The Impact of Small Artery Disease (SAD) and Medial Arterial Calcification (MAC) Scores on Chronic Wound and Amputation Healing: Can It Tell Us More?

BACKGROUND: In 2021, Ferraresi et al. created a novel scoring system based on the impact of small artery disease (SAD) and medial arterial calcification (MAC) on wound healing. SAD and MAC scores functioned similar to Wound, Ischemia, and foot Infection (WIfI) but with minimal resource expenditure. Despite its potential, few studies have expanded on the original dataset. We aim to validate SAD's impact and MAC's impact on wound healing outcomes and determine their utility in relation to current predictive models. METHODS: Single-institution retrospective review was used to identify amputations for chronic (>1 month) podiatric wounds between 2015 and 2020. Foot X-ray (MAC) or angiography (SAD) < 6 months of index procedure was required. Primary outcomes included major amputation, wound healing, major adverse limb events, and amputation-free survival (AFS). Statistical analysis included chi-squared, 1-way analysis of variance, nonparametric correlation, Kaplan-Meier, Cox regression, and Akaike/Bayesian Inclusion Criteria model comparison. RESULTS: Of 136 limbs, 67 received SAD scores (0-2) and 128 received MAC scores (0-2). SAD cohorts exhibited similar comorbidity profiles with exception of coronary disease, heart failure, and chronic kidney disease. MAC cohorts were notably disparate in prevalence of multiple conditions. High mean SAD/MAC scores were seen in severe (3-vessel) below-ankle disease (P = 0.001∗ [SAD], P = 0.041∗ [MAC]). Both SAD and MAC correlated with lower mean toe pressure (P = 0.043∗ [SAD], P ≤ 0.001∗ [MAC]), while only MAC correlated with higher overall WIfI score (P = 0.029∗). No significant procedural differences were noted. However, higher readmission rates (73.9% [2] vs. 46.9% [0], P = 0.014∗) and all-cause mortality (65.2% [2] vs. 26.0% [0], P = 0.002∗) were noted with higher MAC. Survival analysis revealed higher 1-year major amputation rates (P = 0.036∗), impaired wound healing (P < 0.001∗), and lower AFS (P = 0.001∗) with increasing MAC severity. Additionally, MAC-2 patients underwent amputation at faster rates than MAC-0 patients (hazard ratio 5.25, 95% confidence interval [1.82, 9.77]) with longer times to wound healing (hazard ratio 0.21, 95% confidence interval [0.08, 0.53]). Model comparison suggested a combination of WIfI and MAC could improve accuracy of predicted time to major amputation, wound healing, and AFS. CONCLUSIONS: MAC scoring showed significant promise both as individual predictor and adjunct to current predictive models of long-term wound healing outcomes. Routine use of MAC scoring in chronic limb-threatening ischemia evaluation, especially when noninvasive testing is unavailable, could promote timely referral for intervention and efficient resource utilization in limited-resource or critical care settings. Furthermore investigation is necessary to determine MAC's impact on revascularization and how scoring can be used to guide surgical decision-making.

Benefits of early vascular provider involvement in wound care center management of patients with underlying arterial disease.

