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.

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.

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.

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.

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.

Utilization and extravasation of peripheral norepinephrine in the emergency department.

OBJECTIVE: Vasopressors are typically administered through central venous catheters (CVC) due to a historical risk of extravasation with peripheral administration. However, CVC insertion is a time-consuming process that may delay vasopressor administration and is associated with complications. The Virginia Commonwealth University Health System (VCUHS) Emergency Department (ED) implemented a protocol that recommends peripheral norepinephrine (pNE) be administered through an 18 gauge or larger at or above the antecubital fossa or the external jugular vein with a maximum dose of 20 µg/min. This study characterizes the use and incidence of extravasation in all adult patients who received pNE initiated in the VCUHS ED. METHODS: This was an observational, retrospective cohort study in adult patients from March 2016 to March 2019. Of the 331 patients that were screened, 177 met inclusion criteria. Data were analyzed using descriptive statistics. RESULTS: Patients had a median age of 60 years and 59% were male. The median APACHE II score was 25 with an overall hospital mortality of 27%. A majority of patients received pNE for distributive shock (63%). Approximately 69% received pNE through an antecubital infusion site. The median total pNE duration was 62 min (IQR 32, 142). Eighty-four percent of patients received a central line. Only 2.3% of patients had confirmed extravasation in addition to another 2.3% where extravasation could not be excluded, for a total rate of 4.5%. None had subsequent extremity injury. CONCLUSIONS: Administration of pNE according to the VCUHS ED protocol resulted in a low extravasation rate.

Evaluation of prehospital hydroxocobalamin use in the setting of smoke inhalation.

BACKGROUND: The indications for prehospital hydroxocobalamin are not well defined. The aim of this study was to evaluate prehospital signs and symptoms in patients who received hydroxocobalamin to improve future use. METHODS: In this retrospective study, all patients who received prehospital Hydroxocobalamin at a tertiary care burn center from December 2012 to March 2018 were reviewed. Each case was evaluated for evidence of suspected cyanide toxicity: hypotension, syncope, CNS depression/altered mentation, seizures, respiratory or cardiac arrest. A determination was made whether or not hydroxocobalamin was indicated. RESULTS: In this study, EMS providers administered hydroxocobalamin to 42 patients between December 2012 and March 2018. The majority (71%) of suspected cyanide exposures were from house fires. The most common prehospital findings were coma or depressed CNS (36%), followed by hypotension (16%) and cardiac arrest (12%). Sixty percent of patients treated with hydroxocobalamin had none of the six clinical indicators for potential cyanide toxicity. Carboxyhemoglobin and serum lactate were significantly different in patients that had a clinical indication for hydroxocobalamin compared to those who did not. CONCLUSIONS: Prehospital hydroxocobalamin was used empirically however, indications are unclear. Using defined clinical indications may provide greater clarity for providers and reduce unnecessary use of hydroxocobalamin.

Surround Propinquity and Tonic Accommodation.

PURPOSE: Previous studies of dark focus have found evidence of a propinquity response, in which subjects accommodate to the perceived distance of their surroundings despite being in absolute darkness. Their distance perception in a lighted room allows a spatial representation to persist within the darkened room. This study sought to establish the significance and magnitude of the propinquity response in a large sample of young adults, and to determine whether the propinquity response can be predicted by a subject's initial dark focus in an unknown dark room. METHODS: Dark focus was measured with a dynamic infrared optometer (Plusoptix PowerRef 3) in 30 young adult subjects, 26 of whom were naive to the testing room and its dimensions. Dark focus was then measured at varying dioptric wall distances of 0.25-4D. The subject viewed the lighted room before each measurement. For each individual, the dark focus was plotted as a function of dioptric wall distance. The slope of this function was used as a measure of the propinquity response. RESULTS: The mean initial dark focus value was 1.05D (SD 1.04D) for the 26 naive subjects. The mean slope of the plot of dark focus as a function of dioptric wall distance was small (+0.097), yet highly statistically significant (P = .0002). The propinquity response function showed no statistically significant quadratic or cubic trends, and so may be considered linear. No statistically significant correlation was found between naive dark focus and propinquity response (r = +0.246, P = .226). CONCLUSIONS: Propinquity seems to be a small but statistically significant factor in dark focus measurements. Though it is unlikely to contaminate tonic accommodation measurements in large samples under normal laboratory conditions, a minority of individuals exhibit large propinquity responses equal to that of proximal accommodation in lighted conditions.

Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease.

