Growing Adoption of Immunohistochemistry by Mohs Micrographic Surgeons: A National Medicare Trend Analysis.

BACKGROUND: Immunohistochemical (IHC) staining can be used alongside Mohs micrographic surgery to aid in margin assessment of subtle tumors, yet existing estimates of IHC utilization have primarily relied on survey or older data that lacks stratification. OBJECTIVE: To characterize national IHC utilization trends by Mohs surgeons, stratifying by surgeon characteristics and modeling future adoption. METHODS: Longitudinal analysis of 2014 to 2021 Medicare Public Use Files. RESULTS: In 2021, 158 of 2,058 Mohs surgeons (7.7%) used IHC as compared with 4.0% in 2014 (average annual growth rate [AAGR] +3.6%). Adoption change was highest in the Northeast (AAGR +19.9%), whereas volume growth was greatest in the West (AAGR +25.2%). Multivariable regression revealed significantly greater utilization propensity among Mohs surgeons in academics (adjusted odds ratio [aOR] 3.36), American College of Mohs Surgery (ACMS) members (aOR 2.12), and Micrographic Dermatologic Surgery (MDS)-certified surgeons (aOR 1.66). CONCLUSION: Mohs surgeons are steadily incorporating IHC into practice across all regions, with volume growth driven by higher adoption rates. Greater utilization among ACMS members, recipients of MDS certification, and those in academics suggests value of formalized training in enhancing comfort. Additional educational opportunities at conferences may aid in recognition of value and help identify solutions to address integration challenges.

Robust integration of secondary outcomes information into primary outcome analysis in the presence of missing data.

In clinical and observational studies, secondary outcomes are frequently collected alongside the primary outcome for each subject, yet their potential to improve the analysis efficiency remains underutilized. Moreover, missing data, commonly encountered in practice, can introduce bias to estimates if not appropriately addressed. This article presents an innovative approach that enhances the empirical likelihood-based information borrowing method by integrating missing-data techniques, ensuring robust data integration. We introduce a plug-in inverse probability weighting estimator to handle missingness in the primary analysis, demonstrating its equivalence to the standard joint estimator under mild conditions. To address potential bias from missing secondary outcomes, we propose a uniform mapping strategy, imputing incomplete secondary outcomes into a unified space. Extensive simulations highlight the effectiveness of our method, showing consistent, efficient, and robust estimators under various scenarios involving missing data and/or misspecified secondary models. Finally, we apply our proposal to the Uniform Data Set from the National Alzheimer's Coordinating Center, exemplifying its practical application.

Multi-omics analysis for ferroptosis-related genes as prognostic factors in cutaneous melanoma. / é“æ­»äº¡ç›¸å ³åŸºå› ä½œä¸ºçš®è‚¤é»‘è‰²ç´ ç˜¤é¢„åŽå› ç´ çš„å¤šç»„å­¦åˆ†æžï¼ˆè‹±æ–‡ï¼‰.

OBJECTIVES: Melanoma is highly malignant and heterogeneous. It is essential to develop a specific prognostic model for improving the patients' survival and treatment strategies. Recent studies have shown that ferroptosis results from the overproduction of lipid peroxidation and is an iron-dependent form of programmed cell death. Despite this, ferroptosis-related genes (FRGs) and their clinical significances remain unknown in malignant melanoma. This study aims to assess the role of FRGs in melanoma, with the goal of developing a novel prognostic model that provides new insights into personalized treatment and improvement of therapeutic outcomes for melanoma. METHODS: We systematically characterized the genetic alterations and mRNA expression of 73 FRGs in The Cancer Genome Atlas (TCGA)-skin cutaneous melanoma (SKCM) dataset in this study. The results were validated with real-time RT-PCR and Western blotting. Subsequently, a multi-gene feature model was constructed using the TCGA-SKCM cohort. Melanoma patients were classified into a high-risk group and a low-risk group based on the feature model. As a final step, correlations between ferroptosis-related signatures and immune features, immunotherapy efficacy, or drug response were analyzed. RESULTS: By analyzing melanoma samples from TCGA-SKCM dataset, FRGs exhibited a high frequency of genetic mutations and copy number variations (CNVs), significantly impacting gene expression. Additionally, compared with normal skin tissue, 30 genes with significantly differential expression were identified in melanoma tissues. A prognostic model related to FRGs, constructed using the LASSO Cox regression method, identified 13 FRGs associated with overall survival prognosis in patients and was validated with external datasets. Finally, functional enrichment and immune response analysis further indicated significant differences in immune cell infiltration, mutation burden, and hypoxia status between the high-risk group and the low-risk group, and the model was effective in predicting responses to immunotherapy and drug sensitivity. CONCLUSIONS: This study develops a strong ferroptosis-related prognostic signature model which could put forward new insights into target therapy and immunotherapy for patients with melanoma.

