In vivo measurement of strain in the periodontal space of pig (Sus scrofa) incisors using in-fiber Bragg sensors.

The incisor teeth in pigs, Sus scrofa, function in association with a disc-shaped snout to explore the environment for potential food. Understanding how mechanical loading applied to the tooth deforms the periodontal ligament (PDL) is important to determining the role of periodontal mechanoreceptors during food exploration and feeding. The objective of this study was to use fiber Bragg (FBG) sensors to measure strain in vivo within the PDL space of pig incisors. The central mandibular incisors of pigs underwent spring loaded lingual tipping during FBG strain recording within the labial periodontal space. FBG sensors were placed within the periodontal space of the central mandibular incisors of ~2-3-month-old farm pigs. The magnitude and orientation of spring loads are expected to mimic incisor contact with food. During incisor tipping with load calibrated springs, FBG strains in vitro (N = 6) and in vivo (N = 6) recorded at comparable load levels overlapped in range (-10-20 µÎµ). Linear regressions between peak FBG strains, that is, the highest recorded strain value, and baseline strains, that is, strain without applied spring load, were significant across all in vivo experiments (peak strain at 200 g vs. baseline, p = .04; peak strain at 2000 g vs. baseline p = .03; peak strain at 2000 g vs. 200 g, p = .004). These linear relationships indicate that on a per experiment basis, the maximum measured strain at different spring loads showed predictable differences. A Friedman test of the absolute value of peak strain confirmed the significant increase in strain between baseline, 200 g, and 2000 g spring activation (p = .02). Mainly compressive strains were recorded in the labial PDL space and increases in spring load applied in vivo generated increases in FBG strain measurements. These results demonstrate the capacity for FBG sensors to be used in vivo to assess transmission of occlusal loads through the periodontium. PDL strain is associated with mechanoreceptor stimulation and is expected to affect the functional morphology of the incisors. The overall low levels of strain observed may correspond with the robust functional morphology of pig incisors and the tendency for pigs to encounter diverse foods and substrates during food exploration.

Adipose tissue as a linchpin of organismal ageing.

Ageing is a conserved biological process, modulated by intrinsic and extrinsic factors, that leads to changes in life expectancy. In humans, ageing is characterized by greatly increased prevalence of cardiometabolic disease, type 2 diabetes and disorders associated with impaired immune surveillance. Adipose tissue displays species-conserved, temporal changes with ageing, including redistribution from peripheral to central depots, loss of thermogenic capacity and expansion within the bone marrow. Adipose tissue is localized to discrete depots, and also diffusely distributed within multiple organs and tissues in direct proximity to specialized cells. Thus, through their potent endocrine properties, adipocytes are capable of modulating tissue and organ function throughout the body. In addition to adipocytes, multipotent progenitor/stem cells in adipose tissue play a crucial role in maintenance and repair of tissues throughout the lifetime. Adipose tissue may therefore be a central driver for organismal ageing and age-associated diseases. Here we review the features of adipose tissue during ageing, and discuss potential mechanisms by which these changes affect whole-body metabolism, immunity and longevity. We also explore the potential of adipose tissue-targeted therapies to ameliorate age-associated disease burdens.

Submitting a successful National Institutes of Health career development award for the vascular surgeon scientist.

Obtaining a career development award from the National Institutes of Health (K award) is often an important step in establishing a career as a vascular surgeon scientist. The application and review process is competitive, involves many steps, and may be confusing to the prospective applicant. Further, there are requirements involving mentors and the applicant's institution. This article, authored completely by vascular surgeons with active K awards, is intended for potential applicants and personnel at their institution and reviews relevant information including strategies for a successful application.

Holographic stimulation of opposing amygdala ensembles bidirectionally modulates valence-specific behavior via mutual inhibition.

The basolateral amygdala (BLA) is an evolutionarily conserved brain region, well known for valence processing. Despite this central role, the relationship between activity of BLA neuronal ensembles in response to appetitive and aversive stimuli and the subsequent expression of valence-specific behavior has remained elusive. Here, we leverage two-photon calcium imaging combined with single-cell holographic photostimulation through an endoscopic lens to demonstrate a direct causal role for opposing ensembles of BLA neurons in the control of oppositely valenced behavior in mice. We report that targeted photostimulation of either appetitive or aversive BLA ensembles results in mutual inhibition and shifts behavioral responses to promote consumption of an aversive tastant or reduce consumption of an appetitive tastant, respectively. Here, we identify that neuronal encoding of valence in the BLA is graded and relies on the relative proportion of individual BLA neurons recruited in a stable appetitive or quinine ensemble.

