, and 95% CI (1.11 to 3.59)) and functional improvement (SUCRA = 68.8%, SMD 1.67, and 95% CI (0.59 to 2.74)). There were no significant differences in tolerability or safety between biologic drugs and placebo. Conclusions: The novel IL-17 A/F dual variable domain inhibitor, bimekizumab, may be an ideal future treatment choice for AS, while IL-23 and IL-6 inhibitors demonstrate little potential in the treatment of AS. For patients with rapid disease progression and severe functional limitation, TNF-α inhibitors, especially infliximab, are safe and effective and could be a first-line treatment choice.

DNL-Net: deformed non-local neural network for blood vessel segmentation.

BACKGROUND: The non-local module has been primarily used in literature to capturing long-range dependencies. However, it suffers from prohibitive computational complexity and lacks the interactions among positions across the channels. METHODS: We present a deformed non-local neural network (DNL-Net) for medical image segmentation, which has two prominent components; deformed non-local module (DNL) and multi-scale feature fusion. The former optimizes the structure of the non-local block (NL), hence, reduces the problem of excessive computation and memory usage, significantly. The latter is derived from the attention mechanisms to fuse the features of different levels and improve the ability to exchange information across channels. In addition, we introduce a residual squeeze and excitation pyramid pooling (RSEP) module that is like spatial pyramid pooling to effectively resample the features at different scales and improve the network receptive field. RESULTS: The proposed method achieved 96.63% and 92.93% for Dice coefficient and mean intersection over union, respectively, on the intracranial blood vessel dataset. Also, DNL-Net attained 86.64%, 96.10%, and 98.37% for sensitivity, accuracy and area under receiver operation characteristic curve, respectively, on the DRIVE dataset. CONCLUSIONS: The overall performance of DNL-Net outperforms other current state-of-the-art vessel segmentation methods, which indicates that the proposed network is more suitable for blood vessel segmentation, and is of great clinical significance.

Causal Association Between Inflammatory Bowel Disease and Psoriasis: A Two-Sample Bidirectional Mendelian Randomization Study.

Background: Previous observational studies have found an association between inflammatory bowel disease (IBD) and psoriasis. Using the mendelian randomization (MR) approach, we aim to determine whether there was a causal association between IBD and psoriasis. Methods: We performed a two-sample MR with the genetic instruments identified for IBD and its main subtypes, Crohn's disease (CD) and ulcerative colitis (UC), from a genome-wide association study (GWAS) involving 25,042 cases with an IBD diagnosis and 34,915 controls. Summarized data for psoriasis were obtained from different GWAS studies which included 4510 cases and 212,242 controls without psoriasis. Causal estimates are presented as odds ratios (ORs) with 95% confidence intervals (CIs). Results: The overall outcome of MR analysis was to demonstrate that genetic predisposition to IBD was associated with an increased risk of psoriasis (OR: 1.1271; 95% CI: 1.0708 to 1.1864). Psoriatic arthritis (PsA) had a significant association with total IBD (OR: 1.1202; 95% CI: 1.0491 to 1.1961). Casual relationship was also identified for CD-psoriasis (OR: 1.1552; 95% CI: 1.0955 to 1.2182) and CD-PsA (OR: 1.1407; 95% CI: 1.0535 to 1.2350). The bidirectional analysis did not demonstrate that a genetic predisposition to psoriasis was associated with total IBD, although psoriasis showed association with CD (OR: 1.2224; 95% CI: 1.1710 to 1.2760) but not with UC. A genetic predisposition to PsA had a borderline association with IBD (OR: 1.0716; 95% CI: 1.0292 to 1.1157) and a suggestive association with CD (OR: 1.0667; 95% CI: 1.0194 to 1.1162). Conclusion: There appears to be a causal relationship between IBD and psoriasis, especially for PsA, but for psoriasis and IBD, only total psoriasis and PsA were associated with CD. Understanding that specific types of psoriasis and IBD constitute mutual risk factors facilitates the clinical management of two diseases.

