Clinical Relevance Research Articles

AbAMPdb: a database of Acinetobacter baumannii specific antimicrobial peptides.

Acinetobacter baumannii has emerged as a prominent nosocomial pathogen, exhibiting a progressive rise in resistance to therapeutic interventions. This rise in resistance calls for alternative strategies. Here, we propose an alternative yet specialized resource on antimicrobial peptides (AMPs) against A. baumannii. Database 'AbAMPdb' is the manually curated collection of 300 entries containing the 250 experimental AMP sequences and 50 corresponding synthetic or mutated AMP sequences. The mutated sequences were modified with reported amino acid substitutions intended for decreasing the toxicity and increasing the antimicrobial potency. AbAMPdb also provides 3D models of all 300 AMPs, comprising 250 natural and 50 synthetic or mutated AMPs. Moreover, the database offers docked complexes comprising 5000 AMPs and their corresponding A. baumannii target proteins. These complexes, accessible in Protein Data Bank format, enable the 2D visualization of the interacting amino acid residues. We are confident that this comprehensive resource furnishes vital information concerning AMPs, encompassing their docking interactions with virulence factors and antibiotic resistance proteins of A. baumannii. To enhance clinical relevance, the characterized AMPs could undergo further investigation both in vitro and in vivo. Database URL: https://abampdb.mgbio.tech/.

Latent class analysis-derived classification improves the cancer-specific death stratification of lymphomas: A large retrospective cohort study.

Lymphomas have diverse etiologies, treatment approaches, and prognoses. Accurate survival estimation is challenging for lymphoma patients due to their heightened susceptibility to non-lymphoma-related mortality. To overcome this challenge, we propose a novel lymphoma classification system that utilizes latent class analysis (LCA) and incorporates demographic and clinicopathological factors as indicators. We conducted LCA using data from 221,812 primary lymphoma patients in the Surveillance, Epidemiology, and End Results (SEER) database and identified four distinct LCA-derived classes. The LCA-derived classification efficiently stratified patients, thereby adjusting the bias induced by competing risk events such as non-lymphoma-related death. This remains effective even in cases of limited availability of cause-of-death information, leading to an enhancement in the accuracy of lymphoma prognosis assessment. Additionally, we validated the LCA-derived classification model in an external cohort and observed its improved prognostic stratification of molecular subtypes. We further explored the molecular characteristics of the LCA subgroups and identified potential driver genes specific to each subgroup. In conclusion, our study introduces a novel LCA-based lymphoma classification system that provides improved prognostic prediction by accounting for competing risk events. The proposed classification system enhances the clinical relevance of molecular subtypes and offers insights into potential therapeutic targets.

Dynamic contrast-enhanced MRA of the aorta using a Golden-angle RAdial Sparse Parallel (GRASP) sequence: comparison with conventional time-resolved cartesian MRA (TWIST).

To compare the application of two contrast-enhanced time-resolved magnetic resonance angiography sequences on an aortic disease patient cohort: the conventional Cartesian-sampling-based, Time-resolved angiography With Interleaved Stochastic Trajectories (TWIST) sequence, and the radial-sampling-based Golden-angle RAdial Sparse Parallel (GRASP) sequence. TWIST is highly sensitive to patient movement, which can lead to blurring and reduced sharpness of vascular structures, particularly in dynamic regions like the aorta. Such motion artifacts can compromise diagnostic accuracy. Radial-sampling-based techniques are less sensitive to motion than cartesian sampling and are expected to improve the image quality in body parts subjected to motion. 30 patients (60.9 ± 16.1y.o.) with various aortic diseases underwent a 1.5T magnetic resonance angiography examination. Assessment of image quality in the ascending aorta (AA), descending aorta (DA), and abdominal aorta (AbA) on a 4-point Likert scale (1 = excellent, 4 = non-diagnostic) as well as max. aortic diameters (Dmax) were performed. T-test and multilevel mixed-effect proportional-odds models were used for the image analysis. GRASP offered superior depiction of vascular structures in terms of vascular contrast for qualitative analysis(TWIST, reader 1: 1.6 ± 0.5; reader 2: 1.9 ± 0.4; reader 3: 1.1 ± 0.4; GRASP, reader 1: 1.5 ± 0.5; reader 2: 1.4 ± 0.5; reader 3: 1.0 ± 0.2) and vessel sharpness for qualitative (TWIST, reader 1: 1.9 ± 0.6; reader 2: 1.6 ± 0.6; reader 3: 2.0 ± 0.3; GRASP, reader 1: 1.4 ± 0.6; reader 2: 1.2 ± 0.4; reader 3: 1.3 ± 0.6) and quantitative analysis (TWIST, AA = 0.12 ± 0.04, DA = 0.12 ± 0.03, AbA = 0.11 ± 0.03; GRASP, AA = 0.20 ± 0.05, DA = 0.22 ± 0.06, AbA=0.20 ± 0.05). Streaking artefacts of GRASP were more visible compared to TWIST (TWIST, reader 1: 2.2 ± 0.6; reader 2: 1.9 ± 0.3; reader 3: 2.0 ± 0.5; GRASP, reader 1: 2.6 ± 0.6; reader 2: 2.3 ± 0.5; reader 3: 2.8 ± 0.6).Aortic Dmax comparison among the sequence showed no clinical relevance. GRASP outperformed TWIST in SNR, vessel sharpness, and reduction in image blurring; streaking artefacts were stronger with GRASP, but did not affect diagnostic image quality.

