Search

Background:. This study aimed to evaluate the long-term results of hallux valgus correction with a distal metatarsal reversed-L (ReveL) osteotomy. Methods:. Eighty-eight patients (131 feet) were evaluated after a mean follow-up of 14.2 years (range, 10 to 18 years). Weight-bearing foot radiographs were analyzed preoperatively, at 6 weeks postoperatively, and at the final follow-up for the following parameters: hallux valgus angle (HVA), intermetatarsal angle (IMA), first metatarsophalangeal joint (MTPJ) congruence angle, sesamoid position, presence of the round sign, and first MTPJ arthritis. The visual analog scale (VAS) and the Foot and Ankle Outcome Score (FAOS) assessed postoperative pain and function. Univariate and multivariable logistic regression analyses identified risk factors for hallux valgus recurrence and an inferior clinical outcome. Results:. All radiographic parameters significantly improved at the 6-week follow-up and the final follow-up (p < 0.001). The recurrence rate (HVA >20°) was 14%. A preoperative HVA of >28° (odds ratio [OR], 9.1; p = 0.02) and a 6-week postoperative HVA of >15° (OR, 4.6; p = 0.03) were independent risk factors for recurrence. At the final follow-up, all FAOS subscales resembled high postoperative function (median, 100 points [range of the interquartile range (IQR), 81 to 100 points]). A preoperative body mass index of >30 kg/m2 was associated with lower FAOS quality of life (QOL) (p = 0.04), and postoperative hallux varus was associated with lower FAOS activities of daily living (p = 0.048). Patients with first MTPJ arthritis of grade 2 or higher at the final follow-up had significantly lower FAOS subscales (p < 0.01) except for QOL. Hallux valgus recurrence did not influence the long-term outcome. A symptomatic implant was the main cause of revision (15%). In 94% of cases, the patients were satisfied with the hallux appearance and, in 92% of cases, the patients were satisfied with postoperative pain reduction. Conclusions:. Hallux valgus correction with a ReveL osteotomy led to high long-term satisfaction rates. A preoperative HVA of >28° and a 6-week postoperative HVA of >15° increased the risk of hallux valgus recurrence. First MTPJ arthritis was the leading cause of inferior clinical results, whereas radiographic hallux valgus recurrence had no impact on the clinical results. First MTPJ arthritis at the final follow-up was associated with an inferior clinical outcome, whereas radiographic hallux valgus recurrence had no impact on the long-term clinical results. Level of Evidence:. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Summary: Background: Studies on DNA methylation following bariatric surgery have primarily focused on blood cells, while it is unclear to which extend it may reflect DNA methylation profiles in specific metabolically relevant organs such as adipose tissue. Here, we investigated whether adipose tissue depots specific methylation changes after bariatric surgery are mirrored in blood. Methods: Using Illumina 850K EPIC technology, we analysed genome-wide DNA methylation in paired blood, subcutaneous and omental visceral AT (SAT/OVAT) samples from nine individuals (N = 6 female) with severe obesity pre- and post-surgery. Findings: The numbers and effect sizes of differentially methylated regions (DMRs) post-bariatric surgery were more pronounced in AT (SAT: 12,865 DMRs from −11.5 to 10.8%; OVAT: 14,632 DMRs from −13.7 to 12.8%) than in blood (9267 DMRs from −8.8 to 7.7%). Cross-tissue DMRs implicated immune-related genes. Among them, 49 regions could be validated with similar methylation changes in blood from independent individuals. Fourteen DMRs correlated with differentially expressed genes in AT post bariatric surgery, including downregulation of PIK3AP1 in both SAT and OVAT. DNA methylation age acceleration was significantly higher in AT compared to blood, but remained unaffected after surgery. Interpretation: Concurrent methylation pattern changes in blood and AT, particularly in immune-related genes, suggest blood DNA methylation mirrors AT's inflammatory state post-bariatric surgery. Funding: The funding sources are listed in the Acknowledgments section.

