Employing Magnetic Resonance Histology for Precision Chronic Limb-Threatening Ischemia Treatment Planning.

OBJECTIVE: Recent randomized controlled trials have demonstrated a notable prevalence of immediate technical failures (ITFs) in percutaneous vascular interventions (PVIs) for complex arterial lesions associated with chronic limb-threatening ischemia (CLTI). Current imaging modalities present inherent limitations in identifying these lesions, making it challenging to determine the most suitable candidates for PVI. We present a novel preprocedural magnetic resonance imaging (MRI) histology protocol for identifying lesions that might present a higher rate of immediate and mid-term PVI failure. METHODS: 22 patients (13 females, average age 65.8±9.72 years) scheduled for PVI were prospectively enrolled and underwent 3T MRI using ultrashort echo time and 'Steady-State Free Precession' contrasts to characterize target lesions prior to PVI. Lesions were scored as 'hard' if >50% of the lumen was occluded by hard components (calcium/dense collagen) on MRI in the hardest cross-section. Two readers evaluated MRI datasets. TASC/GLASS/WIFi scoring was performed based on intraprocedural angiograms and chart review. The relationship between MRI scoring, TASC/GLASS scoring and procedural outcomes was investigated using univariate analysis. Mid-term follow-up (revascularization and amputation rate) was recorded at 3 months and 6 months, post-intervention. RESULTS: Our cohort of 22 patients yielded 40 target lesions. 5 lesions were excluded (2 non-diagnostic image quality, 3 PVIs were ultimately diagnostic only). 6 lesions (17%) were scored as 'hard'. MRI-scored 'hard' lesions had higher proportion of ITF ('hard' vs 'soft' 83% (n/N=5/6) vs. 3% (n/N=1/29), p<.001). 'Hard' versus 'soft' MRI scoring was the only factor significantly associated with immediate PVI technical success (p < .001), as opposed to TASC/GLASS scoring. Both at 3 months and 6 months after PVI, the re-intervention rate was significantly higher among those lesions which were scored 'hard' on MRI (3-month: hard: 80% vs. soft: 16%, p =.011 6-month: hard: 80%, soft: 27%, p=.047). CONCLUSIONS: MRI histology could be a valuable tool for optimizing PVI patient selection and treatment strategies.

Inferior Vena Cava Filters: An Overview.

For patients with existing venous thromboembolisms (VTEs), anticoagulation remains the standard of care recommended across multiple professional organizations. However, for patients who developed a deep venous thrombosis (DVT) and/or a pulmonary embolism and cannot tolerate anticoagulation, inferior vena cava (IVC) filters must be considered among other alternative treatments. Although placement of a filter is considered a low-risk intervention, there are important factors and techniques that surgeons and interventionalists should be aware of and prepared to discuss. This overview covers the basics regarding the history of filters, indications for placement, associated risks, and techniques for difficult removal.

Peripheral arterial disease treatment planning using noninvasive and invasive imaging methods.

With the growing prevalence and mortality of peripheral arterial disease, preoperative assessment, risk stratification, and determining the correct indication for endovascular and open surgical procedures are essential for therapeutic decision-making. The effectiveness of interventional procedures is significantly influenced by the plaque composition and calcification pattern. Therefore, the identification of patients for whom endovascular treatment is the most appropriate therapeutic solution often remains a challenge. The most commonly used imaging techniques have their own limitations and do not provide findings detailed enough for specific, personalized treatment planning. Using state-of-the-art noninvasive and invasive imaging modalities, it is now possible to obtain a view, not only of the complex vascular anatomy and plaque burden of the lower extremity arterial system, but also of complex plaque structures and various pathologic calcium distribution patterns. In the future, as these latest advancements in diagnostic methods become more widespread, we will be able to obtain more accurate views of the plaque structure and anatomic complexity to guide optimal treatment planning and device selection. We reviewed the implications of the most recent invasive and noninvasive lower extremity imaging techniques and future directions.