Targeting Canonical Wnt-signaling Through GSK-3β in Arrhythmogenic Cardiomyopathy: Conservative or Progressive?

Arrhythmogenic cardiomyopathy is a primary myocardial disease and a major cause of sudden death in all populations of the world. Canonical Wnt signalling is a critical pathway controlling numerous processes including cellular differentiation, hypertrophy and development. GSK3β is a ubiquitous serine/threonine kinase, which acts downstream of Wnt to promote protein ubiquitination and proteasomal degradation. Several studies now suggest that inhibiting GSK3β can prevent and reverse key pathognomonic features of ACM in a range of experimental models. However, varying concerns are reported throughout the literature including the risk of paradoxical arrhythmias, cancer and off-target effects in upstream or downstream pathways. CLINICAL RELEVANCE: In light of the start of the phase 2 TaRGET clinical trial, designed to evaluate the potential therapeutic efficacy of GSK3β inhibition in patients with arrhythmogenic cardiomyopathy, this report aims to review the advantages and disadvantages of this strategy.

Shank3 mutation impairs glutamate signaling and myelination in ASD mouse model and human iPSC-derived OPCs.

Autism spectrum disorder (ASD) is characterized by social and neurocognitive impairments, with mutations of the SHANK3 gene being prominent in patients with monogenic ASD. Using the InsG3680 mouse model with a Shank3 mutation seen in humans, we revealed an unknown role for Shank3 in postsynaptic oligodendrocyte (OL) features, similar to its role in neurons. This was shown by impaired molecular and physiological glutamatergic traits of InsG3680-derived primary OL cultures. In vivo, InsG3680 mice exhibit significant reductions in the expression of key myelination-related transcripts and proteins, along with deficits in myelin ultrastructure, white matter, axonal conductivity, and motor skills. Last, we observed significant impairments, with clinical relevance, in induced pluripotent stem cell-derived OLs from a patient with the InsG3680 mutation. Together, our study provides insight into Shank3's role in OLs and reveals a mechanism of the crucial connection of myelination to ASD pathology.

Relationship between radiation dose and cerebral microbleed formation in dogs with intracranial tumors.

Cerebral microbleeds (CMBs) are a possible sequela in human brain tumor patients treated with radiation therapy (RT). No such association is reported in dogs. To investigate whether CMBs occur in dogs after radiotherapy, and if there is an association between number and dose, and an increase over time. Thirty-four client-owned dogs irradiated for primary intracranial neoplasia. ≥2 magnetic resonance imaging (MRI) scans including susceptibility-weighted imaging (SWI) were required. Retrospective, observational, single-center study. Cerebral microbleeds identified on 3 T SWI were counted within the entire brain, and within low- (<20 Gy), intermediate- (20-30 Gy), and high- (>30 Gy) dose regions. A generalized linear mixed-effects model was used to analyze the relationship between the CMBs count and the predictor variables (irradiation dose, time after treatment). Median follow-up time was 12.6 months (range, 1.8-37.6 months). Eighty-three MR scans were performed. In 4/15 dogs (27%, 95% CI, 10%-52%) CMBs were present at baseline. ≥1 CMBs after RT were identified in 21/34 dogs (62%, 95% CI, 45%-77%). With each month, the number of CMBs increased by 14% (95% CI, 11%-16%; P < .001). The odds of developing CMBs in the high-dose region are 4.7 times (95% CI, 3.9-5.6; P < .001) greater compared with the low-dose region. RT is 1 possible cause of CMBs formation in dogs. Cerebral microbleeds are most likely to occur in the peritumoral high-dose volume, to be chronic, and to increase in number over time. Their clinical relevance remains unknown.