Dermatology workforce projections in the United States, 2021 to 2036.

BACKGROUND: There has been a growing imbalance between supply of dermatologists and demand for dermatologic care. To best address physician shortages, it is important to delineate supply and demand patterns in the dermatologic workforce. The goal of this study was to explore dermatology supply and demand over time. METHODS: We conducted a cross-sectional analysis of workforce supply and demand projections for dermatologists from 2021 to 2036 using data from the Health Workforce Simulation Model from the National Center for Health Workforce Analysis. Estimates for total workforce supply and demand were summarized in aggregate and stratified by rurality. Scenarios with status quo demand and improved access were considered. RESULTS: Projected total supply showed a 12.45% increase by 2036. Total demand increased 12.70% by 2036 in the status quo scenario. In the improved access scenario, total supply was inadequate for total demand in any year, lagging by 28% in 2036. Metropolitan areas demonstrated a relative supply surplus up to 2036; nonmetropolitan areas had at least a 157% excess in demand throughout the study period. In 2021 adequacy was 108% and 39% adequacy for metropolitan and nonmetropolitan areas, respectively; these differences were projected to continue through 2036. CONCLUSIONS: The findings suggest that the dermatology physician workforce is inadequate to meet the demand for dermatologic services in nonmetropolitan areas. Furthermore, improved access to dermatologic care would bolster demand and especially exacerbate workforce inadequacy in nonmetropolitan areas. Continued efforts are needed to address health inequities and ensure access to quality dermatologic care for all.

Dexmedetomidine attenuates acute stress-impaired learning and memory in mice by maintaining the homeostasis of intestinal flora.

Dexmedetomidine (Dex) has been used in surgery to improve patients' postoperative cognitive function. However, the role of Dex in stress-induced anxiety-like behaviors and cognitive impairment is still unclear. In this study, we tested the role of Dex in anxiety-like behavior and cognitive impairment induced by acute restrictive stress and analyzed the alterations of the intestinal flora to explore the possible mechanism. Behavioral and cognitive tests, including open field test, elevated plus-maze test, novel object recognition test, and Barnes maze test, were performed. Intestinal gut Microbe 16S rRNA sequencing was analyzed. We found that intraperitoneal injection of Dex significantly improved acute restrictive stress-induced anxiety-like behavior, recognition, and memory impairment. After habituation in the environment, mice (male, 8 weeks, 18-23 g) were randomly divided into a control group (control, N = 10), dexmedetomidine group (Dex, N = 10), AS with normal saline group (AS + NS, N = 10) and AS with dexmedetomidine group (AS + Dex, N = 10). By the analysis of intestinal flora, we found that acute stress caused intestinal flora disorder in mice. Dex intervention changed the composition of the intestinal flora of acute stress mice, stabilized the ecology of the intestinal flora, and significantly increased the levels of Blautia (A genus of anaerobic bacteria) and Coprobacillus. These findings suggest that Dex attenuates acute stress-impaired learning and memory in mice by maintaining the homeostasis of intestinal flora.