Defective mitochondrial distribution in neurons is proposed to cause ATP depletion and calcium-buffering deficiencies that compromise cell function. However, it is unclear whether aberrant mitochondrial motility and distribution alone are sufficient to cause neurological disease. Calcium-binding mitochondrial Rho (Miro) GTPases attach mitochondria to motor proteins for anterograde and retrograde transport in neurons. Using two new KO mouse models, we demonstrate that Miro1 is essential for development of cranial motor nuclei required for respiratory control and maintenance of upper motor neurons required for ambulation. Neuron-specific loss of Miro1 causes depletion of mitochondria from corticospinal tract axons and progressive neurological deficits mirroring human upper motor neuron disease. Although Miro1-deficient neurons exhibit defects in retrograde axonal mitochondrial transport, mitochondrial respiratory function continues. Moreover, Miro1 is not essential for calcium-mediated inhibition of mitochondrial movement or mitochondrial calcium buffering. Our findings indicate that defects in mitochondrial motility and distribution are sufficient to cause neurological disease.

Allergic Reaction to Ketamine as Monotherapy for Procedural Sedation.

BACKGROUND: Ketamine is a cyclohexamine derivative that acts as a noncompetitive N-methyl D-aspartate receptor antagonist. Its use for procedural sedation is recommended by national clinical policy. However, its immunogenic potential is not well documented. CASE REPORT: We report a case of allergic reaction associated with the administration of intravenous ketamine for procedural sedation in a 16-year-old male. Minutes after administration, the patient developed a morbilliform, erythematous rash that extended to the upper and lower torso and resolved with intravenous diphenhydramine. It is most likely that this allergic reaction was caused by a ketamine-induced histamine release that has been described in vitro. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This is the first case report in which ketamine was used as monotherapy in the emergency department for the facilitation of procedural sedation that resulted in an allergic reaction. Supportive measures, including advanced airway procedures and hemodynamic support, may be necessary in more severe anaphylactic cases. Providers should be aware of this potential adverse effect when using ketamine for procedural sedation.

Patterns of variation in feeding strike kinematics of juvenile ghost praying mantis (Phyllocrania paradoxa): are components of the strike stereotypic?

Functional systems, such as feeding mechanics, often involve the evolution of several components of the musculoskeletal system that are moved in coordination to capture prey. Because these systems often involve the quick movement of several structures, some feeding systems have been hypothesized to be stereotypic. While the motor activity patterns are often stereotyped, the subsequent kinematics can be variable, many times in response to variation in prey stimulus (e.g. prey position). Patterns of feeding kinematics have been well studied among vertebrates, with less attention on invertebrate systems. The goal of this study was to examine the amount of stereotypy in the feeding strike kinematics of praying mantises. We filmed eight juvenile ghost praying mantises (Phyllocrania paradoxa) at 1000 Hz across several days within instar 7. We digitized several points that represent the movement of the coxa, trochanter-femur and tibia of the raptorial foreleg to obtain a set of kinematics including angles and angular velocities of the joint, as well as body lunge. Using the coefficient of variation, we found less stereotypy in the approach stage of the strike compared with the sweep. Using Bonferroni-corrected Pearson's correlations of kinematics with prey position, we found few traits related to prey position with the exception of some kinematics of the coxa joint and the amount of lunge used during the strike. Our results suggest that several components of the praying mantis strike are stereotypic, while others exhibit flexibility to ensure successful capture of the prey.

Functional analysis of three Arabidopsis ARGONAUTES using slicer-defective mutants.

In RNA-directed silencing pathways, ternary complexes result from small RNA-guided ARGONAUTE (AGO) associating with target transcripts. Target transcripts are often silenced through direct cleavage (slicing), destabilization through slicer-independent turnover mechanisms, and translational repression. Here, wild-type and active-site defective forms of several Arabidopsis thaliana AGO proteins involved in posttranscriptional silencing were used to examine several AGO functions, including small RNA binding, interaction with target RNA, slicing or destabilization of target RNA, secondary small interfering RNA formation, and antiviral activity. Complementation analyses in ago mutant plants revealed that the catalytic residues of AGO1, AGO2, and AGO7 are required to restore the defects of Arabidopsis ago1-25, ago2-1, and zip-1 (AGO7-defective) mutants, respectively. AGO2 had slicer activity in transient assays but could not trigger secondary small interfering RNA biogenesis, and catalytically active AGO2 was necessary for local and systemic antiviral activity against Turnip mosaic virus. Slicer-defective AGOs associated with miRNAs and stabilized AGO-miRNA-target RNA ternary complexes in individual target coimmunoprecipitation assays. In genome-wide AGO-miRNA-target RNA coimmunoprecipitation experiments, slicer-defective AGO1-miRNA associated with target RNA more effectively than did wild-type AGO1-miRNA. These data not only reveal functional roles for AGO1, AGO2, and AGO7 slicer activity, but also indicate an approach to capture ternary complexes more efficiently for genome-wide analyses.

Hyperglycemia down-regulates cGMP-dependent protein kinase I expression in first trimester cytotrophoblast cells.