Prospective cohort study on the clinical significance of interferon-γ, D-dimer, LDH, and CRP tests in children with severe mycoplasma pneumonia.

Mycoplasma pneumoniae is a significant cause of respiratory infections in children, often leading to severe pneumonia. This study aimed to assess the clinical relevance of interferon-gamma (interferon-γ), D-dimer, lactate dehydrogenase (LDH), and C-reactive protein (CRP) as biomarkers in the severity of mycoplasma pneumonia in pediatric patients. In this prospective study, 203 pediatric patients with mycoplasma pneumonia were classified into mild (123 patients) and severe (80 patients) groups. Biomarkers including interferon-γ, D-dimer, LDH, and CRP were measured and analyzed. Statistical methods employed included Pearson and Spearman correlation analyses, logistic regression, and receiver operating characteristic curve analysis. The severe group exhibited significantly higher median and interquartile ranges for interferon-γ, D-dimer, LDH, and CRP compared to the mild group. Logistic regression identified IL-10, IL-6, interferon-γ, tumor necrosis factor-alpha, D-dimer, and LDH as independent predictors of severity, with the model achieving 92% accuracy. Receiver operating characteristic curve analysis showed optimal diagnostic efficacy for interferon-γ, D-dimer, and LDH, with the best threshold values being 8.11, 0.64, and 379, respectively. A significant positive correlation was observed between IL-6 and LDH, as well as between interferon-γ and D-dimer. This study showed that interferon-γ >8.11, D-dimer >0.64, and LDH >379 have an important role in the assessment of severe mycoplasma pneumonia.

Liver copper concentration dynamics with different methods of injectable copper supplementation in dairy cows in New Zealand

ABSTRACT Aims To compare the responses of liver Cu concentrations in dairy cows between three forms of injectable Cu supplementation and a negative control group. Methods Across two dairy farms in North Canterbury, New Zealand, 80 mid-lactation dairy cows (n = 28 and 52 per farm) were randomly allocated to four treatment groups: (a) 100-mg or (b) 200-mg dose of Cu administered as Ca Cu EDTA; (c) 75-mg dose of Cu as disodium Cu EDTA combined with Se, Zn, and Mn; or (d) no treatment (negative control). Each treatment group contained 20 cows. Groups were balanced for age, plasma Cu and pre-treatment liver Cu concentration. Blood samples and liver biopsies were collected prior to treatment. Six liver biopsies were performed on the same cow over a period of 70 days and the concentration of liver Cu was measured over time and compared to pre-treatment baseline. A mixed, multivariable, linear regression model was constructed to determine the effect of treatment on the change in liver Cu concentration compared to pre-treatment concentrations, accounting for repeated measurements taken from each cow. Results There was a difference in the distribution of pre-treatment liver Cu concentration between farms (p = 0.008), with medians of 1,400 (IQR 1,200–1,625) and 1,050 (IQR 805–1,425) µmol/kg on Farms 1 and 2, respectively. There was an interaction between treatment group, study day, and farm, with a treatment effect confirmed only on Farm 2. In the final model, the predicted change in liver Cu concentration (compared to pre-treatment concentrations) among cows on Farm 2 that were treated with 200 mg of Ca Cu EDTA was significantly higher than that of control cows on Days 3, 14, 28 and 42, peaking on Day 14 with a difference of 325.35 (95% CI = 97.00–554.03) µmol/kg. The study found no associations between changes in liver Cu concentration and age or prior plasma Cu concentration. The intraclass correlation coefficient was 0.57 (95% CI = 0.45–0.66), indicating the proportion of variability in changes in liver Cu concentration attributable to inter-cow variation. Conclusions and clinical relevance This study shows there are differences in response to injectable Cu supplementation at the farm level and wide variation in liver Cu among cows from the same farm. On one farm, a 200-mg dosage of Ca Cu EDTA significantly increased liver Cu concentration for at least 42 days.