Physical activity regulates the immune response to breast cancer by a hematopoietic stem cell-autonomous mechanism.

Physical activity is a modifiable lifestyle factor that is associated with a decreased risk for the development of breast cancer. While the exact mechanisms for the reduction in cancer risk due to physical activity are largely unknown, it is postulated that the biological reduction in cancer risk is driven by improvements in inflammation and immune function with exercise. Hematopoietic stem cells (HSCs) are the progenitor for all of the cells of the immune system and are involved in cancer immunosurveillance through differentiation into cytotoxic cell population. In this study, we investigate the role of physical activity (PA) in a spontaneously occurring model of breast cancer over time, with a focus on tumor incidence, circulating and tumor-infiltrating immune cells as well gene expression profiles of tumors and hematopoietic stem cells. Furthermore, we show that, in addition to a direct effect of PA on the immune cells of tumor-bearing mice, PA reduces the oxidative stress in HSCs of wildtype and tumor-bearing mice, and by doing so, alters the differentiation of the HSCs towards T cells in order to enhance cancer immunosurveillance.

A distinct class of hematopoietic stem cells develop from the human yellow bone marrow.

Aging and metabolic diseases are accompanied by systemic inflammation, but the mechanisms that induce this state are not known. We developed a human bone-marrow organoid system to explore mechanisms underlying metabolic-disease associated systemic inflammation. We find that a distinct type of hematopoietic stem cell (HSC) develops in the adipose-rich, yellow bone marrow, which is known to gradually replace the hematopoietic red marrow as we age and during metabolic disease. Unlike HSCs derived from the red bone marrow, HSCs derived from the yellow bone marrow have higher proliferation rates, increase myeloid differentiation, skew towards pro-inflammatory M1 macrophage differentiation, and express a distinct transcriptomic profile associated with responsiveness to wounding. Yellow marrow-derived HSCs express higher levels of the leptin receptor, which we find to be further increased in patients with type 2 diabetes. Our work demonstrates that the human long bone yellow marrow is a niche for a distinct class of HSCs which could underlie hematopoietic dysfunction during aging and metabolic disease processes suggesting a shared inflammaging mechanism.

Comprehensive Care of Lower-Extremity Wounds.

There are 5 common types of chronic nonhealing lower-extremity wounds: arterial, venous, diabetic foot ulcer, pressure, and mixed or atypical. Each chronic wound type has distinct features, and understanding the underlying cause will dictate the wound treatment plan. Here, the authors review the distinguishing wound properties for these 5 common chronic nonhealing lower-extremity wounds and outline a comprehensive treatment plan that addresses wound perfusion, debridement, infection control, moisture balance, and use of complementary advanced wound care products.

Wnt signaling preserves progenitor cell multipotency during adipose tissue development.

Mesenchymal stem/progenitor cells are essential for tissue development and repair throughout life, but how they are maintained under chronic differentiation pressure is not known. Using single-cell transcriptomics of human progenitor cells we find that adipose differentiation stimuli elicit two cellular trajectories: one toward mature adipocytes and another toward a pool of non-differentiated cells that maintain progenitor characteristics. These cells are induced by transient Wnt pathway activation and express numerous extracellular matrix genes and are therefore named structural Wnt-regulated adipose tissue cells. We find that the genetic signature of structural Wnt-regulated adipose tissue cells is present in adult human adipose tissue and adipose tissue developed from human progenitor cells in mice. Our results suggest a mechanism whereby adipose differentiation occurs concurrently with the maintenance of a mesenchymal progenitor cell pool, ensuring tissue development, repair and appropriate metabolic control over the lifetime.

Characterization and management of type II and complex endoleaks after fenestrated/branched endovascular aneurysm repair.

