Figeno: multi-region genomic figures with long-read support.

SUMMARY: The vast amount of publicly available genomic data requires analysis and visualization tools. Here, we present figeno, an application for generating publication-quality FIgures for GENOmics. Figeno particularly focuses on multi-region views across genomic breakpoints and on long reads with base modifications. In addition, we support epigenomic data including ATAC-seq, ChIP-seq or HiC, as well as whole genome sequencing data with copy numbers and structural variants. AVAILABILITY AND IMPLEMENTATION: Figeno is available as a python package with both a command line and graphical user interface. It can be installed via PyPI and the source code is available at https://github.com/CompEpigen/figeno.

Late-onset NPM1 mutation in a MYC-amplified relapsed / refractory acute myeloid leukemia patient treated with gemtuzumab ozogamicin and glasdegib.

Not available.

Somatic epimutations enable single-cell lineage tracing in native hematopoiesis across the murine and human lifespan.

Current approaches to lineage tracing of stem cell clones require genetic engineering or rely on sparse somatic DNA variants, which are difficult to capture at single-cell resolution. Here, we show that targeted single-cell measurements of DNA methylation at single-CpG resolution deliver joint information about cellular differentiation state and clonal identities. We develop EPI-clone, a droplet-based method for transgene-free lineage tracing, and apply it to study hematopoiesis, capturing hundreds of clonal trajectories across almost 100,000 single-cells. Using ground-truth genetic barcodes, we demonstrate that EPI-clone accurately identifies clonal lineages throughout hematopoietic differentiation. Applied to unperturbed hematopoiesis, we describe an overall decline of clonal complexity during murine ageing and the expansion of rare low-output stem cell clones. In aged human donors, we identified expanded hematopoietic clones with and without genetic lesions, and various degrees of clonal complexity. Taken together, EPI-clone enables accurate and transgene-free single-cell lineage tracing at scale.

Alterations in the hepatocyte epigenetic landscape in steatosis.

Fatty liver disease or the accumulation of fat in the liver, has been reported to affect the global population. This comes with an increased risk for the development of fibrosis, cirrhosis, and hepatocellular carcinoma. Yet, little is known about the effects of a diet containing high fat and alcohol towards epigenetic aging, with respect to changes in transcriptional and epigenomic profiles. In this study, we took up a multi-omics approach and integrated gene expression, methylation signals, and chromatin signals to study the epigenomic effects of a high-fat and alcohol-containing diet on mouse hepatocytes. We identified four relevant gene network clusters that were associated with relevant pathways that promote steatosis. Using a machine learning approach, we predict specific transcription factors that might be responsible to modulate the functionally relevant clusters. Finally, we discover four additional CpG loci and validate aging-related differential CpG methylation. Differential CpG methylation linked to aging showed minimal overlap with altered methylation in steatosis.

Treatment and Outcome of Osteoporotic Thoracolumbar Vertebral Body Fractures With Deformation of Both Endplates With or Without Posterior Wall Involvement (OF 4): Short-Term Results from the Prospective EOFTT Multicenter Study.

STUDY DESIGN: Multicenter prospective cohort study. OBJECTIVE: To analyse therapeutical strategies applied to osteoporotic thoracolumbar OF 4 injuries, to assess related complications and clinical outcome. METHODS: A multicenter prospective cohort study (EOFTT) including 518 consecutive patients who were treated for an Osteoporotic vertebral compression fracture (OVCF). For the present study, only patients with OF 4 fractures were analysed. Outcome parameters were complications, Visual Analogue Scale, Oswestry Disability Questionnaire, Timed Up & Go test, EQ-5D 5L, and Barthel Index after a minimum follow-up of 6 weeks. RESULTS: A total of 152 (29%) patients presented with OF 4 fractures with a mean age of 76 years (range 41-97). The most common treatment was short-segment posterior stabilization (51%; hybrid stabilization in 36%). Mean follow up was 208 days (±131 days), mean ODI was 30 ± 21. Dorsoventral stabilized patients were younger compared to the other groups (P < .001) and had significant better TuG compared to hybrid stabilization (P = .049). The other clinical outcomes did not differ in the therapy strategies (VAS pain: P = 1.000, ODI: P > .602, Barthel: P > .252, EQ-5D 5L index value: P > .610, VAS-EQ-5D 5L: P = 1.000). The inpatient complication rate was 8% after conservative and 16% after surgical treatment. During follow-up period 14% of conservatively treated patients and 3% of surgical treated patients experienced neurological deficits. CONCLUSIONS: Conservative therapy of OF 4 injuries seems to be viable option in patients with only moderate symptoms. Hybrid stabilization was the dominant treatment strategy leading to promising clinical short-term results. Stand-alone cement augmentation seems to be a valid alternative in selected cases.

