Search Results (235)

The management of adult spinal deformity (ASD) has evolved dramatically over the past century, transitioning from external bracing and in situ fusion to complex, technology-driven surgical interventions. This review traces the historical development of spinal deformity correction and highlights contemporary enabling technologies that are redefining the surgical landscape. Advances in stereoradiographic imaging now allow for precise, low-dose three-dimensional assessment of spinopelvic parameters and segmental bone density, facilitating individualized surgical planning. Robotic assistance and intraoperative navigation improve the accuracy and safety of instrumentation, while patient-specific rods and interbody implants enhance biomechanical conformity and alignment precision. Machine learning and predictive modeling tools have emerged as valuable adjuncts for risk stratification, surgical planning, and outcome forecasting. Minimally invasive deformity correction strategies, including anterior column realignment and circumferential minimally invasive surgery (cMIS), have demonstrated equivalent clinical and radiographic outcomes to traditional open surgery with reduced perioperative morbidity in select patients. Despite these advancements, complications such as proximal junctional kyphosis and failure remain prevalent. Adjunctive strategies—including ligamentous tethering, modified proximal fixation, and vertebral cement augmentation—offer promising preventive potential. Collectively, these innovations signal a paradigm shift toward precision spine surgery, characterized by data-informed decision-making, individualized construct design, and improved patient-centered outcomes in spinal deformity care. Full article

One of the key elements in the analysis of gene expression and its post-translational regulation is miRNAs. Degradome-seq analyses are performed to analyze the cleavage of target RNAs in the transcriptome. This work presents the first degradome-seq library preparation protocol that enables successful construction of libraries, even from highly degraded RNA samples with RIN below 3, thus significantly expanding the possibilities for research when working with low-quality material. The developed protocol improves the efficiency of library preparation in degradome-seq analysis used to identify miRNA targets, reduces library preparation time, and lowers the cost of purchasing reagents by using reagents from the RNA-seq library preparation kit and proprietary-designed primers. A crucial feature of this new protocol is optimizing the purification step for short library fragments, which increases the yield of correctly sized fragments compared to previously used methods. This is achieved by implementing an original method involving tube-spin purification with gauze and precipitation using sodium acetate with glycogen, greatly enhancing recovery efficiency—a factor especially critical when working with degraded RNA. Cloning to a plasmid and sequencing of the inserted fragment verified the correctness of the library preparation using the developed protocol. This protocol represents a groundbreaking tool for degradome research, enabling the construction and sequencing of degradome libraries, even from degraded samples previously considered unsuitable for such analyses. This is due to the use of residues from the sRNA-seq library kit. It noticeably reduces the cost of library construction. The precision of the excised fragment after electrophoresis was performed during the procedure to isolate fragments of the correct length, which was improved using additional size markers. Compared to previously used methods, optimizing the purification method of degradome-seq libraries allowed an increase in the yield of fragments obtained. Full article

Ferroptosis is a type of cell death executed by phospholipid peroxidation in an iron-dependent manner. Ferroptosis plays a central role in inhibiting tumor growth, enhancing the immune response, and is now considered a strategy to combat resistance to anticancer therapies. The oncosuppressor p53 is one of the major regulators of ferroptosis and can either promote or inhibit ferroptosis, depending on the context and/or extent of the damage. p53 governs the transcription of many genes that modulate cell susceptibility to ferroptosis, using this manner of death to fulfill its role as tumor suppressor. The diverse functions of p53 are related to non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), since they can either regulate p53 or be regulated by p53. Therefore, an intricate metabolic network between ncRNAs and p53 ensures the correct response. In this review, we will discuss recent studies on the molecular interplay between p53-mediated ferroptosis and ncRNAs and how this contributes directly or indirectly to the outcome of ferroptosis. Full article

