Chronic foot wounds often require bony resection; however, altering the tripod of the foot carries a risk of new ulcer development nearing 70%. Resulting defects often require free tissue transfer ...(FTT) reconstruction; outcomes data for various bony resection and FTT options may guide clinical decision-making regarding bone and soft-tissue management. The authors hypothesized that alteration of the bony tripod will increase risk of new lesion development after FTT reconstruction.
A single-center retrospective cohort analysis of patients undergoing FTT from 2011 through 2019 with bony resection and soft-tissue defects of the foot was performed. Data collected included demographics, comorbidities, wound locations, and FTT characteristics. Primary outcomes were recurrent lesion (RL) and new lesion (NL) development. Multivariate logistic regression and Cox hazards regression were used to produce adjusted odds ratios and hazard ratios.
Sixty-four patients (mean age, 55.9 years) who underwent bony resection and FTT were included. Mean Charlson Comorbidity Index was 4.1 (SD 2.0), and median follow-up was 14.6 months (range, 7.5 to 34.6 months). Wounds developed after FTT in 42 (67.1%) (RL, 39.1%; NL, 40.6%). Median time to NL development was 3.7 months (range, 0.47 to 9.1 months). First-metatarsal defect (OR, 4.8; 95% CI, 1.5 to 15.7) and flap with cutaneous component (OR, 0.24; 95% CI, 0.07 to 0.8) increased and decreased odds of NL development, respectively.
First-metatarsal defects significantly increase NL risk after FTT. The majority of ulcerations heal with minor procedures but require long-term follow-up. Soft-tissue reconstruction with FTT achieves success in the short term, but NL and RL occur at high rates in the months to years after initial healing.
Risk, III.
Although cyanide's biological effects are pleiotropic, its most obvious effects are as a metabolic poison. Cyanide potently inhibits cytochrome c oxidase and potentially other metabolic enzymes, ...thereby unleashing a cascade of metabolic perturbations that are believed to cause lethality. From systematic screens of human metabolites using a zebrafish model of cyanide toxicity, we have identified the TCA-derived small molecule glyoxylate as a potential cyanide countermeasure. Following cyanide exposure, treatment with glyoxylate in both mammalian and non-mammalian animal models confers resistance to cyanide toxicity with greater efficacy and faster kinetics than known cyanide scavengers. Glyoxylate-mediated cyanide resistance is accompanied by rapid pyruvate consumption without an accompanying increase in lactate concentration. Lactate dehydrogenase is required for this effect which distinguishes the mechanism of glyoxylate rescue as distinct from countermeasures based solely on chemical cyanide scavenging. Our metabolic data together support the hypothesis that glyoxylate confers survival at least in part by reversing the cyanide-induced redox imbalances in the cytosol and mitochondria. The data presented herein represent the identification of a potential cyanide countermeasure operating through a novel mechanism of metabolic modulation.
Epigenetic reprogramming underlies specification of immune cell lineages, but patterns that uniquely define immune cell types and the mechanisms by which they are established remain unclear. Here, we ...identified lineage-specific DNA methylation signatures of six immune cell types from human peripheral blood and determined their relationship to other epigenetic and transcriptomic patterns. Sites of lineage-specific hypomethylation were associated with distinct combinations of transcription factors in each cell type. By contrast, sites of lineage-specific hypermethylation were restricted mostly to adaptive immune cells. PU.1 binding sites were associated with lineage-specific hypo- and hypermethylation in different cell types, suggesting that it regulates DNA methylation in a context-dependent manner. These observations indicate that innate and adaptive immune lineages are specified by distinct epigenetic mechanisms via combinatorial and context-dependent use of key transcription factors. The cell-specific epigenomics and transcriptional patterns identified serve as a foundation for future studies on immune dysregulation in diseases and aging.
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•Identifies differential DNA methylation signatures of six human immune cell types•Combinations of transcription factor motifs associate with lineage-specific methylation•EBF1 binding coincides with DNA hypomethylated sites in human B cells•Adaptive and innate immune cells show distinct methylation and gene expression patterns
Epigenetic patterns that define immune cell lineages remain unclear. Roy et al. define DNA methylation signatures of six human immune cell types. Sites of cell-specific differential methylation are related to transcription factors, other epigenetic modifications, and gene expression. Their study reveals differences in the relationship of DNA methylation to tissue-selective gene expression in adaptive compared with innate immune cell types.
Synovial pathology has been linked to osteoarthritis (OA) pain in patients. Microscopic grading systems for synovial changes in human OA have been described, but a standardized approach for murine ...models of OA is needed. We sought to develop a reproducible approach and set of minimum recommendations for reporting of synovial histopathology in mouse models of OA.