INTRODUCTION: Endoleaks are more common after fenestrated/branched endovascular aneurysm repair (F/B-EVAR) than infrarenal EVAR secondary to the length of aortic coverage and number of component junctions. Although reports have focused on type I and III endoleaks, less is known regarding type II endoleaks after F/B-EVAR. We hypothesized that type II endoleaks would be common and often complex (associated with additional endoleak types), given the potential for multiple inflow and outflow sources. We sought to describe the incidence and complexity of type II endoleaks after F/B-EVAR. METHODS: F/B-EVAR data prospectively collected at a single institution in an investigational device exemption clinical trial (G130210) were retrospectively analyzed (2014-2021). Endoleaks were characterized by type, time to detection, and management. Primary endoleaks were defined as those present on completion imaging or at first postoperative imaging, and secondary were those on subsequent imaging. Recurrent endoleaks were those that developed after a successfully resolved endoleak. Reinterventions were considered for type I or III endoleaks or any endoleak associated with sac growth >5 mm. Technical success defined as the absence of flow in the aneurysm sac at procedure conclusion and methods of intervention were captured. RESULTS: Among 335 consecutive F/B-EVARs (mean ± standard deviation follow-up: 2.5 ± 1.5 years), 125 patients (37%) experienced 166 endoleaks (81 primary, 72 secondary, and 13 recurrent). Of these 125 patients, 50 (40% of patients) underwent 71 interventions for 60 endoleaks. Type II endoleaks were the most frequent (n = 100, 60%), with 20 identified during the index procedure, 12 (60%) of which resolved before 30-day follow-up. Of the 100 type II endoleaks, 20 (20%; 12 primary, 5 secondary, and 3 recurrent) were associated with sac growth; 15 (75%) of those with associated sac growth underwent intervention. At intervention, 6 (40%) were reclassified as complex, with a concomitant type I or type III endoleak. Initial technical success for endoleak treatment was 96% (68 of 71). There were 13 recurrences, all of which were associated with complex endoleaks. CONCLUSIONS: Nearly half of the patients who underwent F/B-EVAR experienced an endoleak. The majority were classified as type II, with nearly a fifth associated with sac expansion. Interventions for a type II endoleak frequently led to reclassification as complex, with a concomitant type I or III endoleak not appreciated on computed tomography angiography and/or duplex. Further study is needed to determine if the primary treatment goal for complex aneurysm repair is sac stability or sac regression, as this would inform both the importance of properly classifying endoleaks noninvasively and the intervention threshold for managing type II endoleaks.

Successful implementation of a nurse-navigator-run program using natural language processing identifying patients with an abdominal aortic aneurysm.

BACKGROUND: Abdominal aortic aneurysms (AAA) are often identified incidentally on imaging studies. Patients and/or providers are frequently unaware of these AAA and the need for long-term follow-up. We sought to evaluate the outcome of a nurse-navigator-run AAA program that uses a natural language processing (NLP) algorithm applied to the electronic medical record (EMR) to identify patients with imaging report-identified AAA not being followed actively. METHODS: A commercially available AAA-specific NLP system was run on EMR data at a large, academic, tertiary hospital with an 11-year historical look back (January 1, 2010, to June 2, 2021), to identify and characterize AAA. Beginning June 3, 2021, a direct link between the NLP system and the EMR enabled for real-time review of imaging reports for new AAA cases. A nurse-navigator (1.0 full-time equivalent) used software filters to categorize AAA according to predefined metrics, including repair status and adherence to Society for Vascular Surgery imaging surveillance protocol. The nurse-navigator then interfaced with patients and providers to reestablish care for patients not being followed actively. The nurse-navigator characterized patients as case closed (eg, deceased, appropriate follow-up elsewhere, refuses follow-up), cases awaiting review, and cases reviewed and placed in ongoing surveillance using AAA-specific software. The primary outcome measures were yield of surveillance imaging performed or scheduled, new clinic visits, and AAA operations for patients not being followed actively. RESULTS: During the prospective study period (January 1, 2021, to December 30, 2021), 6,340,505 imaging reports were processed by the NLP. After filtering for studies likely to include abdominal aorta, 243,889 imaging reports were evaluated, resulting in the identification of 6495 patients with AAA. Of these, 2937 cases were reviewed and closed, 1183 were reviewed and placed in ongoing surveillance, and 2375 are awaiting review. When stratifying those reviewed and placed in ongoing surveillance by maximum aortic diameter, 258 were 2.5 to 3.4 cm, 163 were 3.5 to 3.9 cm, 213 were 4 to 5 cm, and 49 were larger than 5 cm; 36 were saccular, 86 previously underwent open repair, 274 previously underwent endovascular repair, and 104 were other. This process yielded 29 new patient clinic visits, 40 finalized imaging studies, 29 scheduled imaging studies, and 4 AAA operations in 3 patients among patients not being followed actively. CONCLUSIONS: The application of an AAA program leveraging NLP successfully identifies patients with AAA not receiving appropriate surveillance or counseling and repair. This program offers an opportunity to improve best practice-based care across a large health system.