Bioengineered vascular grafts with a pathogenic TGFBR1 variant model aneurysm formation in vivo and reveal underlying collagen defects.

Thoracic aortic aneurysm (TAA) is a life-threatening vascular disease frequently associated with underlying genetic causes. An inadequate understanding of human TAA pathogenesis highlights the need for better disease models. Here, we established a functional human TAA model in an animal host by combining human induced pluripotent stem cells (hiPSCs), bioengineered vascular grafts (BVGs), and gene editing. We generated BVGs from isogenic control hiPSC-derived vascular smooth muscle cells (SMCs) and mutant SMCs gene-edited to carry a Loeys-Dietz syndrome (LDS)-associated pathogenic variant (TGFBR1A230T). We also generated hiPSC-derived BVGs using cells from a patient with LDS (PatientA230T/+) and using genetically corrected cells (Patient+/+). Control and experimental BVGs were then implanted into the common carotid arteries of nude rats. The TGFBR1A230T variant led to impaired mechanical properties of BVGs, resulting in lower burst pressure and suture retention strength. BVGs carrying the variant dilated over time in vivo, resembling human TAA formation. Spatial transcriptomics profiling revealed defective expression of extracellular matrix (ECM) formation genes in PatientA230T/+ BVGs compared with Patient+/+ BVGs. Histological analysis and protein assays validated quantitative and qualitative ECM defects in PatientA230T/+ BVGs and patient tissue, including decreased collagen hydroxylation. SMC organization was also impaired in PatientA230T/+ BVGs as confirmed by vascular contraction testing. Silencing of collagen-modifying enzymes with small interfering RNAs reduced collagen proline hydroxylation in SMC-derived tissue constructs. These studies demonstrated the utility of BVGs to model human TAA formation in an animal host and highlighted the role of reduced collagen modifying enzyme activity in human TAA formation.

γ-Aminobutyric Acid (GABA)-enriched Hemp Milk by Solid-state Co-fermentation and Germination Bioprocesses.

This study introduces the concept of developing a functional hemp drink enriched with γ-Aminobutyric acid (GABA) to enhance its nutritional value and functional properties utilizing Solid-State (SSF) co-Fermentation by Lactobacillus casei and Bacillus subtilis and germination bioprocesses. Bioprocesses may offer an alternative solution to challenges in hemp milk, such as product instability and the use of additives. Notably, the hemp milk produced through the germination for three days or co-fermentation processes yielded the highest GABA content of 79.84 and 102.45 mg/100 mL, respectively, compared to the untreated milk. These bioactive milk samples exhibited higher zeta potential and soluble protein content and also reduced solid particle sedimentation and droplet sizes (D4,3 and D3,2) compared to the untreated milk. Furthermore, the peptide, total phenolic content, and antioxidant activity of the produced GABA-enriched kinds of milk surpassed those of the untreated milk. Overall, the SSF and germination processes present a promising alternative for producing stable milk analogs with enhanced health-boosting properties.

Vestibular Rehabilitation: Intelligent or Traditional?

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Endovascular treatment of symptomatic severe intracranial atherosclerotic stenosis with a novel intracranial dedicated drug-eluting stent: a more effective treatment approach.