Coronal and sagittal sections from male mouse knee joints subjected to destabilization of medial meniscus (DMM) or partial meniscectomy (PMX) were collected as part of other studies. Stains included Hematoxylin and Eosin (H&E), Toluidine Blue (T-Blue), and Safranin O/Fast Green (Saf-O). Four blinded readers graded pathological features (hyperplasia, cellularity, and fibrosis) at specific anatomic locations. Inter-reader agreement of each feature score was determined.
There was acceptable to very good agreement when using 3–4 individual readers. After DMM and PMX, expected medial predominant changes in hyperplasia and cellularity were observed, with fibrosis noted at 12 weeks post-PMX. Synovial changes were consistent from section to section in the mid-joint area. When comparing stains, H&E and T-blue resulted in better agreement compared to Saf-O stain.
To account for the pathologic and anatomic variability in synovial pathology and allow for a more standardized evaluation that can be compared across studies, we recommend evaluating a minimum set of 3 pathological features at standardized anatomic areas. Further, we suggest reporting individual feature scores separately before relying on a single summed “synovitis” score. H&E or T-blue are preferred, inter-reader agreement for each feature should be considered.
Dynamic thermal gradient-based processes for directed self-assembly of block copolymer (BCP) thin films such as cold zone annealing (CZA) have demonstrated much potential for rapidly fabricating ...highly ordered patterns of BCP domains with facile orientation control. As a demonstration, hexagonally packed predominantly vertical cylindrical morphology, technologically relevant for applications such as membranes and lithography, was achieved in 1 μm thick cylinder-forming PS-b-PMMA (cBCP) films by applying sharp thermal gradients (CZA-Sharp) at optimum sample sweep rates. A thorough understanding of the molecular level mechanisms and pathways of the BCP ordering that occur during this CZA-S process is presented, useful to fully exploit the potential of CZA-S for large-scale BCP-based device fabrication. To that end, we developed a customized CZA-S assembly to probe the dynamic structure evolution and ordering of the PS-b-PMMA cBCP film in situ as it undergoes the CZA-S process using the grazing incidence small-angle X-ray scattering (GISAXS) technique. Four distinct regimes of BCP ordering were observed within the gradient that include microphase separation from an “as cast” unordered state (Regime I), evolution of vertical cylinders under a thermally imposed strain gradient (Regime II), reorientation of a fraction of cylinders due to preferential substrate interactions (Regime III), and finally grain-coarsening on the cooling edge (Regime IV). The ordering pathway in the different regimes is further described within the framework of an energy landscape. A novel aspect of this study is the identification of a grain-coarsening regime on the cooling edge of the gradient, previously obscure in zone annealing studies of BCPs. Such insights into the development of highly ordered BCP nanostructures under template-free thermal gradient fields can potentially have important ramifications in the field of BCP-directed self-assembly and self-assembling polymer systems more broadly.
To determine whether use of an antibiotic-irrigating wound protector (AWP) reduces infectious complications after robotic radical cystectomy with extracorporeal urinary diversion (RCUD).
A ...prospectively maintained bladder cancer database was queried for patients undergoing robotic RCUD at a tertiary referral center one year prior to implementing an AWP and one year after (2018–2020). All diversions were performed extra-corporally. 92 patients total. 46 consecutive patients using a traditional wound protector (TWP) and 46 consecutive with an AWP. Infections were classified as symptomatic urinary tract infection, blood stream infection, and surgical site infection. The incidence of infectious complications at 30- and 90-days were compared.
Baseline patient characteristics between the 2 groups showed no statistically significant differences. The overall complication rate was 65.2% in the TWP group and 26.1% in the AWP group at 30-days, and 67.4% vs 30.4% at 90-days. Focusing on infections, the 30-day complication rate was 30.4% in the TWP group compared to 6.5% in the AWP group (P =.003). This pattern persisted at 90-days with 37.0% in the TWP group compared to 6.5% in the AWP group (P =.004). Most complications were symptomatic UTI and blood stream infections, 14/24 (58%), requiring parenteral antibiotic treatment.
We provide preliminary data showing use of an AWP can reduce infectious complications after RCUD. While larger prospective studies are warranted, our findings are a significant step towards decreasing morbidity of an already highly morbid procedure.