Current state and future directions of genomic medicine in aortic dissection: A path to prevention and personalized care.

Aortic dissection confers high mortality and morbidity rates despite advances in treatment, impacts quality of life, and contributes immense burden to the healthcare system globally. Efforts to prevent aortic dissection through screening and management of modifiable risk factors and early detection of aneurysms should incorporate genomic information, as it is integral to stratifying risk. However, effective integration of genomic-guided risk assessment into clinical practice will require addressing implementation barriers that currently permeate our healthcare systems. The Aortic Dissection Collaborative was established to define aortic dissection research priorities through patient engagement. Using a collaborative patient-centered feedback model, our Genomic Medicine Working Group identified related research priorities that could be investigated by pragmatic interventional studies aimed at aortic dissection prevention, utilization of genomic information to improve patient outcomes, and access to genomic medicine services. Further research is also needed to identify the genomic, lifestyle, and environmental risk factors that contribute to aortic dissection so these data can be incorporated into future comparative effectiveness studies to prevent aortic dissection.

Pancreatic stromal Gremlin 1 expression during pancreatic tumorigenesis.

Chronic pancreatitis (CP) is a major risk factor of pancreatic ductal adenocarcinoma (PDAC). How CP promotes pancreatic oncogenesis remains unclear. A characteristic feature of PDAC is its prominent desmoplasia in the tumor microenvironment, composed of activated fibroblasts and macrophages. Macrophages can be characterized as M1 or M2, with tumor-inhibiting or -promoting functions, respectively. We reported that Gremlin 1 (GREM1), a key pro-fibrogenic factor, is upregulated in the stroma of CP. The current study aimed to investigate the expression of GREM1 and correlation between GREM1 and macrophages within the pancreas during chronic inflammation and the development of PDAC. By mRNA in situ hybridization, we detected GREM1 mRNA expression within α-smooth muscle actin (SMA)-positive fibroblasts of the pancreatic stroma. These designated FibroblastsGrem1+ marginally increased from CP to pancreatic intraepithelial neoplasia (PanIN) and PDAC. Within PDAC, FibroblastsGrem1+ increased with higher pathological tumor stages and in a majority of PDAC subtypes screened. Additionally, FibroblastsGrem1+ positively correlated with total macrophages (MacCD68+) and M2 macrophages (M2CD163+) in PDAC. To begin exploring potential molecular links between FibroblastsGrem1+ and macrophages in PDAC, we examined the expression of macrophage migration inhibitory factor (MIF), an endogenous counteracting molecule of GREM1 and an M1 macrophage promoting factor. By IHC staining of MIF, we found MIF to be expressed by tumor cells, positively correlated with GREM1; by IHC co-staining, we found MIF to be negatively correlated with M2CD163+ expression. Our findings suggest that GREM1 expression by activated fibroblasts may promote PDAC development, and GREM1/MIF may play an important role in macrophage phenotype.

Distinct Murine Pancreatic Transcriptomic Signatures during Chronic Pancreatitis Recovery.

We have previously demonstrated that the pancreas can recover from chronic pancreatitis (CP) lesions in the cerulein-induced mouse model. To explore how pancreatic recovery is achieved at the molecular level, we used RNA-sequencing (seq) and profiled transcriptomes during CP transition to recovery. CP was induced by intraperitoneally injecting cerulein in C57BL/6 mice. Time-matched controls (CON) were given normal saline. Pancreata were harvested from mice 4 days after the final injections (designated as CP and CON) or 4 weeks after the final injections (designated as CP recovery (CPR) and control recovery (CONR)). Pancreatic RNAs were extracted for RNA-seq and quantitative (q) PCR validation. Using RNA-seq, we identified a total of 3,600 differentially expressed genes (DEGs) in CP versus CON and 166 DEGs in CPR versus CONR. There are 132 DEGs overlapped between CP and CPR and 34 DEGs unique to CPR. A number of selected pancreatic fibrosis-relevant DEGs were validated by qPCR. The top 20 gene sets enriched from DEGs shared between CP and CPR are relevant to extracellular matrix and cancer biology, whereas the top 10 gene sets enriched from DEGs specific to CPR are pertinent to DNA methylation and specific signaling pathways. In conclusion, we identified a distinct set of DEGs in association with extracellular matrix and cancer cell activities to contrast CP and CPR. Once during ongoing CP recovery, DEGs relevant to DNA methylation and specific signaling pathways were induced to express. The DEGs shared between CP and CPR and the DEGs specific to CPR may serve as the unique transcriptomic signatures and biomarkers for determining CP recovery and monitoring potential therapeutic responses at the molecular level to reflect pancreatic histological resolution.