Initial single-center experience using Fiber Optic RealShape guidance in complex endovascular aortic repair.

OBJECTIVE: In the present study, we have described the technical success using Fiber Optic RealShape (FORS) endovascular guidance and its effects on the overall procedural time and radiation usage during complex endovascular aortic repair (EVAR). METHODS: Fenestrated and branched EVARs performed at a single center from 2017 to 2022 were prospectively studied. FORS-guided procedures were matched retrospectively 1:3 to non-FORS-guided procedures by the incorporated target arteries and body mass index. Technical success was defined as successful target vessel cannulation using FORS for the entirety of navigation (wire insertion to exchange for a stiff wire). The predictors of technical success were evaluated via logistic regression. The procedural times and radiation doses were compared between the matched cohorts using the Wilcoxon rank sum test. RESULTS: A total of 21 FORS-guided procedures were matched to 61 non-FORS-guided procedures. A total of 95 FORS cannulations were attempted (87 for the visceral target artery and 8 for the bifurcate gate). Technical success was achieved in 81 cannulations (85%); 15 (16%) were completed without the use of live fluoroscopy. The univariate predictors of FORS technical success included <50% target artery stenosis, <50% target artery calcification, and the target vessel attempted (P < .05 for each). FORS failures were attributed to device material properties in six cases, device failure in two cases, and the wire/catheter combination in six. The use of FORS guidance was associated with shorter median procedural and fluoroscopy times and a lower dose area product and air kerma (P ≤ .0001 for each). CONCLUSIONS: The results from our initial experience with FORS during complex EVAR, including our learning curve, has shown promise, with acceptable technical success and reductions in procedural times and radiation usage.

A neurogenic signature involving monoamine Oxidase-A controls human thermogenic adipose tissue development.

Mechanisms that control 'beige/brite' thermogenic adipose tissue development may be harnessed to improve human metabolic health. To define these mechanisms, we developed a species-hybrid model in which human mesenchymal progenitor cells were used to develop white or thermogenic/beige adipose tissue in mice. The hybrid adipose tissue developed distinctive features of human adipose tissue, such as larger adipocyte size, despite its neurovascular architecture being entirely of murine origin. Thermogenic adipose tissue recruited a denser, qualitatively distinct vascular network, differing in genes mapping to circadian rhythm pathways, and denser sympathetic innervation. The enhanced thermogenic neurovascular network was associated with human adipocyte expression of THBS4, TNC, NTRK3, and SPARCL1, which enhance neurogenesis, and decreased expression of MAOA and ACHE, which control neurotransmitter tone. Systemic inhibition of MAOA, which is present in human but absent in mouse adipocytes, induced browning of human but not mouse adipose tissue, revealing the physiological relevance of this pathway. Our results reveal species-specific cell type dependencies controlling the development of thermogenic adipose tissue and point to human adipocyte MAOA as a potential target for metabolic disease therapy.

Acute management of atrial fibrillation in congestive heart failure with reduced ejection fraction in the emergency department.

INTRODUCTION: Acute heart rate control for atrial fibrillation (AF) with rapid ventricular response (RVR) in the emergency department (ED) is often achieved utilizing intravenous (IV) non-dihydropyridine calcium channel blockers (CCB) or beta blockers (BB). For patients with concomitant heart failure with a reduced ejection fraction (HFrEF), the American Heart Association and other clinical groups note that CCB should be avoided due to their potential negative inotropic effects. However, minimal evidence exists to guide this current recommendation. The primary objective of this study was to compare the incidence of adverse effects in the HFrEF patient population whose AF with RVR was treated with IV diltiazem or metoprolol in the ED. METHODS: This single center, retrospective review included patients ≥18 years old with HFrEF who presented in AF with RVR and received IV diltiazem or metoprolol in the ED. The primary outcome was adverse effects of therapy defined as: 1) hypotension (systolic blood pressure < 90 mmHg requiring fluid bolus or vasopressors) or bradycardia (heart rate < 60 beats/min) within 60 min of medication administration 2) worsening heart failure symptoms defined as increased oxygen requirements within four hours or inotropic support within 48 h. Secondary outcomes included the incidence of rate control failure, patient disposition, ED length of stay, hospital length of stay, and in-hospital mortality. RESULTS: One hundred and twenty-five patients met inclusion criteria, with 57 receiving diltiazem and 68 receiving metoprolol. Overall adverse effects for diltiazem and metoprolol were similar (32% vs. 21%, P = 0.217). However, there was a significantly higher incidence of worsening heart failure symptoms within the diltiazem group (33% vs 15%, P = 0.019). Rate control failure at 60 min did not differ significantly between diltiazem and metoprolol (51% vs 62%, P = 0.277). CONCLUSIONS: In HFrEF patients with AF, there was no difference in total adverse events in patients treated with IV diltiazem compared to metoprolol. However, the diltiazem group had a higher incidence of worsening CHF symptoms defined as increased oxygen requirement within four hours or initiation of inotropic support within 48 h.

