Citations

Abstract Summary We recently introduced the Gut Microbiome Wellness Index (GMWI), a stool metagenome-based indicator for assessing health by determining the likelihood of disease given the state of one’s gut microbiome. The calculation of our wellness index depends on the relative abundances of health-prevalent and health-scarce species. Encouragingly, GMWI has already been utilized in various studies focusing on differences in the gut microbiome between cases and controls. Herein, we introduce the GMWI-webtool, a user-friendly browser application that computes GMWI, health-prevalent/-scarce species’ relative abundances, and α-diversities from stool shotgun metagenome taxonomic profiles. Users of our interactive online tool can visualize their results and compare them side-by-side with those from our pooled reference dataset of metagenomes, as well as export data in.csv format and high-resolution figures. Availability and implementation GMWI-webtool is freely available here: https://gmwi-webtool.github.io/. Supplementary information Supplementary data are available at Bioinformatics online.

Background Transvenous embolization is emerging as a promising treatment for cerebrospinal fluid-venous fistulas (CVF) associated with spontaneous intracranial hypotension (SIH). Objective To perform an independent validation of the efficacy and safety of the procedure and describe the procedural techniques used at our institution. Methods A retrospective review was performed including consecutive patients with SIH who had undergone CVF embolization with 3-month clinical and imaging follow-up. Clinical evaluation included the Patient Global Impression of Change (PGIC) Scale and six-item Headache Impact Test (HIT-6). Bern SIH score was used for imaging evaluation on brain MRI. Post-treatment changes in scores were assessed by Wilcoxon signed rank test. Procedural technical details, including use of upper-extremity access and dual-microcatheter pressure cooker technique, were recorded. Results 18 patients (13 female, median age 60 years) were included. 17 (94%) procedures were performed with upper-extremity access and 12 (67%) using dual-microcatheter pressure cooker technique. After embolization, 16 (89%) patients reported much or very much improved at follow-up PGIC; median (IQR) HIT-6 score improved from 68 (62–72) to 36 (36–38) and Bern SIH score improved from 8 (6–8) to 3 (1.5–3.5), p values <0.001. Side effects were transient embolization site back pain in 15 (83%) and rebound intracranial hypertension requiring medical management in 9 (50%) patients. HIT-6 and Bern SIH score changes were similar between conventional and pressure cooker techniques ( p values >0.05). Conclusion Transvenous embolization is independently validated as a highly effective and safe treatment for CVF and is feasible using upper-extremity venous access. Dual-microcatheter and balloon/coil pressure cooker techniques may be used to optimize distribution of embolic material and potentially, treatment efficacy.

Background Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis. Methods A retrospective cohort of patients diagnosed with ICI-nephritis was compared with three prospectively enrolled control cohorts: ICI-treated controls without immune-related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression of IL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls. Results sIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal (ULN), IQR 1.9–3.3), compared with ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5–0.9, p<0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7–1.1, p=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (area under the curve >96%) when compared with either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+T cells, CD45RA+CD8+ T cells, memory CD27+B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared with ICI-treated controls. Gene expressions for IL2RA , IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls. Conclusion Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.

Abstract Objectives To explore current management practices for PMR by general practitioners (GPs) and rheumatologists including implications for clinical trial recruitment. Methods An English language questionnaire was constructed by a working group of rheumatologists and GPs from six countries. The questionnaire focused on: 1: Respondent characteristics; 2: Referral practices; 3: Treatment with glucocorticoids; 4: Diagnostics; 5: Comorbidities; and 6: Barriers to research. The questionnaire was distributed to rheumatologists and GPs worldwide via members of the International PMR/Giant Cell Arteritis Study Group. Results In total, 394 GPs and 937 rheumatologists responded to the survey. GPs referred a median of 25% of their suspected PMR patients for diagnosis and 50% of these were returned to their GP for management. In general, 39% of rheumatologists evaluated patients with suspected PMR &gt;2 weeks after referral, and a median of 50% of patients had started prednisolone before rheumatologist evaluation. Direct comparison of initial treatment showed that the percentage prescribing &gt;25 mg prednisolone daily for patients was 30% for GPs and 12% for rheumatologists. Diagnostic imaging was rarely used. More than half (56%) of rheumatologists experienced difficulties recruiting people with PMR to clinical trials. Conclusion This large international survey indicates that a large proportion of people with PMR are not referred for diagnosis, and that the proportion of treatment-naive patients declined with increasing time from referral to assessment. Strategies are needed to change referral and management of people with PMR, to improve clinical practice and facilitate recruitment to clinical trials.