The Development of a Simulated Umbilical Line Insertion Model and Curriculum in the Neonatal Intensive Care Unit.

Background Insertion of an umbilical venous catheter (UVC) is a required skill for pediatric residents to learn and perform effectively. However, there is known variability in the ability of residents to perform this essential neonatal skill. Objective The objective of our study was to create a competency-based curriculum for umbilical vein catheter insertion using a human umbilical tissue simulated model, and to assess the feasibility of the curriculum on resident learners during their neonatology rotations. Methods We evaluated the curriculum by assessment of resident learning, reactions, and behaviours. Performance was assessed using the Ottawa Surgical Competency Operating Room Evaluation (O-SCORE). Results A total of 14 residents were included for analysis. The majority were 'senior' residents (postgraduate year (PGY)-3 and PGY-4 n = 10; PGY-1 n =4), and they reported a wide range of previous experience with UVC insertion prior to this curriculum implementation. The residents' reaction to the curriculum was overwhelmingly positive. All residents maintained or improved in their knowledge assessment. O-SCORE results showed improvement in UVC insertion before and after curriculum completion for both junior (2.5 +/- 0.71 to 4.5 +/- 0.41) and senior (3.55 +/- 0.42 to 4.95 +/- 0.15, p < 0.001) residents. The mean improvement in O-SCORE was greater for junior residents than senior residents. Conclusion The results of this study demonstrate the feasibility and emerging impact of a competency-based curriculum using simulation for procedural skills.

Sex-Related Differences of Acute and Chronic Pancreatitis in Adults.

The incidence of acute and chronic pancreatitis is increasing in the United States. Rates of acute pancreatitis (AP) are similar in both sexes, but chronic pancreatitis (CP) is more common in males. When stratified by etiology, women have higher rates of gallstone AP, while men have higher rates of alcohol- and tobacco-related AP and CP, hypercalcemic AP, hypertriglyceridemic AP, malignancy-related AP, and type 1 autoimmune pancreatitis (AIP). No significant sex-related differences have been reported in medication-induced AP or type 2 AIP. Whether post-endoscopic retrograde cholangiopancreatography pancreatitis is sex-associated remains controversial. Animal models have demonstrated sex-related differences in the rates of induction and severity of AP, CP, and AIP. Animal and human studies have suggested that a combination of risk factor profiles, as well as genes, may be responsible for the observed differences. More investigation into the sex-related differences of AP and CP is desired in order to improve clinical management by developing effective prevention strategies, diagnostics, and therapeutics.

Sex-associated preventive effects of low-dose aspirin on obesity and non-alcoholic fatty liver disease in mouse offspring with over-nutrition in utero.

Aspirin has been found to diminish hypertriglyceridemia and hyperglycemia in both obese rodents and patients with type 2 diabetes mellitus. We aimed to test whether low-dose aspirin can prevent obesity and the progression of non-alcoholic fatty liver disease (NAFLD) in high-risk subjects. We used offspring mice with maternal over-nutrition as a high-risk model of obesity and NAFLD. The offspring were given postnatal HF-diet and diethylnitrosamine (DEN) to induce obesity and NAFLD, and were treated with or without a low dose of aspirin for 12 weeks (ASP or CTL groups). Aspirin treatment reduced body weight gain, reversed glucose intolerance, and depressed hepatic lipid accumulation in female, but not in male mice. Female mice displayed re-sensitized insulin/Akt signaling and overactivated AMPK signaling, with enhanced level of hepatic PPAR-γ, Glut4, and Glut2, while male mice only enhanced hepatic PPAR-α and PPAR-γ levels. The female ASP mice had inhibited p44/42 MAPK activity and enhanced Pten expression, while male displayed activated p38 MAPK signaling. Furthermore, the female but not the male ASP mice reduced Wnt-signaling activity via both the epigenetic regulation of Apc expression and the post-transcriptional regulation of ß-catenin degradation. In summary, our study demonstrates a sex-associated effect of low-dose aspirin on obesity and NAFLD prevention in female but not in male mice.