Development of spirulina for the manufacture and oral delivery of protein therapeutics.

The use of the edible photosynthetic cyanobacterium Arthrospira platensis (spirulina) as a biomanufacturing platform has been limited by a lack of genetic tools. Here we report genetic engineering methods for stable, high-level expression of bioactive proteins in spirulina, including large-scale, indoor cultivation and downstream processing methods. Following targeted integration of exogenous genes into the spirulina chromosome (chr), encoded protein biopharmaceuticals can represent as much as 15% of total biomass, require no purification before oral delivery and are stable without refrigeration and protected during gastric transit when encapsulated within dry spirulina. Oral delivery of a spirulina-expressed antibody targeting campylobacter-a major cause of infant mortality in the developing world-prevents disease in mice, and a phase 1 clinical trial demonstrated safety for human administration. Spirulina provides an advantageous system for the manufacture of orally delivered therapeutic proteins by combining the safety of a food-based production host with the accessible genetic manipulation and high productivity of microbial platforms.

Hemoglobin A1c monitoring practices before lower extremity bypass in patients with diabetes vary broadly and do not predict outcomes.

OBJECTIVE: Hemoglobin A1c (HbA1c) is used as a marker of glycemic control, but the role of HbA1c before lower extremity bypass (LEB) in patients with diabetes remains unclear. We sought to characterize patients with diabetes undergoing LEB with and without HbA1c monitoring and to determine if HbA1c monitoring practices correlate with better outcomes. METHODS: The Vascular Quality Initiative was queried for all LEB in patients with diabetes (2010-2020). Patients with diabetes were characterized based on therapy: diet-controlled, noninsulin medication use, or insulin use. Glycemic control was characterized by preoperative HbA1c within 6 months of surgery: unknown control (no HbA1c), well-controlled (HbA1c <7%), poorly-controlled (HbA1c 7%-10%), and uncontrolled (HbA1c >10%). Centers with >5 LEB/y were stratified into terciles according to rate of HbA1c monitoring. The unadjusted associations between glycemic control and in-hospital major adverse limb events, major adverse cardiac events, and mortality were assessed with univariate methods. The independent association of center-level HbA1c monitoring with 5-year survival and 3-year amputation-free survival (AFS) was determined with Kaplan-Meier analyses and Cox regression modeling, adjusted for differences in patient characteristics and center volume. RESULTS: Of 16,092 patients with diabetes undergoing LEB, 4055 (25%) did not have a documented HbA1c. Insulin use was less common in no A1c (48%) and well-controlled diabetes (39%) compared with poorly controlled (67%) and uncontrolled diabetes (78%) (P < .01). In univariate analyses, glycemic control was not associated with differences for in-hospital major adverse limb events, major adverse cardiac events, or mortality. Of 162 centers, HbA1c monitoring practices varied widely (range: 12.5%-100% of LEB). The 3-year AFS and 5-year survival were worse in the highest monitoring tercile vs the lowest (73.6% vs 77.3%, P < .01, 72.1% vs 77.5%, P < .01, respectively). On multivariable analyses, centers in the highest tercile of monitoring had the greatest hazard of AFS (hazard ratio: 1.21, 95% confidence interval: 1.1-1.3, P < .001) and overall mortality (hazard ratio: 1.19, 95% confidence interval: 1.1-1.3, P < 0.001), compared with the centers in the lowest tercile of monitoring. CONCLUSIONS: Patients with diabetes and no preoperative HbA1c monitoring do not have worse LEB outcomes compared with those with HbA1c monitoring. Preoperative HbA1c monitoring varies widely, suggesting broad differences in practice and documentation. Centers with the highest rates of monitoring demonstrated inferior outcomes, likely due to other confounding unmeasured variables. These findings indicate that HbA1c monitoring before LEB, unto itself, should not be used as a measure of surgical quality.