How much does an MRI change over a period of up to 2years in patients with chronic low back pain? Is a repeated MRI really necessary in the follow-up of patients with chronic low back pain?

Clinical practices vary between healthcare providers when it comes to asking for a Magnetic Resonance Imaging (MRI) during follow-up for chronic low-back pain (LBP). The association between progressive changes on the MRI and the clinical relevance of these findings is not clearly defined. The objective of our study is to investigate to what extent do MRI findings change during a period less than or equal to two years in patients with chronic LBP. We question the efficacy of its routinary use as a tool for follow-up and we also study the correlation between new changes on MRI and modifications in therapeutic attitude. Data was collected from 468 lumbar spine MRIs from 209 patients undergoing two or more MRIs between January 2015 and December 2019 with a mean of 2.24 MRIs per patient. The evaluated data included diagnosis, reason for request, MRI findings and treatment offered post-MRI. MRIs were assessed according to a standardized scoring system from 0 to 14 points according to the severity in findings (modified Babinska Score). Radiological changes were defined as increased severity of findings in the most affected segment. 51.06% of MRI requests had no documented reason to be asked for. The average score of the findings on the first MRI was 5,733 (SD 2,462) and 6,131 (SD 2,376) on the second, not reaching a statistically significant difference (p = 0.062). There was no difference on the findings between the first and the second MRI in 40, 15% (n = 104) and up to 89, 96% with only mild changes (-1/ + 2 points over 14 possibles). After repeating the MRI, no modification to the treatment plan was made in 44, 79% of patients (n = 116) and only in 11.58% (n = 30) was surgical treatment indicated. The rate of lumbar MRI has risen to an alarming pace without evidence of consequent improvements in patient outcomes. A significant number of repeated MRIs did not show radiological changes, nor did they give rise to further surgical treatment after obtaining these images. This study should help to review the real applications of clinical guides on the appropriate use for image tests.

Arcuate anterior jugular vein: a rare case report and its clinical relevance.

The present study describes a rare anatomical variation of the anterior jugular vein (AJV) and discusses its clinical relevance. A head and neck specimen fixed in 10% formaldehyde from a 42-year-old female cadaver was submitted to angio technique with pre-vulcanized latex and water-soluble ink. During a routine dissection for the discipline of topographic anatomy, the presence of an arcuate AJV was detected in the anterior triangle of the neck. An arcuate AJV was formed by the confluence of the submental and facial veins in the left submandibular region, which presented a complex network of anastomoses superficially to the left submandibular gland. After its origin, this vessel curved to the right at the level of the laryngeal prominence and followed the medial border of the right sternohyoid muscle to flow into the right AJV. In this topography, the arcuate AJV was located between the sternocleidomastoid muscle's anterior margin and the thyroid gland's right lobe. The presence of anastomoses between the two AJVs communicating the submandibular triangles was not detected. The arcuate AJV is a relevant anatomical variant in the superficial venous drainage of the neck that should be known by head and neck surgeons and radiologists to avoid surgical iatrogenic events.

Impact of Skin Pigmentation on Pulse Oximetry Blood Oxygenation and Wearable Pulse Rate Accuracy: Systematic Review and Meta-Analysis.