Treatment and Outcome of Osteoporotic Thoracolumbar Vertebral Fractures With Anterior or Posterior Tension Band Failure (OF 5): Short-Term Results From the Prospective EOFTT Multicenter Study.

STUDY DESIGN: Subgroup analysis of a multicenter prospective cohort study. OBJECTIVE: To analyse surgical strategies applied to osteoporotic thoracolumbar osteoporotic fracture (OF) 5 injuries with anterior or posterior tension band failure and to assess related complications and clinical outcome. METHODS: A multicenter prospective cohort study (EOFTT) was conducted at 17 spine centers including 518 consecutive patients who were treated for an osteoporotic vertebral fracture (OVF). For the present study, only patients with OF 5 fractures were analysed. Outcome parameters were complications, Visual Analogue Scale (VAS), Oswestry Disability Questionnaire (ODI), Timed Up & Go test (TUG), EQ-5D 5L, and Barthel Index. RESULTS: In total, 19 patients (78 ± 7 years, 13 female) were analysed. Operative treatment consisted of long-segment posterior instrumentation in 9 cases and short-segment posterior instrumentation in 10 cases. Pedicle screws were augmented in 68 %, augmentation of the fractured vertebra was performed in 42%, and additional anterior reconstruction was done in 21 %. Two patients (11 %) received short-segment posterior instrumentation without either anterior reconstruction or cement-augmentation of the fractured vertebra. No surgical or major complications occurred, but general postoperative complications were observed in 45%. At a follow-up of mean 20 ± 10 weeks (range, 12 to 48 weeks), patients showed significant improvements in all functional outcome parameters. CONCLUSIONS: In this analysis of patients with type OF 5 fractures, surgical stabilization was the treatment of choice and lead to significant short-term improvement in terms of functional outcome and quality of life despite a high general complication rate.

Clinical Evaluation of the Osteoporotic Fracture Treatment Score (OF-Score): Results of the Evaluation of the Osteoporotic Fracture Classification, Treatment Score and Therapy Recommendations (EOFTT) Study.

STUDY DESIGN: Multicenter prospective cohort study. OBJECTIVE: The study aims to validate the recently developed OF score for treatment decisions in patients with osteoporotic vertebral compression fractures (OVCF). METHODS: This is a prospective multicenter cohort study (EOFTT) in 17 spine centers. All consecutive patients with OVCF were included. The decision for conservative or surgical therapy was made by the treating physician independent of the OF score recommendation. Final decisions were compared to the recommendations given by the OF score. Outcome parameters were complications, Visual Analogue Scale, Oswestry Disability Questionnaire, Timed Up & Go test, EQ-5D 5 L, and Barthel Index. RESULTS: In total, 518 patients (75.3% female, age 75 ± 10) years were included. 344 (66%) patients received surgical treatment. 71% of patients were treated following the score recommendations. For an OF score cut-off value of 6.5, the sensitivity and specificity to predict actual treatment were 60% and 68% (AUC .684, P < .001). During hospitalization overall 76 (14.7%) complications occurred. The mean follow-up rate and time were 92% and 5 ± 3.5 months, respectively. While all patients in the study cohort improved in clinical outcome parameters, the effect size was significantly less in the patients not treated in line with the OF score's recommendation. Eight (3%) patients needed revision surgery. CONCLUSIONS: Patients treated according to the OF score's recommendations showed favorable short-term clinical results. Noncompliance with the score resulted in more pain and impaired functional outcome and quality of life. The OF score is a reliable and save tool to aid treatment decision in OVCF.

Mental health care equity and access: A group therapy solution.