Background: Endovascular treatment of severe intracranial atherosclerotic stenosis (ICAS) using coronary drug-eluting stents (DESs) significantly reduces the risk of in-stent restenosis (ISR) and stroke recurrence. However, there are few reports regarding the treatment of ICAS with intracranial dedicated DES. Herein, we present our experience with the feasibility, safety, and medium-term follow-up outcomes of a novel intracranial DES, named NOVA stent, in patients with symptomatic severe ICAS (≥70%). Methods: From December 2021 to May 2022, patients with symptomatic severe ICAS who underwent implantation of the NOVA stent in our institution were retrospectively analyzed for procedural results, perioperative complications, imaging and clinical follow-up outcomes. Results: Twenty-four patients, 16 (66.7%) with anterior circulation lesions and 8 (33.3%) with posterior circulation lesions, were enrolled. All patients with intracranial ICA (n = 6), middle cerebral artery (n = 10), basilar artery (n = 3), intracranial vertebral artery (n = 3), and the vertebrobasilar junction (n = 2) stenosis were treated successfully using NOVA stents. The severity of stenosis ranged from 75 to 96% (mean 85.9%) before treatment and this was reduced to 0 to 20% (mean 8.6%) immediately after stent placement. Symptomatic distal embolism occurred in one case; however, there were no other perioperative complications. The mean follow-up duration was 12.2 ± 1.06 months. No symptomatic ischemic events occurred during follow-up. Follow-up cerebral angiography was performed in 22 of 24 patients (91.7%), and significant ISR occurred in one patient (4.2%). Conclusion: Our results demonstrate that implantation of the novel intracranial DES NOVA in severe ICAS is feasible, safe, and effective in selected cases, reducing the incidence of ISR, and showing excellent midterm clinical outcomes, providing a promising option for ICAS treatment.

imply: improving cell-type deconvolution accuracy using personalized reference profiles.

Using computational tools, bulk transcriptomics can be deconvoluted to estimate the abundance of constituent cell types. However, existing deconvolution methods are conditioned on the assumption that the whole study population is served by a single reference panel, ignoring person-to-person heterogeneity. Here, we present imply, a novel algorithm to deconvolute cell type proportions using personalized reference panels. Simulation studies demonstrate reduced bias compared with existing methods. Real data analyses on longitudinal consortia show disparities in cell type proportions are associated with several disease phenotypes in Type 1 diabetes and Parkinson's disease. imply is available through the R/Bioconductor package ISLET at https://bioconductor.org/packages/ISLET/ .

Crystalline metal phosphide-coated amorphous iron oxide-hydroxide (FeOOH) with oxygen vacancies as highly active and stable oxygen evolution catalyst in alkaline seawater at high current density.

In this study, we employed a straightforward phosphorylation approach to achieve a dual objective: constructing c-a heterostructures consisting of crystalline Ni12P5 and amorphous FeOOH, while simultaneously enhancing oxygen vacancies. The resulting oxygen evolution reaction (OER) catalyst, Ni12P5/FeOOH/NF, exhibited remarkable performance with current densities of 500 mA cm-2 in both 1 M KOH and 1 M KOH + seawater, requiring low overpotentials of only 288 and 365 mV, respectively. Furthermore, Ni12P5/FeOOH/NF exhibited only a slight increase in overpotential, with increments of 18 mV and 70 mV in 1 M KOH after 15 and 150 h, and 32 mV and 108 mV in 1 M KOH + seawater at 500 mA cm-2 after 15 and 150 h, respectively. This minimal change can be attributed to the stabilized c-a structure, the protective coating of Ni12P5, and superhydrophilic. Through in-situ Raman and ex-situ XPS analysis, we discovered that Ni12P5/FeOOH/NF can undergo a reconfiguration into an oxygen vacancy-rich (Fe/Ni)OOH phase during OER process. The elevated OER activity is mainly due to the contribution of the oxygen vacancy-rich (Fe/Ni)OOH phase from the reconfigure of the Ni12P5/FeOOH/NF. This finding emphasizes the critical role of oxygen vacancies in facilitating the production of OO species and overcoming the limitations associated with OOH formation, ultimately enhancing the kinetics of the OER.

USP14 negatively regulates IFN signaling by dampening K63-linked ubiquitination of TBK1 in black carp.