Background: In the emergency setting, many diagnostic pathways incorporate change in high-sensitivity cardiac troponin (hs-cTn) concentrations (i.e., the delta) to classify patients as low-risk (rule-out) or high-risk (rule-in) for possible myocardial infarction (MI). However, the impact of analytical variation on the delta for correct classification is unknown, especially at concentrations below and around the 99th percentile. Our objective was to assess the impact of delta variation for correct risk classification across the European Society of Cardiology (ESC 0/1 h and 0/2 h), the High-STEACS, and the common change criteria (3C) pathways. Methods: A yearlong accuracy study for hs-cTnT was performed where laboratories across Canada tested three patient-based samples (level 1 target value = 6 ng/L, level 2 target value = 9 ng/L, level 3 target value = 12 ng/L) monthly across 41 different analyzers. The assigned low-delta between levels 1 and 2 was 3 ng/L (i.e., 9 − 6 = 3 ng/L) and the assigned high-delta between levels 1 and 3 was 6 ng/L (i.e., 12 − 6 = 6 ng/L). The low- and high-deltas for each analyzer were determined monthly from the measured values, with the difference calculated from the assigned deltas. The obtained deltas were then assessed via the different pathways on correct classification (i.e., percent correct with 95% confidence intervals, CI) and using non-parametric analyses. Results: The median (interquartile range) difference between the measured versus assigned low-delta (n = 436) and high-delta (n = 439) was −1 ng/L (−1 to 0). The correct classification differed among the pathways. The ESC 0/1 h pathway yielded the lowest percentage of correct classification at 35.3% (95% CI: 30.8 to 40.0) for the low-delta and 90.0% (95% CI: 86.8 to 92.6) for the high-delta. The 3C and ESC 0/2 h pathways yielded higher and equivalent estimates on correct classification: 95.2% (95% CI: 92.7 to 97.0) for the low-delta and 98.2% (95% CI: 96.4 to 99.2) for the high-delta. The High-STEACS pathway yielded 99.5% (95% CI: 98.4 to 99.9) of correct classifications for the high-delta but only 36.2% (95% CI: 31.7 to 40.9) for the low-delta. Conclusions: Analytical variation will impact risk classification for MI when using hs-cTn deltas alone per the pathways. The 3C and ESC 0/2 h pathways have <5% misclassification when using deltas for hs-cTnT in this dataset. Additional studies with different hs-cTnI assays at concentrations below and near the 99th percentile are warranted to confirm these findings. Full article

Background: A significant proportion of post-myocardial infarction (MI) patients do not reach target low-density lipoprotein cholesterol (LDL-C) levels. Suboptimal LDL-C reduction is often attributed to poor adherence to pharmacological therapy and lifestyle recommendations. Methods: In a prospective registry of 179 post-MI patients who completed a Phase 2 Cardiac Rehabilitation Program (CRP), we evaluated the characteristics and predictors of suboptimal LDL-C reduction. Key indicators were assessed before and after CRP: adherence to the Mediterranean diet (using the PREDIMED questionnaire), weekly physical activity (via the IPAQ questionnaire), therapeutic adherence (using the Morisky–Green questionnaire), and peak oxygen consumption (VO₂) on exercise testing. Lipid-lowering therapy (LLT) and LDL-C were recorded prior to MI and both before and after Phase 2 CRP. At the end of Phase 2, we analyzed the difference between measured and theoretical LDL-C (basal LDL-C minus expected LDL-C reduction by LLT), which was defined as “residual difference in LDL-C” (RD-LDL-C). We analyzed the predictors of positive RD-LDL-C (lower than theoretically expected). Results: After CRP, 54 (30.2%) patients exhibited positive RD-LDL-C. Within this subgroup, LLT was uptitrated, and patients received more potent LLT at the conclusion of CRP (theoretical potency: 69.81 ± 7.07 vs. 66.41 ± 7.48%, p = 0.005). However, they were less likely to reach the target LDL-C level <55 mg/dL (66.7% vs. 93.6%, p < 0.001). Male sex (HR 17.96 [2.15, 149.92], p = 0.008) and higher lipoprotein (a) levels (HR 1.02 [1.01, 1.03] per mg/dL, p = 0.001) were associated with a positive RD-LDL-C. Conversely, diabetes mellitus (HR 0.17 [0.06, 0.51], p = 0.002), higher corrected basal LDL-C levels (HR 0.98 [0.97, 0.99] per mg/dL, p = 0.001), and supervised in-hospital training during CRP (HR 0.28 [0.09, 0.86], p = 0.03) were associated with a reduced probability of positive RD-LDL-C. No association was found with adherence to the Mediterranean diet (88.1%), therapeutic adherence (89.1%), reported weekly physical activity (median 3545 [1980, 6132] metabolic equivalents per week), or change in peak VO₂. Conclusions: More than one-third of post-MI patients demonstrated lower than expected LDL-C reduction (positive RD-LDL-C) following CRP, a finding that could not be attributed to poor adherence to pharmacological therapy or lifestyle recommendations. These findings suggest that a personalized approach to prescribing and uptitrating LLT may help achieve LDL-C targets, particularly in MI patients with healthy lifestyle habits who exhibit a lower response to LLT. Full article