Photoplethysmography (PPG) is a technology routinely used in clinical practice to assess blood oxygenation (SpO2) and pulse rate (PR). Skin pigmentation may influence accuracy, leading to health outcomes disparities. This systematic review and meta-analysis primarily aimed to evaluate the accuracy of PPG-derived SpO2 and PR by skin pigmentation. Secondarily, we aimed to evaluate statistical biases and the clinical relevance of PPG-derived SpO2 and PR according to skin pigmentation. We identified 23 pulse oximetry studies (n=59,684; 197,353 paired SpO2-arterial blood observations) and 4 wearable PR studies (n=176; 140,771 paired PPG-electrocardiography observations). We evaluated accuracy according to skin pigmentation group by comparing SpO2 accuracy root-mean-square values to the regulatory threshold of 3% and PR 95% limits of agreement values to +5 or -5 beats per minute (bpm), according to the standards of the American National Standards Institute, Association for the Advancement of Medical Instrumentation, and the International Electrotechnical Commission. We evaluated biases and clinical relevance using mean bias and 95% CI. For SpO2, accuracy root-mean-square values were 3.96%, 4.71%, and 4.15%, and pooled mean biases were 0.70% (95% CI 0.17%-1.22%), 0.27% (95% CI -0.64% to 1.19%), and 1.27% (95% CI 0.58%-1.95%) for light, medium, and dark pigmentation, respectively. For PR, 95% limits of agreement values were from -16.02 to 13.54, from -18.62 to 16.84, and from -33.69 to 32.54, and pooled mean biases were -1.24 (95% CI -5.31 to 2.83) bpm, -0.89 (95% CI -3.70 to 1.93) bpm, and -0.57 (95% CI -9.44 to 8.29) bpm for light, medium, and dark pigmentation, respectively. SpO2 and PR measurements may be inaccurate across all skin pigmentation groups, breaching U.S. Food and Drug Administration guidance and industry standard thresholds. Pulse oximeters significantly overestimate SpO2 for both light and dark skin pigmentation, but this overestimation may not be clinically relevant. PRs obtained from wearables exhibit no statistically or clinically significant bias based on skin pigmentation.

Resting natural killer cells promote the progress of colon cancer liver metastasis by elevating tumor-derived stem cell factor.

The abundance and biological contribution of natural killer (NK) cells in cancer are controversial. Here, we aim to uncover clinical relevance and cellular roles of NK cells in colon cancer liver metastasis (CCLM). Here, we integrated single-cell RNA-sequencing, spatial transcriptomics (ST), and bulk RNA-sequencing datasets to investigate NK cells' biological properties and functions in the microenvironment of primary and liver metastatic tumors. Results were validated through an in vitro co-culture experiment based on bioinformatics analysis. Useing single-cell RNA-sequencing and ST, we mapped the immune cellular landscape of colon cancer and well-matched liver metastatic cancer. We discovered that GZMK+ resting NK cells increased significantly in tumor tissues and were enriched in the tumor regions of both diseases. After combining bulk RNA and clinical data, we observed that these NK cell subsets contributed to a worse prognosis. Meanwhile, KIR2DL4+ activated NK cells exhibited the opposite position and relevance. Pseudotime cell trajectory analysis revealed the evolution of activated to resting NK cells. In vitro experiments further confirmed that tumor-cell-co-cultured NK cells exhibited a decidual-like status, as evidenced by remarkable increasing CD9 expression. Functional experiments finally revealed that NK cells exhibited tumor-activating characteristics by promoting the dissociation of SCF (stem cell factor) on the tumor cells membrane depending on cell-to-cell interaction, as the supernatant of the co-culture system enhanced tumor progression. In summary, our findings revealed resting NK cells exhibited a clinical relevance with CCLM, which may be exploited for novel strategies to improve therapeutic outcomes for patients with CCLM.

Tuina versus physiotherapy or a combination of both for the management of chronic nonspecific low back pain: A randomized controlled trial

ObjectiveTo rigorously evaluate the short-term and long-term effectiveness of Tuina (TN), alone and in combination with physiotherapy (PT), for Chronic nonspecific low back pain (CNLBP) through a comprehensive, high-quality clinical trial. MethodsThis randomized, single-blind trial was conducted from September 2020 to July 2023, involving 204 CNLBP patients from the First Affiliated Hospital of Jinan University. Participants underwent a baseline assessment, 6 treatment sessions over 8 weeks, a post-treatment evaluation in the 9th week, and a 20-week follow-up. Participants were randomly assigned to TN, PT, or a combination of TN and PT (TP) groups. Each treatment involved 6 sessions with a minimum 7-day interval, each lasting 30 minutes. Primary outcome was the change in Visual Analog Scale (VAS) for pain. Secondary outcomes included the Oswestry Disability Index (ODI), 36-Item Short Form Health Survey (SF-36), Range of Motion (ROM) of the spine, Traditional Chinese Medicine Syndrome Scale (TCMSS), and adverse events (AE). ResultsAmong the 204 participants, 67.16 % were female, and 88.73 % completed the 20-week follow-up. All groups showed significant reductions in VAS scores post-treatment and at follow-up. Secondary outcomes improved significantly, with notable decreases in ODI and TCMSS scores. Pairwise comparisons within groups indicated statistical significance, particularly in ODI scores, with clinical relevance. No significant differences were found between the groups. ROM and SF-36 showed statistical but not clinical significance. Only one AE (0.49 %) was reported, with no severe incidents. ConclusionAll treatment groups, including TN, TP, and PT, demonstrated significant reductions in VAS scores for CNLBP patients, with effects lasting up to 20 weeks. While TN and TP showed substantial improvements in secondary outcomes, particularly in ODI scores, no significant differences were found between the groups. These findings suggest that all treatments can be effective for managing CNLBP, supporting clinical practitioners in selecting appropriate interventions for patients, especially for those unable to engage in active exercises, utilizing passive movements like TN to enhance health outcomes.