USP14 regulates the immune related pathways by deubiquitinating the signaling molecules in mammals. In teleost, USP14 is also reported to inhibit the antiviral immune response through TBK1, but its regulatory mechanism remains obscure. To elucidate the role of USP14 in the RLR/IFN antiviral pathway in teleost, the homolog USP14 (bcUSP14) of black carp (Mylopharyngodon piceus) has been cloned and characterize in this paper. bcUSP14 contains 490 amino acids (aa), and the sequence is well conserved among in vertebrates. Over-expression of bcUSP14 in EPC cells attenuated SVCV-induced transcription activity of IFN promoters and enhanced SVCV replication. Knockdown of bcUSP14 in MPK cells led to the increased transcription of IFNs and decreased SVCV replication, suggesting the improved antiviral activity of the host cells. The interaction between bcUSP14 and bcTBK1 was identified by both co-immunoprecipitation and immunofluorescent staining. Co-expressed bcUSP14 obviously inhibited bcTBK1-induced IFN production and antiviral activity in EPC cells. K63-linked polyubiquitination of bcTBK1 was dampened by co-expressed bcUSP14, and bcTBK1-mediated phosphorylation and nuclear translocation of IRF3 were also inhibited by this deubiquitinase. Thus, all the data demonstrated that USP14 interacts with and inhibits TBK1 through deubiquitinating TBK1 in black carp.

Cancer on motors: How kinesins drive prostate cancer progression?

Prostate cancer causes numerous male deaths annually. Although great progress has been made in the diagnosis and treatment of prostate cancer during the past several decades, much about this disease remains unknown, especially its pathobiology. The kinesin superfamily is a pivotal group of motor proteins, that contains a microtubule-based motor domain and features an adenosine triphosphatase activity and motility characteristics. Large-scale sequencing analyses based on clinical samples and animal models have shown that several members of the kinesin family are dysregulated in prostate cancer. Abnormal expression of kinesins could be linked to uncontrolled cell growth, inhibited apoptosis and increased metastasis ability. Additionally, kinesins may be implicated in chemotherapy resistance and escape immunologic cytotoxicity, which creates a barrier to cancer treatment. Here we cover the recent advances in understanding how kinesins may drive prostate cancer progression and how targeting their function may be a therapeutic strategy. A better understanding of kinesins in prostate cancer tumorigenesis may be pivotal for improving disease outcomes in prostate cancer patients.

Biocontrol activity of an endophytic Alternaria alternata Aa-Lcht against apple Valsa canker.

Apple Valsa canker (AVC), caused by Valsa mali, is the most serious branch disease for apples in East Asia. Biocontrol constitutes a desirable alternative strategy to alleviate the problems of orchard environment pollution and pathogen resistance risk. It is particularly important to explore efficient biocontrol microorganism resources to develop new biocontrol technologies and products. In this study, an endophytic fungus, which results in the specific inhibition of the growth of V. mali, was isolated from the twig tissue of Malus micromalus with a good tolerance to AVC. The fungus was identified as Alternaria alternata, based on morphological observations and phylogenetic analysis, and was named Aa-Lcht. Aa-Lcht showed a strong preventive effect against AVC, as determined with an in vitro twig evaluation method. When V. mali was inhibited by Aa-Lcht, according to morphological and cytological observations, the hyphae was deformed and it had more branches, a degradation in protoplasm, breakages in cell walls, and then finally died completely due to mycelium cells. Transcriptome analysis indicated that Aa-Lcht could suppress the growth of V. mali by inhibiting the activity of various hydrolases, destroying carbohydrate metabolic processes, and damaging the pathogen membrane system. It was further demonstrated that Aa-Lcht could colonize apple twig tissues without damaging the tissue's integrity. More importantly, Aa-Lcht could also stimulate the up-regulated expression of defense-related genes in apples together with the accumulation of reactive oxygen species and callose deposition in apple leaf cells. Summarizing the above, one endophytic biocontrol resource was isolated, and it can colonize apple twig tissue and play a biocontrol role through both pathogen inhibition and resistance inducement.

Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice. METHODS: A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated. RESULTS: Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1ß and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1ß and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway. CONCLUSIONS: Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.