BackgroundThe bedside diagnosis of acute pulmonary edema is challenging. This study evaluated the breath-by-breath information from electrical impedance tomography (EIT), respiratory mechanics and volumetric capnography (VCap) to assess acute pulmonary edema induced by xylazine administration in anesthetized sheep.ObjectiveTo determine the ability and efficiency of each monitoring modality in detecting changes in lung function associated with onset of pulmonary edema.MethodsTwenty healthy ewes were anesthetized, positioned in sternal (prone) recumbency and instrumented. Synchronized recordings of EIT, spirometry and VCap were performed for 60 s prior to start of injection, during xylazine injection over 60 s (0–60 s) and continuously for 1 min (60–120 s) after the end of injection. After visual assessment of the recorded mean variables, statistical analysis was performed using a mixed effect model for repeated measures with Bonferroni’s correction for multiple comparisons, to determine at which breath after start of injection the variable was significantly different from baseline. A significant change over time was defined as an adjusted p

Despite growing numbers of scientific publications on the optimal antibiotic treatment for diabetic foot infections, the data on the adult population with non-diabetic (postsurgical) foot infections is limited. Therefore, one of the largest single-center databases at the Balgrist University Hospital in Zurich, Switzerland, was established between January 2014 and August 2022. Using a case–control study design, we retrospectively investigated failures of combined surgical and antibiotic therapy for surgical site foot infections (SSIs). Overall, 17.4% of the episodes experienced therapeutic failures, particularly in patients with infected ankle prostheses. However, age, biological sex, pathogens, the duration of post-debridement antibiotic treatment, the number of surgical debridements, or the use of negative-pressure wound care altered the failure risk. In the multivariate logistic regression analyses, the duration of postsurgical antibiotic use was completely indifferent (as a continuous variable with an odds ratio of 1.0 and a 95% confidence interval ranging from 0.96 to 1.03) when stratified into inter-tertiary groups. Our findings suggest that shorter courses of systemic antibiotics may be appropriate in non-diabetic adults, supporting better antibiotic stewardship. Ongoing randomized controlled trials are under way to investigate which patients might safely receive shorter antibiotic treatments for surgical site infections following elective foot and ankle procedures.

Abstract Background and goal of study Pulse pressure variation (PPV) and stroke volume variation (SVV), which are based on the forces caused by controlled mechanical ventilation, are commonly used to predict fluid responsiveness. When PPV and SVV were introduced into clinical practice, volume-controlled ventilation (VCV) with tidal volumes (VT) ≥ 10 ml kg− 1 was most commonly used. Nowadays, lower VT and the use of pressure-controlled ventilation (PCV) has widely become the preferred type of ventilation. Due to their specific flow characteristics, VCV and PCV result in different airway pressures at comparable tidal volumes. We hypothesised that higher inspiratory pressures would result in higher PPVs and aimed to determine the impact of VCV and PCV on PPV and SVV. Methods In this self-controlled animal study, sixteen anaesthetised, paralysed, and mechanically ventilated (goal: VT 8 ml kg− 1) pigs were instrumented with catheters for continuous arterial blood pressure measurement and transpulmonary thermodilution. At four different intravascular fluid states (IVFS; baseline, hypovolaemia, resuscitation I and II), ventilatory and hemodynamic data including PPV and SVV were assessed during VCV and PCV. Statistical analysis was performed using U-test and RM ANOVA on ranks as well as descriptive LDA and GEE analysis. Results Complete data sets were available of eight pigs. VT and respiratory rates were similar in both forms. Heart rate, central venous, systolic, diastolic, and mean arterial pressures were not different between VCV and PCV at any IVFS. Peak inspiratory pressure was significantly higher in VCV, while plateau, airway and transpulmonary driving pressures were significantly higher in PCV. However, these higher pressures did not result in different PPVs nor SVVs at any IVFS. Conclusion VCV and PCV at similar tidal volumes and respiratory rates produced PPVs and SVVs without clinically meaningful differences in this experimental setting. Further research is needed to transfer these results to humans.

Abstract Circular RNAs (circRNAs) are a regulatory RNA class. While cancer-driving functions have been identified for single circRNAs, how they modulate gene expression in cancer is not well understood. We investigate circRNA expression in the pediatric malignancy, neuroblastoma, through deep whole-transcriptome sequencing in 104 primary neuroblastomas covering all risk groups. We demonstrate that MYCN amplification, which defines a subset of high-risk cases, causes globally suppressed circRNA biogenesis directly dependent on the DHX9 RNA helicase. We detect similar mechanisms in shaping circRNA expression in the pediatric cancer medulloblastoma implying a general MYCN effect. Comparisons to other cancers identify 25 circRNAs that are specifically upregulated in neuroblastoma, including circARID1A. Transcribed from the ARID1A tumor suppressor gene, circARID1A promotes cell growth and survival, mediated by direct interaction with the KHSRP RNA-binding protein. Our study highlights the importance of MYCN regulating circRNAs in cancer and identifies molecular mechanisms, which explain their contribution to neuroblastoma pathogenesis.