Abstract Tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) play an important role in tumor growth and progression. TAMs have been involved in producing immunosuppressive TME via various factors; however, the underlying mechanisms remain unclear in B-cell lymphoma, including mantle cell lymphoma (MCL). We identified that chemokine receptor-1 (CCR1) is highly expressed on monocytes (Mo) and macrophages (MΦ), and CCR1 pharmacological inhibition or CCR1 siRNA abolished lymphoma-mediated Mo/MΦ migration in a chemotaxis assay. The deficiency of host CCR1 (CCR1 KO) was associated with decreased infiltration of peritoneal-MΦ compared with WT-CCR1. Functional studies indicated that the genetic depletion of CCR1 or treatment inhibited protumor MΦ (M2-like) phenotype by decreasing CD206 and IL-10 expression. Moreover, CCR1 depletion reprogrammed MΦ toward an MHCII+/TNFα+ immunogenic phenotype. Mechanistically, protumor MΦ driven–IL-10 provides a positive feedback loop to tumor-CCL3 by regulating the CCL3 promoter via STAT1 signaling. Therapeutic in vivo targeting of CCR1 with CCR1 antagonist BX-471 significantly reduced FC-muMCL1 mouse tumors in the syngeneic MCL model by the depletion of M2-TAMs and increased infiltration of cytotoxic CD8+ T cells. Our study established that CCR1 exerts a pivotal role in macrophage programming, thus shaping protumor TME and lymphoma progression. CCR1 inhibition through CCR1 antagonists may be a promising therapeutic strategy to reprogram macrophages in lymphoma-TME and achieve better clinical outcomes in patients.

Importance Patients with atrial fibrillation (AF) treated with mechanical thrombectomy (MT) for acute ischemic stroke (AIS) have been reported to experience worse outcomes compared with patients without AF. Objective To assess differences between patients with AF and their counterparts without AF treated with MT for AIS, focusing on safety outcomes, clinical outcomes, and baseline characteristics in both groups. Data Sources A systematic literature review of the English language literature from inception to July 14, 2022, was conducted using Web of Science, Embase, Scopus, and PubMed databases. Study Selection Studies that focused on patients with and without AF treated with MT for AIS were included. Multiple reviewers screened studies to identify studies included in analysis. Data Extraction and Synthesis Data were extracted following the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline to ensure accuracy. Data were pooled using a random-effects model. Main Outcomes and Measures The primary outcome of interest was rate of modified Rankin Scale (mRS) scores of 0 to 2 at 90 days. Secondary outcomes of interest included rates of successful reperfusion, defined as thrombolysis in cerebral infarction (TICI) scores of 2b to 3, 90-day mortality, symptomatic intracranial hemorrhage (SICH), and baseline patient characteristics. Results Of 1696 initially retrieved studies, 10 studies were included, with 6543 patients. Patients with AF were a mean of 10.17 (95% CI, 8.11-12.23) years older ( P &amp;lt; .001) and had higher rates of hypertension (OR, 1.89 [95% CI, 1.57-2.27]; P &amp;lt; .001) and diabetes (OR, 1.16 [95% CI, 1.02-1.31]; P = .02). Overall, there were comparable rates of mRS scores of 0 to 2 between patients with AF and patients without AF (odds ratio [OR], 0.72 [95% CI, 0.47-1.10]; P = .13), with significant heterogeneity among the included studies. After sensitivity analysis, the rate of mRS scores of 0 to 2 was significantly lower among patients with AF (OR, 0.65 [95% CI, 0.52-0.81]; P &amp;lt; .001). Successful reperfusion rates were similar between the groups (OR, 1.11 [95% CI, 0.78-1.58]; P = .57). The rate of SICH was similar between groups (OR, 1.05 [95% CI, 0.84-1.31]; P = .68). Mortality was significantly higher in the AF group (OR, 1.47 [95% CI, 1.12-1.92]; P = .005). Conclusions and Relevance In this systematic review and meta-analysis, patients with AF experienced worse 90-day outcomes, even in the setting of similar rates of successful reperfusion. This was likely associated with greater age and greater rates of comorbidities among patients with AF.