Genes related to microglia polarization and immune infiltration in Alzheimer's Disease.

Alzheimer's Disease (AD) remains a significant challenge due to its complex etiology and socio-economic burden. In this study, we investigated the roles of macrophage polarization-related hub genes in AD pathology, focusing on their impact on immune infiltration and gene regulation in distinct brain regions. Using Gene Expression Omnibus (GEO) datasets GSE110226 (choroid plexus) and GSE1297 (hippocampal CA1), we identified key genes-EDN1, HHLA2, KL, TREM2, and WWTR1-associated with AD mechanisms and immune responses. Based on these findings, we developed a diagnostic model demonstrating favorable calibration and clinical applicability. Furthermore, we explored molecular interactions within mRNA-transcription factor and mRNA-miRNA regulatory networks, providing deeper insights into AD progression and identifying potential therapeutic targets. The novel identification of WWTR1 and HHLA2 as biomarkers expands the diagnostic toolkit for AD, offering new perspectives on the disease's underlying immune dynamics. However, external dataset validation and further in vitro and in vivo studies are required to confirm these results and their clinical relevance.

The SRC-family serves as a therapeutic target in triple negative breast cancer with acquired resistance to chemotherapy.

Resistance to chemotherapy, combined with heterogeneity among resistant tumors, represents a significant challenge in the clinical management of triple negative breast cancer (TNBC). By dissecting molecular pathways associated with treatment resistance, we sought to define patient sub-groups and actionable targets for next-line treatment. Bulk RNA sequencing and reverse phase protein array profiling were performed on isogenic patient-derived xenografts (PDX) representing paclitaxel-sensitive and -resistant tumors. Pathways identified as upregulated in the resistant model were further explored as targets in PDX explants. Their clinical relevance was assessed in two distinct patient cohorts (NeoAva and MET500). Increased activity in signaling pathways involving SRC-family kinases (SFKs)- and MAPK/ERK was found in treatment resistant PDX, with targeted inhibitors being significantly more potent in resistant tumors. Up-regulation of SFKs- and MAPK/ERK-pathways was also detected in a sub-group of chemoresistant patients after neoadjuvant treatment. Furthermore, High SFK expression (of either SRC, FYN and/or YES1) was detected in metastatic lesions of TNBC patients with fast progressing disease (median disease-free interval 27 vs 105 months). Upregulation of SFK-signaling is found in a subset of chemoresistant tumors and is persistent in metastatic lesions. Based on pre-clinical results, these patients may respond favorably to treatment targeting SFKs.

Major clinical relevance and considerations of zygomatic implants in elderly patients: a systematic review