Neonicotinoid insecticides, the fastest-growing class in recent decades, interfere with cholinergic neurotransmission by binding to the nicotinic acetylcholine receptor. This disruption affects both targeted and non-targeted insects, impairing cognitive functions such as olfaction and related behaviors, with a particular emphasis on olfactory memory due to its ecological impact. Despite the persistent presence of these chemicals in the environment, significant research gaps remain in understanding the intricate interplay between cognitive function, development, neuronal activity, and neonicotinoid-induced toxicity. This study focuses on the fruit fly Drosophila melanogaster, chosen for its genetic tractability, well-characterized neural circuitry, and remarkable parallels with bees in neurotransmitter systems and brain structures. Our aim is to establish the fruit fly as a valuable model organism for studying the effects of neonicotinoids on behavior and neuronal circuitry, with particular attention to olfactory memory and associated brain circuitries. To achieve this aim, we conducted experiments to investigate the effects of short-term exposure to sublethal doses of the neonicotinoid imidacloprid, mimicking realistic environmental insecticide exposure, on the formation of odor memories. Additionally, we evaluated synaptic contacts and cholinergic neurotransmission within the mushroom body, the primary memory network of insects. Our results showed significant impairments in odor memory formation in flies exposed to imidacloprid, with exposure during the adult stage showing more pronounced effects than exposure during the larval stage. Additionally, functional studies revealed a decrease in synaptic contacts within the intrinsic olfactory projection neurons and the mushroom body. Furthermore, another experiment showed an odor-dependent reduction in cholinergic neurotransmission within this network. In summary, employing Drosophila as a model organism provides a robust framework for investigating neonicotinoid effects and understanding their diverse impacts on insect physiology and behavior. Our study initiates the establishment of the fruit fly as a pivotal model for exploring neonicotinoid influences, shedding light on their effects on olfactory memory, neuronal integrity, and synaptic transmission.

Uniparental disomy (UPD) is the inheritance of both alleles of a chromosome from only one parent. So far, the detection of UPDs in sequencing data is not well established and a known gap in next-generation sequencing (NGS) diagnostics. By developing a new tool for UPD detection, we re-evaluated an eight-year-old individual presenting with scoliosis, muscle weakness and global developmental delay. Previous panel analysis identified a homozygous likely pathogenic loss-of-function variant in the PIEZO2-gene associated with arthrogryposis (OMIM # 617146). Interestingly, during a re-evaluation process, we identified a region of homozygosity (ROH) covering over 95% of chromosome 18. Segregation and microsatellite analysis within the family revealed that only the father is a heterozygous carrier of the variant in PIEZO2 and confirmed paternal uniparental isodisomy (iUPD) on chromosome 18 in the individual. Further methylation analysis indicated demethylation of the promotor region of PARD6G-AS1, which is described to be maternally imprinted and could possibly influence the individuals’ phenotype. Our report describes the first complete iUPD on chromosome 18 and highlights that UPDs can be a cause for homozygous pathogenic variants, which reduces the risk of reoccurrence in case of a new pregnancy in comparison to an autosomal recessive inheritance trait significantly.

Abstract Background Amputation of the second toe is associated with destabilization of the first toe. Possible consequences are hallux valgus deformity and subsequent pressure ulcers on the lateral side of the first or on the medial side of the third toe. The aim of this study was to investigate the incidence and possible influencing factors of interdigital ulcer development and hallux valgus deformity after second toe amputation. Methods Twenty-four cases of amputation of the second toe between 2004 and 2020 (mean age 68 ± 12 years; 79% males) were included with a mean follow-up of 36 ± 15 months. Ulcer development on the first, third, or fourth toe after amputation, the body mass index (BMI) and the amputation level (toe exarticulation versus transmetatarsal amputation) were recorded. Pre- and postoperative foot radiographs were evaluated for the shape of the first metatarsal head (round, flat, chevron-type), the hallux valgus angle, the first–second intermetatarsal angle, the distal metatarsal articular angle and the hallux valgus interphalangeal angle by two orthopedic surgeons for interobserver reliability. Results After amputation of the second toe, the interdigital ulcer rate on the adjacent toes was 50% and the postoperative hallux valgus rate was 71%. Neither the presence of hallux valgus deformity itself (r = .19, p = .37), nor the BMI (r = .09, p = .68), the shape of the first metatarsal head (r = − .09, p = .67), or the amputation level (r = .09, p = .69) was significantly correlated with ulcer development. The interobserver reliability of radiographic measurements was high, oscillating between 0.978 (p = .01) and 0.999 (p = .01). Conclusions The interdigital ulcer rate on the first or third toe after second toe amputation was 50% and hallux valgus development was high. To date, evidence on influencing factors is lacking and this study could not identify parameters such as the BMI, the shape of the first metatarsal head or the amputation level as risk factors for the development of either hallux valgus deformity or ulcer occurrence after second toe amputation. Trial Registration: BASEC-Nr. 2019-01791

Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for “RS-type” de novo DLBCLs.

Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease.

Abstract The human SBF1 (SET binding factor 1) gene, alternatively known as MTMR5, is predominantly expressed in the brain, and its epigenetic dysregulation is linked to late-onset neurocognitive disorders (NCDs), such as Alzheimer’s disease. This gene contains a (GCC)-repeat at the interval between + 1 and + 60 of the transcription start site (SBF1-202 ENST00000380817.8). We sequenced the SBF1 (GCC)-repeat in a sample of 542 Iranian individuals, consisting of late-onset NCDs (N = 260) and controls (N = 282). While multiple alleles were detected at this locus, the 8 and 9 repeats were predominantly abundant, forming > 95% of the allele pool across the two groups. Among a number of anomalies, the allele distribution was significantly different in the NCD group versus controls (Fisher’s exact p = 0.006), primarily as a result of enrichment of the 8-repeat in the former. The genotype distribution departed from the Hardy–Weinberg principle in both groups (p

International challenges have become the de facto standard for comparative assessment of image analysis algorithms. Here, the authors present the results of a biomedical image segmentation challenge, showing that a method capable of performing well on multiple tasks will generalize well to a previously unseen task.

Abstract By learning, through experience, which stimuli coincide with dangers, it is possible to predict outcomes and act pre-emptively to ensure survival. In insects, this process is localized to the mushroom body (MB), the circuitry of which facilitates the coincident detection of sensory stimuli and punishing or rewarding cues and, downstream, the execution of appropriate learned behaviors. Here, we focused our attention on the mushroom body output neurons (MBONs) of the γ-lobes that act as downstream synaptic partners of the MB γ-Kenyon cells (KCs) to ask how the output of the MB γ-lobe is shaped by olfactory associative conditioning, distinguishing this from non-associative stimulus exposure effects, and without the influence of downstream modulation. This was achieved by employing a subcellularly localized calcium sensor to specifically monitor activity at MBON postsynaptic sites. Therein, we identified a robust associative modulation within only one MBON postsynaptic compartment (MBON-γ1pedc > α/β), which displayed a suppressed postsynaptic response to an aversively paired odor. While this MBON did not undergo non-associative modulation, the reverse was true across the remainder of the γ-lobe, where general odor-evoked adaptation was observed, but no conditioned odor-specific modulation. In conclusion, associative synaptic plasticity underlying aversive olfactory learning is localized to one distinct synaptic γKC-to-γMBON connection.

Despite growing numbers of scientific publications on the optimal antibiotic treatment for diabetic foot infections, the data on the adult population with non-diabetic (postsurgical) foot infections is limited. Therefore, one of the largest single-center databases at the Balgrist University Hospital in Zurich, Switzerland, was established between January 2014 and August 2022. Using a case–control study design, we retrospectively investigated failures of combined surgical and antibiotic therapy for surgical site foot infections (SSIs). Overall, 17.4% of the episodes experienced therapeutic failures, particularly in patients with infected ankle prostheses. However, age, biological sex, pathogens, the duration of post-debridement antibiotic treatment, the number of surgical debridements, or the use of negative-pressure wound care altered the failure risk. In the multivariate logistic regression analyses, the duration of postsurgical antibiotic use was completely indifferent (as a continuous variable with an odds ratio of 1.0 and a 95% confidence interval ranging from 0.96 to 1.03) when stratified into inter-tertiary groups. Our findings suggest that shorter courses of systemic antibiotics may be appropriate in non-diabetic adults, supporting better antibiotic stewardship. Ongoing randomized controlled trials are under way to investigate which patients might safely receive shorter antibiotic treatments for surgical site infections following elective foot and ankle procedures. [ABSTRACT FROM AUTHOR]