Broadly neutralizing antibodies (bNAbs) are potent in neutralizing a wide range of HIV strains. VRC01 is a CD4-binding-site (CD4-bs) class of bNAbs that binds to the conserved CD4-binding region of HIV-1 envelope (env) protein. Natural products that mimic VRC01 bNAbs by interacting with the conserved CD4-binding regions may serve as a new generation of HIV-1 entry inhibitors by being broadly reactive and potently neutralizing. This study aimed to identify compounds that mimic VRC01 by interacting with the CD4-bs of HIV-1 gp120 and thereby inhibiting viral entry into target cells. Libraries of purchasable natural products were virtually screened against clade A/E recombinant 93TH057 (PDB: 3NGB) and clade B (PDB ID: 3J70) HIV-1 env protein. Protein–ligand interaction profiling from molecular docking and dynamics simulations showed that the compounds had intermolecular hydrogen and hydrophobic interactions with conserved amino acid residues on the CD4-binding site of recombinant clade A/E and clade B HIV-1 gp120. Four potential lead compounds, NP-005114, NP-008297, NP-007422, and NP-007382, were used for cell-based antiviral infectivity inhibition assay using clade B (HXB2) env pseudotype virus (PV). The four compounds inhibited the entry of HIV HXB2 pseudotype viruses into target cells at 50% inhibitory concentrations (IC50) of 15.2 µM (9.7 µg/mL), 10.1 µM (7.5 µg/mL), 16.2 µM (12.7 µg/mL), and 21.6 µM (12.9 µg/mL), respectively. The interaction of these compounds with critical residues of the CD4-binding site of more than one clade of HIV gp120 and inhibition of HIV-1 entry into the target cell demonstrate the possibility of a new class of HIV entry inhibitors.

Background and Objectives: Brain Tumor Fusion-based Segments and Classification-Non-enhancing tumor (BTFSC-Net) is a hybrid system for classifying brain tumors that combine medical image fusion, segmentation, feature extraction, and classification procedures. Materials and Methods: to reduce noise from medical images, the hybrid probabilistic wiener filter (HPWF) is first applied as a preprocessing step. Then, to combine robust edge analysis (REA) properties in magnetic resonance imaging (MRI) and computed tomography (CT) medical images, a fusion network based on deep learning convolutional neural networks (DLCNN) is developed. Here, the brain images’ slopes and borders are detected using REA. To separate the sick region from the color image, adaptive fuzzy c-means integrated k-means (HFCMIK) clustering is then implemented. To extract hybrid features from the fused image, low-level features based on the redundant discrete wavelet transform (RDWT), empirical color features, and texture characteristics based on the gray-level cooccurrence matrix (GLCM) are also used. Finally, to distinguish between benign and malignant tumors, a deep learning probabilistic neural network (DLPNN) is deployed. Results: according to the findings, the suggested BTFSC-Net model performed better than more traditional preprocessing, fusion, segmentation, and classification techniques. Additionally, 99.21% segmentation accuracy and 99.46% classification accuracy were reached using the proposed BTFSC-Net model. Conclusions: earlier approaches have not performed as well as our presented method for image fusion, segmentation, feature extraction, classification operations, and brain tumor classification. These results illustrate that the designed approach performed more effectively in terms of enhanced quantitative evaluation with better accuracy as well as visual performance.

Leukemia cells accumulate DNA damage but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine/one-carbon cycle metabolism contributed to accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases [OTKs: FLT3(ITD), JAK2(V617F), BCR/ABL1]. To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLq) by ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLq and its proteasomal degradation. Overexpression of POLq in OTK-positive cells resulted in efficient repair of DPC-containing DNA double-strand breaks (DSBs) by POLq-mediated end-joining (TMEJ). Transforming activity of OTKs and other leukemia-inducing oncogenes, especially of those causing inhibition of BRCA1/2 -mediated homologous recombination (HR) with and without concomitant inhibition of DNA-PK -dependent non-homologous end-joining (D-NHEJ), was abrogated in Polq-/- murine bone marrow cells. Genetic and pharmacological targeting of POLq polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitor or DPC-inducing drug etoposide enhanced anti-leukemia effect of POLq inhibitor (POLqi) in vitro and in vivo. In conclusion, we demonstrated that POLq plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde and that it can be targeted to achieve therapeutic effect.