Mental health services are experiencing unprecedented levels of demand from clients during COVID resulting in longer wait lists and therapist burnout. As Nemoyer et al. (2019) point out, minorities experience a higher burden of mental illness while having less access and lower quality treatments. COVID has increased demands for mental health services even further, creating bottlenecks of care, therapist burnout, and leading to ever longer wait lists. This article will argue that inefficient supply of services is created by mental health providers being incentivized toward individual therapy. Group therapy offers a solution because it is a "triple E treatment"-efficient, effective, and equivalent to individual therapy in terms of outcomes (Burlingame & Strauss, 2021). Group interventions also address systemic racism and the needs of minorities who have been marginalized and cope with minority stress. This article will utilize a labor and financial impact analysis to demonstrate how increasing group therapy by 10% nationally, particularly in private practice and primary care integration settings, would increase treatment access for over 3.5 million people while reducing the need for 34,473 additional new therapists and simultaneously saving over $5.6 billion. It will discuss how incentivizing groups while holding therapists accountable for training, competency when working with people from diverse backgrounds, and outcomes can result in improved efficiency. This will allow therapists greater freedom to collaboratively select the most effective treatments for those from underserved and minority backgrounds and create easier access to quality treatments. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Clonally resolved single-cell multi-omics identifies routes of cellular differentiation in acute myeloid leukemia.

Inter-patient variability and the similarity of healthy and leukemic stem cells (LSCs) have impeded the characterization of LSCs in acute myeloid leukemia (AML) and their differentiation landscape. Here, we introduce CloneTracer, a novel method that adds clonal resolution to single-cell RNA-seq datasets. Applied to samples from 19 AML patients, CloneTracer revealed routes of leukemic differentiation. Although residual healthy and preleukemic cells dominated the dormant stem cell compartment, active LSCs resembled their healthy counterpart and retained erythroid capacity. By contrast, downstream myeloid progenitors constituted a highly aberrant, disease-defining compartment: their gene expression and differentiation state affected both the chemotherapy response and leukemia's ability to differentiate into transcriptomically normal monocytes. Finally, we demonstrated the potential of CloneTracer to identify surface markers misregulated specifically in leukemic cells. Taken together, CloneTracer reveals a differentiation landscape that mimics its healthy counterpart and may determine biology and therapy response in AML.

Georg Schmorl prize of the German spine society (DWG) 2022: current treatment for inpatients with osteoporotic thoracolumbar fractures-results of the EOFTT study.

AIM: Osteoporotic thoracolumbar fractures are of increasing importance. To identify the optimal treatment strategy this multicentre prospective cohort study was performed. PURPOSE: Patients suffering from osteoporotic thoracolumbar fractures were included. Excluded were tumour diseases, infections and limb fractures. Age, sex, trauma mechanism, OF classification, OF-score, treatment strategy, pain condition and mobilization were analysed. METHODS: A total of 518 patients' aged 75 ± 10 (41-97) years were included in 17 centre. A total of 174 patients were treated conservatively, and 344 were treated surgically, of whom 310 (90%) received minimally invasive treatment. An increase in the OF classification was associated with an increase in both the likelihood of surgery and the surgical invasiveness. RESULTS: Five (3%) complications occurred during conservative treatment, and 46 (13%) occurred in the surgically treated patients. 4 surgical site infections and 2 mechanical failures requested revision surgery. At discharge pain improved significantly from a visual analogue scale score of 7.7 (surgical) and 6.0 (conservative) to a score of 4 in both groups (p < 0.001). Over the course of treatment, mobility improved significantly (p = 0.001), with a significantly stronger (p = 0.007) improvement in the surgically treated patients. CONCLUSION: Fracture severity according to the OF classification is significantly correlated with higher surgery rates and higher invasiveness of surgery. The most commonly used surgical strategy was minimally invasive short-segmental hybrid stabilization followed by kyphoplasty/vertebroplasty. Despite the worse clinical conditions of the surgically treated patients both conservative and surgical treatment led to an improved pain situation and mobility during the inpatient stay to nearly the same level for both treatments.

Influence of the layer thickness on the flexural strength of aged and nonaged additively manufactured interim dental material.