Opposing Roles of BMP and TGF-ß Signaling Pathways in Pancreatitis: Mechanisms and Therapeutic Implication.

Bone morphogenetic proteins (BMPs) comprise a major subgroup of the transforming growth factor (TGF)-ß superfamily. They play pivotal roles in embryonic development and tissue homeostasis in adults. Deregulation of BMP and TGF-ß signaling contributes to developmental anomalies and multiple diseases. In this mini-review, we focus on BMP signaling in inflammatory disorders of the pancreas, acute and chronic pancreatitis, in contrast to TGF-ß signaling. We then discuss molecular mechanisms that interact with and connect between the BMP and TGF-ß signaling pathways. Lastly, we review potential implications of these molecular mechanisms for therapeutic development. In summary, BMP signaling pathway plays different roles during pancreatitis disease development, and the antagonism between BMP and TGF-ß signaling can be manipulated for therapeutic development against pancreatitis.

The role of stochastic thermal environments in modulating the thermal physiology of an intertidal limpet, Lottia digitalis.

Much of our understanding of the thermal physiology of intertidal organisms comes from experiments with animals acclimated under constant conditions and exposed to a single heat stress. In nature, however, the thermal environment is more complex. Aerial exposure and the unpredictable nature of thermal stress during low tides may be critical factors in defining the thermal physiology of intertidal organisms. In the fingered limpet, Lottia digitalis, we investigated whether upper temperature tolerance and thermal sensitivity were influenced by the pattern of fluctuation with which thermal stress was applied. Specifically, we examined whether there was a differential response (measured as cardiac performance) to repeated heat stress of a constant and predictable magnitude compared with heat stress applied in a stochastic and unpredictable nature. We also investigated differences in cellular metabolism and damage following immersion for insights into biochemical mechanisms of tolerance. Upper temperature tolerance increased with aerial exposure, but no significant differences were found between predictable treatments of varying magnitudes (13°C versus 24°C versus 32°C). Significant differences in thermal tolerance were found between unpredictable trials with different heating patterns. There were no significant differences among treatments in basal citrate synthase activity, glycogen content, oxidative stress or antioxidants. Our results suggest that aerial exposure and recent thermal history, paired with relief from high low-tide temperatures, are important factors modulating the capacity of limpets to deal with thermal stress.

Ethics: end-of-life decision-making in a pediatric patient with SMA type 2: the influence of the media.

OBJECTIVE: Spinal muscular atrophy (SMA) is a group of progressive and fatal neurodegenerative disorders that are characterized by destruction of the anterior horn cells of the spinal cord. In this case report we outline the medical and ethical issues involved in a 7-year-old boy with SMA type 2 who experienced acute respiratory failure. METHODS: A review of the literature was conducted focusing particularly on the pathology, presentation, and outcomes of SMA and end-of-life decision-making in pediatrics. RESULTS: In a world where 40%-60% of deaths in pediatric intensive care units are a result of withdrawal or limitation of life-sustaining treatment, end-of-life decision-making has become an integral and difficult part of pediatric practice. CONCLUSION: Limitation or withdrawal of life-sustaining treatment in a cognitively normal child with SMA poses a significant medical and ethical dilemma. This difficult decision is influenced by confluence of parental, doctor, social, cultural, moral, religious, legal, and economic factors and more recently the media.