Diabetes in pregnancy is associated with microvascular complications and a higher incidence of preeclampsia. The regulatory signaling pathways involving nitric oxide, cGMP, and cGMP-dependent protein kinase (PKG) have been shown to be down-regulated under diabetic conditions and contribute to the pathogenesis of vascular complications in diabetes. The present study was undertaken to investigate how high glucose concentrations regulate PKG expression in cytotrophoblast cells (CTBs). Human CTBs (Sw. 71) were treated with 45, 135, 225, 495, or 945 mg/dL glucose for 48 h. Some cells were pretreated with a p38 inhibitor (10 µM SB203580) or 10 µM rosiglitazone. After treatment, the cell lysates were subjected to measure the expression of protein kinase G1α (PKG1α), protein kinase G1ß (PKG1ß), soluble guanylate cyclase 1α (sGC1α), and soluble guanylate cyclase 1 ß (sGC1ß) by Western blot. Statistical comparisons were performed using analysis of variance with Duncan's post hoc test. The expressions of PKG1α, PKG1ß, sGC1α, and sGC1ß were significantly down-regulated (p < 0.05) in CTBs treated with >135 mg/dL glucose compared to basal (45 mg/dL). The hyperglycemia-induced down-regulation of cGMP and cGMP-dependent PKG were attenuated by the SB203580 or rosiglitazone pretreatment. Exposure of CTBs to excess glucose down-regulates cGMP and cGMP-dependent PKG, contributing to the development of vascular complications in diabetic mothers during pregnancy. The attenuation of hyperglycemia-induced down-regulation of PKG proteins by SB203580 or rosiglitazone pretreatment further suggests the involvement of stress signaling mechanisms in this process.

Lack of adverse effects from flumazenil administration: an ED observational study.

BACKGROUND: Flumazenil is an effective benzodiazepine (BZD) antagonist. Empiric use of flumazenil in the emergency department (ED) is not widely recommended due to concerns of seizures, which are commonly associated with coingestants and BZD withdrawal. OBJECTIVE: The objective of the study is to assess adverse events and clinical outcomes of flumazenil administration in known and suspected BZD overdose in an ED at a tertiary academic medical center. METHODS: This is a retrospective observational study of adult patients administered flumazenil for known or suspected BZD overdose in the ED over 7 years. Outcomes included mental status improvement, the incidence of seizures, and intubation of the trachea after flumazenil administration. RESULTS: Twenty-three patients were included in the analysis, of which 15 (65%) of patients experienced some type of clinically significant mental status improvement. No seizures were identified despite 7 (35%) reported proconvulsant coingestants. One patient required intubation of the trachea but was subsequently extubated in the ED. CONCLUSIONS: A majority of patients had improved mental status after the administration of flumazenil. No patient experienced seizures. Additional studies that clarify the role of flumazenil for ED patients with suspected BZD toxicity are warranted.

Gem1 and ERMES do not directly affect phosphatidylserine transport from ER to mitochondria or mitochondrial inheritance.

In yeast, a protein complex termed the ER-Mitochondria Encounter Structure (ERMES) tethers mitochondria to the endoplasmic reticulum. ERMES proteins are implicated in a variety of cellular functions including phospholipid synthesis, mitochondrial protein import, mitochondrial attachment to actin, polarized mitochondrial movement into daughter cells during division, and maintenance of mitochondrial DNA (mtDNA). The mitochondrial-anchored Gem1 GTPase has been proposed to regulate ERMES functions. Here, we show that ERMES and Gem1 have no direct role in the transport of phosphatidylserine (PS) from the ER to mitochondria during the synthesis of phosphatidylethanolamine (PE), as PS to PE conversion is not affected in ERMES or gem1 mutants. In addition, we report that mitochondrial inheritance defects in ERMES mutants are a secondary consequence of mitochondrial morphology defects, arguing against a primary role for ERMES in mitochondrial association with actin and mitochondrial movement. Finally, we show that ERMES complexes are long-lived, and do not depend on the presence of Gem1. Our findings suggest that the ERMES complex may have primarily a structural role in maintaining mitochondrial morphology.

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.

Translational Challenges in Drug Therapy and Delivery Systems for Treating Chronic Lower Extremity Wounds.

Despite several promising preclinical studies performed over the past two decades, there remains a paucity of market-approved drugs to treat chronic lower extremity wounds in humans. This translational gap challenges our understanding of human chronic lower extremity wounds and the design of wound treatments. Current targeted drug treatments and delivery systems for lower extremity wounds rely heavily on preclinical animal models meant to mimic human chronic wounds. However, there are several key differences between animal preclinical wound models and the human chronic wound microenvironment, which can impact the design of targeted drug treatments and delivery systems. To explore these differences, this review delves into recent new drug technologies and delivery systems designed to address the chronic wound microenvironment. It also highlights preclinical models used to test drug treatments specific for the wound microenvironments of lower extremity diabetic, venous, ischemic, and burn wounds. We further discuss key differences between preclinical wound models and human chronic wounds that may impact successful translational drug treatment design.