OBJECTIVES: Peripheral arterial disease (PAD) can reduce wound healing rates by ≤30%. Current literature suggests wound outcomes are improved when management is driven by vascular providers. However, whether this benefit is derived solely from early vascular provider involvement remains unclear. METHODS: A retrospective analysis was performed of 80 limbs with chronic wounds and underlying PAD seen at our institution's wound center between July 2022 and July 2023. Arterial disease was defined by the following criteria: (1) prior PAD diagnosis, (2) ankle-brachial-index of <0.9 or toe pressure of <70 mm Hg, or (3) absent peripheral pulses. Patients were divided into early (<6 week) vascular provider exposure (EVE; n = 45) or late/no vascular exposure (LNVE; n = 35). Providers included vascular surgeons and affiliated advanced practitioners. The primary outcome studied was overall time to wound healing. Statistical analysis included χ2 tests, t test, Pearson correlation, Kaplan-Meier analysis, and Cox regression modeling (variables included in a multivariate model if univariate effect on healing was associated at P < .1). RESULTS: Baseline demographic profiles were similar between groups with exception of lower baseline albumin (P = .037), more heart failure (P = .013), and more prior peripheral endovascular interventions (P = .013) in the EVE group. Although the initial wound locations and sizes were similar, EVE wounds had significantly higher WIfI wound scores (1.9 ± 0.1 vs 1.6 ± 0.1; P = .039). Although more LNVE patients developed radiographic osteomyelitis (31.8% vs 55.6%; P = .033), fewer underwent operative debridement or amputation (100% vs 63.2%; P = .008). On univariate analysis, healing time tended to be shorter in EVE, but not significantly (P = .089). When controlled for comorbidities, however, healing rates were nearly two-fold higher in EVE (hazard ratio, 2.42; 95% confidence interval, 1.21-4.84). LNVE wounds also took significantly longer to reach checkpoints including time to >75% granulation (P = .05), 15% weekly size decrease (P = .044), and epithelialization (P = .026). LNVE patients required more wound center visits (P = .024) and procedures (P = .005) with a longer time to intervention (P = .041). All EVE patients obtained ankle-brachial indices, with 90.9% of them available at their first wound care visit (P < .001). Although a slightly greater proportion of patients underwent a major amputation in EVE (15.6% vs 11.4%; P = .595), this difference did not attain significance; additionally, 100% of EVE patients had documented discussion of nonsalvageable limbs before amputation. CONCLUSIONS: Early exposure to vascular practitioners improves wound healing time, timeliness to intervention, and wound center and hospital resource use in patients with PAD. Further investigation into benefits of vascular involvement within community wound center models could significantly improve awareness and accessibility of arterial wound care in smaller/remote communities.

Ultrasound Examination Without Axial Imaging is Sufficient for Preoperative Planning in Transcarotid Artery Revascularization (TCAR).

BACKGROUND: Duplex ultrasound is frequently used to determine the degree of carotid stenosis. However, axial imaging is typically obtained for operative planning for transcarotid artery revascularization (TCAR). We examined if ultrasound alone is sufficient before TCAR. METHODS: Data from the Vascular Quality Initiative TCAR Surveillance Project registry between 2016 and 2021 was obtained. Patients were divided into 2 groups-those with preoperative ultrasound-alone (US) and those with additional axial imaging (AX). Perioperative outcomes were compared utilizing univariate Chi-square, independent t-test, multivariate logistic regression, and Kaplan-Meier analysis. RESULTS: There were 3,418 patients identified: 682 in the US group and 2,736 in the AX group. More preoperative hypertension was reported in US (16.1% vs. 10.2%, P < 0.001) while cardiovascular disease (23% vs. 28.9%, P = 0.006) and prior ipsilateral stroke (22% vs. 32.7%, P = 0.002) were more prevalent in AX. More patients had history of contralateral carotid endarterectomy (13.6% vs. 16.7%, P = 0.035) or either ipsilateral (2.6% vs. 1.2%, P = 0.002) or contralateral (7.9% vs. 4.9%, P = 0.008) carotid artery stenting in the US group. Lower preoperative creatinine was reported in the US cohort (1.09 ± 0.01 vs. 1.18 ± 0.02, P < 0.001) while more were symptomatic in AX (28.2% vs. 36.2%, P < 0.001). There were no significant differences between lesion characteristics or operative decision making. A slightly higher total procedure time was seen in AX (73.7 ± 0.6 vs. 68.6 ± 1.3 min, P = 0.017). No differences were seen in perioperative transient ischemic attack/stroke or other immediate complications. At 2-year follow-up, both groups reported no significant differences in stroke-free survival (P = 0.750) and independent functional status remained near-identical (97.3% vs. 97.4%, P = 0.921). Kaplan-Meier analysis yielded no significant difference between mortality at 2 years (P = 0.563). Bivariate logistic regression modeling did reveal a statistically significant increase in likelihood of long-term ipsilateral stroke (odds ratio 1.77, P = 0.015) and non stroke-related complication in the postoperative period (odds ratio 4.81, P = 0.005). However, only a statistically significant relationship persisted in non-stroke complication when the model was controlled for between-group differences. CONCLUSIONS: No significant differences in postoperative or long-term complications were noted with additional AX in preoperative TCAR planning. Thus, duplex ultrasound offers a safe and effective alternative for those with contraindication or axial imaging.