PURPOSE: To measure the flexural strength and Weibull characteristics of aged and nonaged printed interim dental material fabricated with different layer thickness. MATERIAL AND METHODS: Bars (25×2×2 mm) were additively fabricated by using a polymer printer (Asiga Max) and an interim resin (Nexdent C&B MFH). Specimens were fabricated with the same printing parameters and postprocessing procedures, but with 7 different layer thickness: 50 (control or 50-G group), 10 (10-G group), 25 (25-G group), 75 (75-G group), 100 (100-G group), 125 (125-G group), and 150 µm (150-G group). Two subgroups were created: nonaged and aged subgroups (n = 10). A universal testing machine was selected to measure flexural strength. Two-parameter Weibull distribution values were computed. Two-way ANOVA and Tukey tests were selected for statistical evaluation of the data (α = 0.05). RESULTS: Artificial aging methods (p < 0.001) were a significant predictor of the flexural strength computed. Aged specimens acquired less flexural strength than nonaged specimens. The Weibull distribution obtained the highest shape for nonaged 50-G and 75-G group specimens compared with those of other nonaged groups, while the Weibull distribution showed the highest shape for aged 125-G specimens. CONCLUSIONS: The flexural strength of the additively fabricated interim material examined was not influenced by the layer thickness at which the specimens were fabricated; however, artificial aging techniques reduced its flexural strength. Aged specimens presented lower Weibull distribution values compared with nonaged specimens, except for the 125-G specimens.

Adapting the Digital Reference Denture Technique for Full-Arch Cases Using a Novel Fixed Attachment System.

Digital technology has tremendously impacted implant dentistry and particularly the production of full-arch reconstructions. The use of digital methods to fabricate removable and fixed complete dental prostheses with implants offers many benefits, yet for some clinicians a hybrid method that combines analog and digital techniques for full-arch restorations may be beneficial. This article describes a combination analog-digital method that utilizes the patient's existing removable prosthesis to guide fabrication of a fixed full-arch restoration using a novel stud-style abutment system with a contemporary housing and insert combination.

Perfluorocarbons cause thrombocytopenia, changes in RBC morphology and death in a baboon model of systemic inflammation.

A perfluorocarbon (PFC) investigated for treatment of traumatic brain injury (TBI) delivers oxygen to support brain function, but causes transient thrombocytopenia. TBI can cause acute inflammation with resulting thrombocytopenia; an interaction between the PFC effects and TBI inflammation might exacerbate thrombocytopenia. Therefore, PFC effects on platelet (PLT) function and hemostasis in a lipopolysaccharide (LPS) model of inflammation in the baboon were studied. Animals were randomized to receive saline ±LPS, and ± one of two doses of PFC. PLT count, transmission electron microscopy, and microparticle populations were quantified at baseline (BL) and at 2, 24, 48, 72, and 96 hours; hemostatic parameters for aggregometry and for blood clotting were measured at baseline (BL) and days 3 and 4. Injection of vehicle and LPS caused thrombocytopenia within hours; PFCs caused delayed thrombocytopenia beginning 48 hours post-infusion. LPS+PFC produced a more prolonged PLT decline and decreased clot strength. LPS+PFC increased ADP-stimulated aggregation, but PFC alone did not. Microparticle abundance was greatest in the LPS+PFC groups. LPS+PFC caused diffuse microvascular hemorrhage and death in 2 of 5 baboons in the low dose LPS-PFC group and 2 of 2 in the high dose LPS-PFC group. Necropsy and histology suggested death was caused by shock associated with hemorrhage in multiple organs. Abnormal morphology of platelets and red blood cells were notable for PFC inclusions. In summary, PFC infusion caused clinically significant thrombocytopenia and exacerbated LPS-induced platelet activation. The interaction between these effects resulted in decreased hemostatic capacity, diffuse bleeding, shock and death.

scTAM-seq enables targeted high-confidence analysis of DNA methylation in single cells.

Single-cell DNA methylation profiling currently suffers from excessive noise and/or limited cellular throughput. We developed scTAM-seq, a targeted bisulfite-free method for profiling up to 650 CpGs in up to 10,000 cells per experiment, with a dropout rate as low as 7%. We demonstrate that scTAM-seq can resolve DNA methylation dynamics across B-cell differentiation in blood and bone marrow, identifying intermediate differentiation states that were previously masked. scTAM-seq additionally queries surface-protein expression, thus enabling integration of single-cell DNA methylation information with cell atlas data. In summary, scTAM-seq is a high-throughput, high-confidence method for analyzing DNA methylation at single-CpG resolution across thousands of single cells.