Objective: Microcirculatory disturbances can contribute to organ dysfunction in patients undergoing major surgeries and critical illness. Incident dark field imaging (CytoCam, Braedius Medical BV, Huizen, Netherlands) provides direct visualization of the microcirculation. To utilize this method in daily clinical practice, automated image analysis is essential. This study aims to compare the automated analysis of recorded microcirculation video sequences using CytoCamTools V2 Analysis Manager (Braedius Medical BV) with established manual analysis using Capillary Mapper (Version 1.4.5, University Hospital Münster, Germany) as reference method. Methods: Sublingual microcirculation video sequences were recorded in patients undergoing laparotomy at four time points (before surgery, 2 and 6 h after surgery, and on the first postoperative day) using incident dark field imaging. Agreement between automated and manual analysis of total vessel density (TVD), perfused vessel density (PVD), and proportion of perfused vessels (PPV) was compared using intraclass correlation (ICC) and Bland–Altman method. Results: A total of 336 videos from 30 patients were analyzed. The ICC between the two measurement methods was 0.13 for TVD, 0.14 for PVD, and 0.16 for PPV. Bland–Altman analysis showed mean differences (95% limits of agreement) of 10.46 mm/mm2 (−1.73–22.65 mm/mm2) for TVD, 8.25 mm/mm2 (−9.88–26.39 mm/mm2) for PVD, and − 3.96% (−59.58%–51.65%) for PPV. Discussion: Automated microcirculatory analysis using the Analysis Manager did not show clinically acceptable agreement with manual analysis using Capillary Mapper. Consequently, automated video analysis using the Analysis Manager does not appear to be a suitable approach. Trial Registration: ClinicalTrials.gov identifier: DRKS00020264 [ABSTRACT FROM AUTHOR]

Patients with chronic kidney disease (CKD) have a high incidence and prevalence of atrial fibrillation (AF). While general treatment strategies for AF may largely be transferred to patients with mild to moderate CKD, patients with advanced CKD—particularly hemodialysis (HD) patients—with AF pose substantial therapeutical challenges to cardiologists and nephrologists. The arguably greatest dilemma is the very limited evidence on appropriate strategies for prevention of stroke and systemic embolism in HD patients with AF, since the risk for both thromboembolic events without oral anticoagulation and severe bleeding events with oral anticoagulation are substantially increased in advanced CKD, compared with the general population. Thus, the benefit to risk ratio of either vitamin K antagonists or direct oral anticoagulants is less evident in HD than in non-CKD patients with AF. As a multidisciplinary panel of clinicians, we here propose 10 tips that may help our colleagues to navigate between the risk of undertreatment—exposing CKD patients with AF to a high stroke risk—and overtreatment—exposing the very same patients to a prohibitively high bleeding risk. These tips include ideas on alternative risk stratification strategies and novel treatment approaches that are currently in clinical studies—such as factor XI inhibitors or left atrial appendage closure—and may become game-changers for HD patients with AF. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small non coding RNAs responsible for posttranscriptional regulation of gene expression. Even though almost 2000 precursors have been described so far, additional miRNAs are still being discovered in normal as well as malignant cells. Alike protein coding genes, miRNAs may acquire oncogenic properties in consequence of altered expression or presence of gain or loss of function mutations. In this study we mined datasets from miRNA expression profiling (miRNA-seq) of 7 classic Hodgkin Lymphoma (cHL) cell lines, 10 non-Hodgkin lymphoma (NHL) cell lines and 56 samples of germinal center derived B-cell lymphomas. Our aim was to discover potential novel cHL oncomiRs not reported in miRBase (release 22.1) and expressed in cHL cell lines but no other B-cell lymphomas. We identified six such miRNA candidates in cHL cell lines and verified the expression of two of them encoded at chr2:212678788-212678849 and chr5:168090507-168090561 (GRCh38). Interestingly, we showed that one of the validated miRNAs (located in an intron of the TENM2 gene) is expressed together with its host gene. TENM2 is characterized by hypomethylation and open chromatin around its TSS in cHL cell lines in contrast to NHL cell lines and germinal centre B-cells respectively. It indicates an epigenetic mechanism responsible for aberrant expression of both, the TENM2 gene and the novel miRNA in cHL cell lines. Despite the GO analysis performed with the input of the in silico predicted novel miRNA target genes did not reveal ontologies typically associated with cHL pathogenesis, it pointed to several interesting candidates involved in i.e. lymphopoiesis. These include the lymphoma related BCL11A gene, the IKZF2 gene involved in lymphocyte development or the transcription initiator GTF2H1.