For decades, zygomatic implants (ZI) have been used to rehabilitate atrophic maxillae and reconstruct maxillary defects, demonstrating significant survival rates, and have emerged as an alternative to extensive bone grafting. Despite their efficacy, surgical techniques for ZI placement have consistently been associated with perioperative complications, with additional problems arising later, especially in elderly patients. Objective: The present study developed a systematic review to address the main clinical relevance and considerations of zygomatic implants in elderly patients. Methods: The present study followed a concise systematic review model. The search was carried out in the PubMed, Embase, Ovid, Cochrane Library, Web of Science, and Scopus databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: A total of 220 articles were found. In total, 77 articles were fully evaluated and 57 were included and evaluated in this study, and of the total of 57 articles, only 42 articles were developed in the item results of the systematic review. Of the initial total of articles, 108 articles were excluded because they did not meet the GRADE and AMSTAR-2 classification, and 20 were excluded because they presented a risk of bias that could compromise the credibility of the studies. The symmetric funnel plot does not suggest a risk of bias. According to the GRADE instrument, most studies presented homogeneity in their results, with X2=85.6%&gt;50%. It was concluded the ZI has a high rate of survival accumulated in 12 years, with the majority of failures occurring in the early stages of the postoperative period. The main complication observed related to zygomatic implants in elderly patients was sinusitis, which can appear several years after implantation surgery. The presence of increased maxillary sinus pneumatization with advanced resorption of the posterior alveolus may result in insufficient bone to anchor the implant. Bone augmentation is generally necessary under these conditions to allow the placement of a sufficient number and length of implants. Another more serious condition would be defects of maxillectomy, aplasia of the maxillary sinus, and cleft deformities. Zygomatic implants appear to be a consolidated therapeutic option for a significantly atrophic maxilla in elderly patients, offering a promising alternative to costly heavy bone graft techniques, fewer complications, less time for rehabilitation, less required prosthodontic work, and significantly higher survival rates.

Dopamine Transporter and CYP2D6 Gene Relationships with Attention-Deficit/Hyperactivity Disorder Treatment Response in the Methylphenidate and Atomoxetine Crossover Study.

Background: Few biological or clinical predictors guide medication selection and/or dosing for attention-deficit/hyperactivity disorder (ADHD). Accumulating data suggest that genetic factors may contribute to clinically relevant pharmacodynamic (e.g., dopamine transporter-SLC6A3 also commonly known as DAT1) or pharmacokinetic (e.g., the drug metabolizing enzyme Cytochrome P450 2D6 CYP2D6) effects of methylphenidate (stimulant) and atomoxetine (non-stimulant), which are commonly prescribed medications. This is the first study of youth with ADHD exposed to both medications examining the clinical relevance of genetic variation on treatment response. Methods: Genetic variations in DAT1 and CYP2D6 were examined to determine how they modified time relationships with changes in ADHD symptoms over a 4-week period in 199 youth participating in a double-blind crossover study following a stepped titration dose optimization protocol. Results: Our results identified trends in the modification effect from CYP2D6 phenotype and the time-response relationship between ADHD total symptoms for both medications (atomoxetine [ATX]: p = 0.058, Methylphenidate [MPH]: p = 0.044). There was also a trend for the DAT1 3' untranslated region (UTR) variable number of tandem repeat (VNTR) genotype to modify dose relationships with ADHD-RS total scores for atomoxetine (p = 0.029). Participants with DAT1 9/10 repeat genotypes had a more rapid dose-response to ATX compared to 10/10, while those with 9/9 genotypes did not respond as doses were increased. Regardless of genotype, ADHD symptoms and doses were similar across CYP2D6 metabolizer groups after 4 weeks of treatment. Conclusions: Most children with ADHD who were CYP2D6 normal metabolizers or had DAT1 10/10 or 9/10 genotypes responded well to both medications. While we observed some statistically significant effects of CYP2D6 and DAT1 with treatment response over time, our data indicate that genotyping for clinical purposes may have limited utility to guide treatment decisions for ATX or MPH because both medications were generally effective in the studied cohort after 3 weeks of titration to higher doses. The potential DAT1 association with ATX treatment is a novel finding, consistent with prior reports suggesting an association of the DAT1 in 9/9 genotypes with lower responsive rates to treatment at low and moderate doses.

Resting natural killer cells promote the progress of colon cancer liver metastasis by elevating tumor-derived stem cell factor

The abundance and biological contribution of natural killer (NK) cells in cancer are controversial. Here, we aim to uncover clinical relevance and cellular roles of NK cells in colon cancer liver metastasis (CCLM). Here, we integrated single-cell RNA-sequencing, spatial transcriptomics (ST), and bulk RNA-sequencing datasets to investigate NK cells’ biological properties and functions in the microenvironment of primary and liver metastatic tumors. Results were validated through an in vitro co-culture experiment based on bioinformatics analysis. Useing single-cell RNA-sequencing and ST, we mapped the immune cellular landscape of colon cancer and well-matched liver metastatic cancer. We discovered that GZMK+ resting NK cells increased significantly in tumor tissues and were enriched in the tumor regions of both diseases. After combining bulk RNA and clinical data, we observed that these NK cell subsets contributed to a worse prognosis. Meanwhile, KIR2DL4+ activated NK cells exhibited the opposite position and relevance. Pseudotime cell trajectory analysis revealed the evolution of activated to resting NK cells. In vitro experiments further confirmed that tumor-cell-co-cultured NK cells exhibited a decidual-like status, as evidenced by remarkable increasing CD9 expression. Functional experiments finally revealed that NK cells exhibited tumor-activating characteristics by promoting the dissociation of SCF (stem cell factor) on the tumor cells membrane depending on cell-to-cell interaction, as the supernatant of the co-culture system enhanced tumor progression. In summary, our findings revealed resting NK cells exhibited a clinical relevance with CCLM, which may be exploited for novel strategies to improve therapeutic outcomes for patients with CCLM.