Longitudinal multi-omics analysis identifies early blood-based predictors of anti-TNF therapy response in inflammatory bowel disease.

BACKGROUND AND AIMS: Treatment with tumor necrosis factor α (TNFα) antagonists in IBD patients suffers from primary non-response rates of up to 40%. Biomarkers for early prediction of therapy success are missing. We investigated the dynamics of gene expression and DNA methylation in blood samples of IBD patients treated with the TNF antagonist infliximab and analyzed the predictive potential regarding therapy outcome. METHODS: We performed a longitudinal, blood-based multi-omics study in two prospective IBD patient cohorts receiving first-time infliximab therapy (discovery: 14 patients, replication: 23 patients). Samples were collected at up to 7 time points (from baseline to 14 weeks after therapy induction). RNA-sequencing and genome-wide DNA methylation data were analyzed and correlated with clinical remission at week 14 as a primary endpoint. RESULTS: We found no consistent ex ante predictive signature across the two cohorts. Longitudinally upregulated transcripts in the non-remitter group comprised TH2- and eosinophil-related genes including ALOX15, FCER1A, and OLIG2. Network construction identified transcript modules that were coherently expressed at baseline and in non-remitting patients but were disrupted at early time points in remitting patients. These modules reflected processes such as interferon signaling, erythropoiesis, and platelet aggregation. DNA methylation analysis identified remission-specific temporal changes, which partially overlapped with transcriptomic signals. Machine learning approaches identified features from differentially expressed genes cis-linked to DNA methylation changes at week 2 as a robust predictor of therapy outcome at week 14, which was validated in a publicly available dataset of 20 infliximab-treated CD patients. CONCLUSIONS: Integrative multi-omics analysis reveals early shifts of gene expression and DNA methylation as predictors for efficient response to anti-TNF treatment. Lack of such signatures might be used to identify patients with IBD unlikely to benefit from TNF antagonists at an early time point.

Cannabis Adaptation During and After Alcohol Ignition Interlock Device Installation: A Longitudinal Study.

OBJECTIVE: A common intervention to prevent alcohol-impaired driving are alcohol ignition interlock devices (IIDs), which prevent drivers with a blood alcohol concentration greater than .025% from starting the car. These devices force drivers to adapt their drinking to accommodate the device. Prior studies indicated a transfer of risk as some drivers with an IID may increase cannabis use as they decrease alcohol use. This study examines whether this increase in cannabis use persists after IID removal when alcohol use reverts to pre-IID levels. METHOD: The data are from the Managing Heavy Drinking (MHD) study of drivers in New York State. The MHD is a comprehensive three-wave study of drivers convicted of driving under the influence from 2015 to 2020. Participants (N = 189) completed all waves, and provided oral fluid/blood and hair samples to measure cannabis and alcohol use, respectively. Mixed between-within analysis of variance was conducted to assess cannabis use at IID installation (Time 1), removal (Time 2), and at 6-month follow-up (Time 3). RESULTS: In aggregate, participants increased their cannabis use over the course of the study. Drivers who decreased their alcohol use while the IID was installed on their car significantly increased their cannabis use while the IID was in place and further increased cannabis use after the device's removal. CONCLUSIONS: IIDs are efficacious in preventing alcohol-impaired driving. However, in some cases, they may have the unintended effect of increasing other substance use. The current study outlines the need for supplemental treatment interventions while on IID to prevent a transfer of risk to other substances, or polysubstance use after the device is removed.

Influence of postprocessing rinsing solutions and duration on flexural strength of aged and nonaged additively manufactured interim dental material.