Preeclampsia (PE) remains a significant obstetric challenge, having complex pathophysiology and limited early diagnostic and therapeutic options. MicroRNAs (miRNAs) have emerged as critical regulators in PE, offering insight into the molecular mechanisms underlying placental dysfunction and impaired maternal adaptation. Differentially expressed miRNAs in both placental tissue and maternal circulation, such as miR-155, play key roles in regulating angiogenesis, trophoblast invasion, and inflammatory pathways, all of which are central to the development of PE. Ongoing investigations increasingly highlight miRNAs as promising non-invasive molecular indicators for the early diagnosis and risk stratification of PE. Furthermore, therapeutic strategies targeting miRNA pathways using mimics or inhibitors show promise in correcting molecular dysfunctions and improving maternal and fetal outcomes. However, clinical translation faces several challenges, including targeted delivery, off-target effects, and the assessment of long-term efficacy. Overall, miRNAs hold significant potential as both diagnostic tools and therapeutic agents, marking a promising direction for improving care in PE pregnancies. Full article

Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a severe hepatocellular cholestasis due to biallelic variations in the ABCB11 (ATP-binding cassette B11) gene encoding the canalicular bile salt export pump (BSEP). Some missense variants identified in patients with PFIC2 do not traffic properly to the canalicular membrane. However, 4-phenybutyrate (4-PB) has been shown in vitro to partially correct the mis-trafficking of selected variants, resulting in an improvement of the medical conditions of corresponding PFIC2 patients. Herein, we report the ability of 4-PB analogous or homologous drugs and of non-4-PB related chemical correctors to rescue the canalicular expression and the activity of the folding-defective Abcb11^R1128C variant. New compounds, either identified by screening a chemical library or designed by structural homology with 4-PB (or its metabolites) and synthesized, were evaluated in vitro for their ability to (i) correct the canalicular localization of Abcb11^R1128C after transfection in hepatocellular polarized cell lines; (ii) restore the ³H-taurocholate transport of the Abcb11^R1128C protein in Madin–Darby canine kidney (MDCK) cells stably co-expressing Abcb11 and the sodium taurocholate co-transporting polypeptide (Ntcp/Slc10A1). Glycerol phenylbutyrate (GPB), phenylacetate (PA, the active metabolite of 4-PB), 3-hydroxy-2-methyl-4-phenylbutyrate (HMPB, a 4-PB metabolite analog chemically synthesized in our laboratory) and 4-oxo-1,2,3,4-tetrahydro-naphthalene-carboxylate (OTNC, from the chemical library screening) significantly increased the proportion of canalicular Abcb11^R1128C protein. GPB, PA, ursodeoxycholic acid (UDCA), alone or in combination with 4-PB, suberoylanilide hydroxamic acid (SAHA), C18, VX-445, and/or VX-661, significantly corrected both the traffic and the activity of Abcb11^R1128C. Such correctors could represent new pharmacological insights for improving the condition of patients with ABCB11 deficiency due to missense variations affecting the transporter’s traffic. Full article

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons, which causes muscle atrophy. Genetic forms of ALS are recorded only in 10% of cases. However, over the past decade, studies in genetics have substantially contributed to our understanding of the molecular mechanisms underlying ALS. The identification of key mutations such as SOD1, C9orf72, FUS, and TARDBP has led to the development of targeted therapy that is gradually being introduced into clinical trials, opening up a broad range of opportunities for correcting these mutations. In this review, we aimed to present an extensive overview of the currently known mechanisms of motor neuron degeneration associated with mutations in these genes and also the gene therapy methods for inhibiting the expression of their mutant proteins. Among these, antisense oligonucleotides, RNA interference (siRNA and miRNA), and gene-editing (CRISPR/Cas9) methods are of particular interest. Each has shown its efficacy in animal models when targeting mutant genes, whereas some of them have proven to be efficient in human clinical trials. Full article