An exploratory study of the impact of CT slice thickness and inter-rater variability on anatomical accuracy of malunited distal radius models and surgical guides for corrective osteotomy.

High-resolution CT images are essential in clinical practice to accurately replicate patient anatomy for 3D virtual surgical planning and designing patient-specific surgical guides. These technologies are commonly used in corrective osteotomy of the distal radius. This study evaluated how the virtual radius models and the surgical guides' surface that is in contact with the bone vary between experienced raters. Further, the discrepancies from the reference radius of surgical guides and radius models created from CT images with slice thicknesses larger than the reference standard of 0.625mm were assessed. Maximum overlap with radius model was measured for guides, and absolute average distance error was measured for radius models. The agreement between the lower-resolution guides surface and the raters' guide surface was evaluated. The average inter-rater guide surface overlap was -0.11mm [95% CI: -0.13-0.09]. The surface of surgical guides designed on CT images with a 1mm slice thickness deviated from the reference radius within the inter-rater range (0.03mm). For slice thicknesses of 1.25mm and 1.5mm, the average guide surface overlap was 0.12mm and 0.15mm, respectively. The average inter-rater radius surface variability was 0.03mm [95% CI: 0.025-0.035]. The discrepancy from the reference of all radius models created from CT images with a slice thickness larger than the reference slice thickness was notably larger than the inter-rater variability but, excluding one case, did not exceed 0.2mm. The results suggest that 1mm CT images are suitable for surgical guide design. While 1.25mm slices are commonly used for virtual planning in hand and forearm surgery, slices larger than 1mm may approach the limit of clinical acceptability. Discrepancies in radius models were below 1mm, likely below clinical relevance.

Mandibular second molar impaction: introducing a novel and validated 3D classification system

BackgroundMandibular second molar (M2M) impaction is a clinically significant manifestation of eruption disturbance in dental development. The primary aim of this study was to investigate the impact of the three-dimensional (3D) characterization on clinical and therapeutic decisions for M2M impaction. The secondary aim was to introduce a validated 3D classification system incorporating both surgical and orthodontic parameters.MethodsBidimensional (2D) and 3D radiological records of 15 impacted M2M were collected and deidentified. Ten experienced clinicians (5 oral surgeons;5 orthodontists) categorized each case, first based on 2D records and then with 3D scans. The degree of orthodontic and surgical difficulty in treating impacted M2M was evaluated using a novel classification system based on anatomical and radiological features. The primary outcome variable was the assessment of differences in diagnosis and decision-making protocol using 2D or 3D records, where clinical relevance ranged from 0 to 4. The secondary outcome variable was the validation analysis of the proposed 3D classification system to determine the concordance among the clinicians. Descriptive statistics and multivariable inferential analysis based on Akaike information criterion (AIC) were performed (α = 0.05).Results3D examination allowed a better visualization of M2M impaction with higher clinical relevance for diagnosis of M2M root relationship to alveolar nerve and lingual plate, height to alveolar crest, depth, and inclination relative to the first molar and position relative to the third molar (range:2.69–3.43). The proposed 3D classification of M2M impaction changed clinical decisions regarding surgical-orthodontic approach, biomechanics, patient education, and treatment time estimate (range:2.59–3.33). In the validation analysis of the classification, no evidence of inter- or intra-group (surgeon/orthodontist) bias in score attribution occurred: the model with the minimum AIC was the null model (AIC = 718.04).Conclusion3D evaluation of impacted M2Ms could enhance diagnostic accuracy, and a classification system was proposed and validated by a group of experienced surgeons and orthodontists with high concordance.