A causal relationship between childhood obesity and risk of osteoarthritis: results from a two-sample Mendelian randomization analysis.

PURPOSE: It has been found that childhood obesity (CO) may play an important role in the onset and progression of osteoarthritis (OA). Thus we conducted this mendelian randomisation analysis (MR) to evaluate the causal association between childhood obesity and osteoarthritis. METHODS: Instrumental variables (IVs) were obtained from publicly available genome-wide association study datasets. The leave-one-out sensitivity test, MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO), and Cochran's Q test were used to confirm the heterogeneity and pleiotropy of identified IVs, then five different models, including the inverse variance weighted model (IVW), weighted median estimator model (WME), weighted model-based method (WM), MR-Egger regression model (MER), and MR-Robust Adjusted Profile Score (MRAPS) were applied in this MR analysis. RESULTS: After excluding all outliers identified by the MR-PRESSO test, no evident directional pleiotropy was found. Significant heterogeneity was found in the secondary MR and as a result, the multiplicative random-effect model was used. Significant causal association between CO and OA (OR 1.0075, 95% CI [1.0054, 1.0010], p = 8.12 × 10-13). The secondary MR also revealed that CO was causally associated with knee OA (OR 1.1067, 95% CI [1.0769, 1.1373], p = 3.30 × 10-13) and hip OA (OR 1.1272, 95% CI [1.0610, 1.1976], p = 1.07 × 10-4). The accuracy and robustness of these findings were confirmed by sensitivity tests. CONCLUSION: There appears to be a causal relationship between childhood obesity and OA. Our results indicate that individuals with a history of childhood obesity require specific clinical attention to prevent the development of knee and hip OA.

Evaluating the Causal Effects of TIMP-3 on Ischaemic Stroke and Intracerebral Haemorrhage: A Mendelian Randomization Study.

Aim: Since tissue inhibitors of matrix metalloproteinase 3 (TIMP-3) was reported to be a potential risk factor of atherosclerosis, aneurysm, hypertension, and post-ischaemic neuronal injury, it may also be a candidate risk factor of stress. Therefore, this study was designed to explore the causal role of TIMP-3 in the risk of ischaemic stroke (IS) and intracerebral haemorrhage (ICH), which are the two main causes of stress via this Mendelian Randomisation (MR) study. Methods: The summarised data of TIMP-3 level in circulation was acquired from the Cooperative Health Research in the Region of Augsburg public database and the outcome of IS and ICH was obtained from genome-wide association studies conducted by MEGASTROKE and the International Stroke Genetics Consortium, respectively. Five statistical methods including inverse-variance weighting, weighted-median analysis, MR-Egger regression, MR Pleiotropy RESidual Sum and Outlier test, and MR-Robust Adjusted Profile Score were applied to evaluate the causal role of TIMP-3 in the occurrence of IS and ICH. Inverse-variance weighting was applied for assessing causality. Furthermore, heterogeneity and pleiotropic tests were utilised to confirm the reliability of this study. Results: We found that TIMP-3 could be a positively causal relationship with the incidence of IS (OR = 1.026, 95% CI: 1.007-1.046, p = 0.0067), especially for the occurrence of small vessel stroke (SVS; OR = 1.045, 95% CI: 1.016-1.076, p = 0.0024). However, the causal effects of TIMP-3 on another IS subtype cardioembolic stroke (CES; OR = 1.049, 95% CI: 1.006-1.094, p = 0.024), large artery stroke (LAS; OR = 1.0027, 95% CI: 0.9755-1.0306, p = 0.849) and ICH (OR = 0.9900, 95% CI: 0.9403-1.0423, p = 0.701), as well as ICH subtypes were not observed after Bonferroni corrections (p = 0.00714). Conclusion: Our results revealed that high levels of circulating TIMP-3 causally increased the risk of developing IS and SVS, but not CES, LAS, ICH, and all ICH subtypes. Further investigation is required to elucidate the underlying mechanism.