Congenital diaphragmatic hernia (CDH) remains associated with high morbidity and mortality, primarily due to pulmonary hypoplasia and hypertension. Current antenatal diagnostic methods, such as ultrasound and magnetic resonance imaging (MRI), are unable to assess the severity of defects in lung and pulmonary vascular structures, which are critical determinants of the diverse phenotypes of CDH. Aberrant epigenetic regulation of lung development during gestation is believed to play a significant role in the pathogenesis of CDH. In this study, we aimed to identify miRNA patterns in amniotic fluid capable of categorizing CDH-fetuses for the personalized selection of effective treatment strategies at the antenatal and/or postnatal stages. Using deep sequencing and quantitative real-time polymerase chain reaction (PCR), we identified a set of miRNAs—miR-485-3p, miR-320b, miR-320a-3p, miR-221-3p, miR-200b-3p, miR-100-5p, miR-92a-3p, miR-30c-5p, miR-26a-5p, and let-7c-5p—whose reduced expression in amniotic fluid at 19–24 weeks of gestation allowed us to categorize fetuses with CDH into two distinct groups: one significantly different from the control group (non-CDH) and the other closely resembling it. Notably, no significant correlations were found between the content of these miRNAs in amniotic fluid and severity of lung hypoplasia assessed by ultrasound or MRI. However, there was significant positive correlation between the level of each of the miRNAs with that of miR-200b-3p, whose role in ensuring proper bronchopulmonary tissue structure during prenatal development—as well as its therapeutic potential for CDH-associated hypoplastic lungs—has been previously demonstrated. These findings lay the groundwork for the future development of genetically engineered drug formulations designed for antenatal endotracheal administration to correct abnormal miRNA levels in lung tissue and mitigate the progression of pulmonary hypoplasia and hypertension in CDH-fetuses. Full article

Background: Minimally invasive surgery (MIS) is an advanced surgical technique that relies on a camera to provide the surgeon with a visual field. When the camera rotates along its longitudinal axis, the horizon of the surgical view tilts, increasing the difficulty of the procedure and the cognitive load on the surgeon. To address this, we proposed training a convolutional neural network (CNN) to detect camera rotation, laying the groundwork for the automatic correction of this issue during MIS procedures. Methods: We collected trans-nasal MIS procedure videos from YouTube and labeled each frame as either “tilted” or “non-tilted”. The dataset consisted of 2116 video frames, with 497 frames labeled as “tilted” and 1619 frames as “non-tilted”. This dataset was randomly divided into three subsets: training (70%), validation (20%), and testing (10%) Results: The ResNet50 was trained on the dataset for 10 epochs, achieving an accuracy of 96.9% at epoch 6 with a validation loss of 0.0242 before validation accuracy began to decrease. On the test set, the model achieved an accuracy of 96% with an average loss of 0.0256. The final F1 score was 0.94, and the Matthews Correlation Coefficient was 0.9168, with no significant bias toward either class. The trained ResNet50 model demonstrated a high success rate in predicting significant camera rotation without favoring the more frequent class in the dataset. Conclusions: The trained CNN accurately detected camera rotation with high precision, establishing a foundation for developing an automatic correction system for camera rotation in MIS procedures. Full article

Fibrosing disorders including idiopathic pulmonary fibrosis (IPF) are progressive irreversible diseases, often with poor prognoses, characterized by the accumulation of excessive scar tissue and extracellular matrix. Translational regulation has emerged as a critical aspect of gene expression control, and the dysregulation of key effectors is associated with disease pathogenesis. This review examines the current literature on translational regulators in IPF, focusing on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and RNA transcript modifications including alternative polyadenylation and chemical modification. Some of these translational regulators potentiate fibrosis, and some of the regulators inhibit fibrosis. In IPF, some of the profibrotic regulators are upregulated, and some of the antifibrotic regulators are downregulated. Correcting these defects in IPF-associated translational regulators could be an intriguing avenue for therapeutics. Full article