STATEMENT OF PROBLEM: Additive manufacturing procedures for fabricating interim restorations include rinsing postprocessing procedures. However, the impact of different rinsing solutions and times on flexural strength is unknown. PURPOSE: The purpose of this in vitro study was to assess the influence of the rinsing solutions and duration, as well as accelerated aging (thermocycling) procedures, on the flexural strength and Weibull characteristics of an additively manufactured interim dental material. MATERIAL AND METHODS: A bar design (25×2×2 mm) file was used to fabricate all the specimens with 3D printing and an interim material (Nextdent C&B MFH). Five groups were created based on the rinsing solution used during the postprocessing procedures: 91% isopropyl alcohol (IPA) (control or IPA-91), 99% IPA (IPA-99 group), bio-ethyl alcohol 100% (BE group), tripropylene glycol monomethyl ether (TPM) 100% (TPM group), and water miscible formula (Resinaway) (RA group). Each group was divided into 4 subgroups depending on the total rinsing time: 5, 6, 7, and 8 minutes (5, 6, 7, and 8 subgroups). Additionally, each subgroup was distributed between nonaged and aged thermocycling procedures (n=10). Flexural strength measurements were made by using a universal testing machine. Two-parameter Weibull distribution values, including the Weibull modulus, scale (m), and shape (0), were calculated. Three-way ANOVA and pairwise multiple comparison Tukey tests were used to analyze the data (α=.05). RESULTS: Three-way ANOVA showed that the rinsing solution (P<.001), rinsing time (P=.004), and thermocycling procedures (P<.001) were significant predictors of the flexural strength values obtained. The IPA-91 and IPA-99 groups obtained the highest flexural strength, while the RA, TPM, and BE groups obtained the lowest flexural strength. The 7- and 8-minute subgroups obtained the highest flexural strength, while the 5-minute subgroup obtained the lowest flexural strength. The nonaged specimens obtained significantly higher mean flexural strength values than the aged specimens. CONCLUSIONS: The vat-polymerized additively manufactured interim dental material tested with differing rinsing solutions and times demonstrated significant differences in the flexural strength values measured. Accelerated artificial aging procedures significantly decreased the flexural strength of the vat-polymerized interim dental material tested.

Blacklight sintering of ceramics.

For millennia, ceramics have been densified via sintering in a furnace, a time-consuming and energy-intensive process. The need to minimize environmental impact calls for new physical concepts beyond large kilns relying on thermal radiation and insulation. Here, we realize ultrarapid heating with intense blue and UV-light. Thermal management is quantified in experiment and finite element modelling and features a balance between absorbed and radiated energy. With photon energy above the band gap to optimize absorption, bulk ceramics are sintered within seconds and with outstanding efficiency (≈2 kWh kg-1) independent of batch size. Sintering on-the-spot with blacklight as a versatile and widely applicable power source is demonstrated on ceramics needed for energy storage and conversion and in electronic and structural applications foreshadowing economic scalability.

Examining the role of trauma in alcohol interlock performance: A structural pathway analysis.

OBJECTIVE: Self-medication using alcohol is a common coping response among individuals dealing with trauma as is driving under the influence of alcohol (DUI). A common intervention for drivers convicted of DUI, is an alcohol ignition interlock device (IID)-which requires breath samples before starting the car. If the sample is above a predetermined limit (.025), the car will not start, thus preventing impaired driving. IIDs are an effective intervention to reduce rates of drinking and driving among high risk populations; however, limited research has examined how traumatic experiences may impact performance on IIDs. METHODS: This study is an archival analysis of the Managing Heavy Drinking (MHD) study of drivers in New York state. The MHD is a comprehensive study of drivers convicted of a DUI from 2015-2020. Participants (N = 121) completed questionnaires and provided consent to retrieve information from interlock providers. Outcome variable included high BAC lockout ratios (number of high BAC lockouts [BAC>.08]/number of clean blows [BAC ≤ .025]). Other variables included demographic variables, alcohol treatment history, trauma experiences, and prior DUI history. Variables were entered into a structural equation model. RESULTS: In the final structural model, pathways that demonstrated a p-value of greater than .10 were dropped from the model. This produced acceptable overall model fit statistics (χ2 = 27.059(10), p=.003; CFI = .900; NFI = .898; RMSEA = .063). A significant pathway was found from the trauma measure to alcohol use (ß = .132), and from alcohol use to interlock performance (ß = .636). However, no significant relationship was found between trauma and interlock performance other than through alcohol use. CONCLUSIONS: The current study provides a useful framework upon which to understand the role traumatic experiences have on alcohol IID performance. Traumatic experiences are in of themselves insufficient to impact IID performance directly, but it may indirectly impact IID performance through increasing alcohol use.