Cystectomy is a standard treatment for muscle-invasive bladder cancer (MIBC), but it is life-altering. We initiated a phase 2 study in which patients with MIBC received four cycles of gemcitabine, ...cisplatin, plus nivolumab followed by clinical restaging. Patients achieving a clinical complete response (cCR) could proceed without cystectomy. The co-primary objectives were to assess the cCR rate and the positive predictive value of cCR for a composite outcome: 2-year metastasis-free survival in patients forgoing immediate cystectomy or <ypT1N0 in patients electing immediate cystectomy. Seventy-six patients were enrolled; of these, 33 achieved a cCR (43%, 95% confidence interval (CI): 32%, 55%), and 32 of 33 who achieved a cCR opted to forgo immediate cystectomy. The positive predictive value of cCR was 0.97 (95% CI: 0.91, 1), meeting the co-primary objective. The most common adverse events were fatigue, anemia, neutropenia and nausea. Somatic alterations in pre-specified genes (ATM, RB1, FANCC and ERCC2) or increased tumor mutational burden did not improve the positive predictive value of cCR. Exploratory analyses of peripheral blood mass cytometry and soluble protein analytes demonstrated an association between the baseline and on-treatment immune contexture with clinical outcomes. Stringently defined cCR after gemcitabine, cisplatin, plus nivolumab facilitated bladder sparing and warrants further study. ClinicalTrials.gov identifier: NCT03451331 .
Ionizing radiation (IR) triggers adaptive changes in gene expression. Here, we show that survival after IR strongly depends on the checkpoint kinase Chk2 acting upon its substrate HuR, an RNA‐binding ...protein that stabilizes and/or modulates the translation of target mRNAs. Microarray analysis showed that in human HCT116 colorectal carcinoma cells (WT), IR‐activated Chk2 triggered the dissociation of virtually all of HuR‐bound mRNAs, since IR did not dissociate HuR target mRNAs in Chk2‐null (CHK2−/−) HCT116 cells. Accordingly, several HuR‐interacting mRNAs encoding apoptosis‐ and proliferation‐related proteins (TJP1, Mdm2, TP53BP2, Bax, K‐Ras) dissociated from HuR in WT cells, but remained bound and showed altered post‐transcriptional regulation in CHK2−/− cells. Use of HuR mutants that were not phosphorylatable by Chk2 (HuR(3A)) and HuR mutants mimicking constitutive phosphorylation by Chk2 (HuR(3D)) revealed that dissociation of HuR target transcripts enhanced cell survival. We propose that the release of HuR‐bound mRNAs via an IR‐Chk2‐HuR regulatory axis improves cell outcome following IR.
The RNA‐binding protein HuR is phosphorylated by the checkpoint kinase Chk2. Here, Chk2‐mediated HuR phosphorylation upon ionizing radiation induces global dissociation of HuR from its target RNAs. This regulation of HuR activity is important for cell survival after IR.
Thoracic endovascular aortic repair (TEVAR) is the gold standard for surgical management of descending thoracic aortic pathology. Depending on the anatomy, TEVAR often requires deployment across the ...origin of the left subclavian artery (LSA) to obtain a proximal seal, thus potentially compromising perfusion to the left upper extremity (LUE). However, in most patients this is generally well tolerated without revascularization due to collateralization from the left vertebral artery (LVA).
We present a complex 59-year-old Caucasian patient case of TEVAR with a history of prior arch debranching and intraoperative LSA coverage requiring subsequent LSA embolization and emergency take-back for left carotid-subclavian bypass.
The purpose of this case report is to highlight an often overlooked anatomic LVA variant and an atypical, delayed presentation of acute LUE limb ischemia.
Controlling crystallization and grain growth is crucial for realizing highly efficient hybrid perovskite solar cells (PSCs). In this work, enhanced PSC photovoltaic performance and stability by ...accelerating perovskite crystallization and grain growth via 2D hexagonal boron nitride (hBN) nanosheet additives incorporated into the active perovskite layer are demonstrated. In situ X‐ray scattering and infrared thermal imaging during the perovskite annealing process revealed the highly thermally conductive hBN nanosheets promoted the phase conversion and grain growth in the perovskite layer by facilitating a more rapid and spatially uniform temperature rise within the perovskite film. Complementary structural, physicochemical, and electrical characterizations further showed that the hBN nanosheets formed a physical barrier at the perovskite grain boundaries and the interfaces with charge transport layers, passivating defects, and retarding ion migration. As a result, the power conversion efficiency of the PSC is improved from 17.4% to 19.8%, along with enhanced device stability, retaining ≈90% of the initial efficiency even after 500 h ambient air storage. The results not only highlight 2D hBN as an effective additive for PSCs but also suggest enhanced thermal transport as one of the pathways for improved PSC performance by 2D material additives in general.
In situ synchrotron X‐ray scattering and real‐time thermal imaging for the first time unraveled the effects of the thermally conductive additive, hexagonal boron nitride nanosheets, on enhancing the crystallization kinetics in organic‐inorganic hybrid perovskites and the associated solar cell performance and stability.
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