Baseline neuropsychological profiles in prion disease predict survival time.

OBJECTIVE: Few studies have captured the neuropsychological profile of sporadic Creutzfeldt-Jakob disease (sCJD) with neuropsychological testing, and little is known about cognitive predictors of survival. We characterized baseline neuropsychological performance in sCJD and investigated associations with survival. METHODS: sCJD participants who completed the MMSE (n = 118), 61 sCJD of whom also completed a neuropsychological battery at baseline, and 135 age-matched healthy controls, were included. Composite scores of global cognition, memory, executive functions, visuospatial, and language were derived. Cox proportional hazard models estimated survival time, controlling for age and education. Additional models adjusted for Barthel Index and PRNP codon 129 polymorphism. RESULTS: sCJD participants performed significantly worse than controls on all cognitive tasks and composites with most showing very large effect sizes. The three tests showing the largest group differences were delayed verbal recall (Hedges'g = 4.08, P < 0.0001), Stroop Inhibition (Hedges'g = 3.14, P < 0.0001), and Modified Trails (Hedges'g = 2.94, P < 0.0001). Memory (95%) and executive functioning (87%) composites were most commonly impaired. Poorer global (HR = 0.65, P < 0.0001), visuospatial (HR = 0.82, P < 0.0001), and memory (HR = 0.82, P = 0.01) composites predicted shorter survival. Visuospatial cognition remained a significant predictor even after adjusting for all other cognitive composites; each standard deviation decrease in visuospatial cognition was associated with an 18% higher chance of death (HR = 0.82, P < 0.003). Global (HR = 0.68, P = 0.03) and visuospatial (HR = 0.82, P = 0.001) composites remained significant predictors after controlling for Barthel Index and codon 129. INTERPRETATION: sCJD participants exhibit a broad range of cognitive impairments, with memory and executive functioning deficits in the vast majority. Neuropsychological assessment, particularly of visuospatial abilities, informs prognostication in sCJD.

Cell type-specific modulation of sensory and affective components of itch in the periaqueductal gray.

Itch is a distinct aversive sensation that elicits a strong urge to scratch. Despite recent advances in our understanding of the peripheral basis of itch, we know very little regarding how central neural circuits modulate acute and chronic itch processing. Here we establish the causal contributions of defined periaqueductal gray (PAG) neuronal populations in itch modulation in mice. Chemogenetic manipulations demonstrate bidirectional modulation of scratching by neurons in the PAG. Fiber photometry studies show that activity of GABAergic and glutamatergic neurons in the PAG is modulated in an opposing manner during chloroquine-evoked scratching. Furthermore, activation of PAG GABAergic neurons or inhibition of glutamatergic neurons resulted in attenuation of scratching in both acute and chronic pruritis. Surprisingly, PAG GABAergic neurons, but not glutamatergic neurons, may encode the aversive component of itch. Thus, the PAG represents a neuromodulatory hub that regulates both the sensory and affective aspects of acute and chronic itch.

Establishing a framework for neuropathological correlates and glymphatic system functioning in Parkinson's disease.

Recent evidence has advanced our understanding of the function of sleep to include removal of neurotoxic protein aggregates via the glymphatic system. However, most research on the glymphatic system utilizes animal models, and the function of waste clearance processes in humans remains unclear. Understanding glymphatic function offers new insight into the development of neurodegenerative diseases that result from toxic protein inclusions, particularly those characterized by neuropathological sleep dysfunction, like Parkinson's disease (PD). In PD, we propose that glymphatic flow may be compromised due to the combined neurotoxic effects of alpha-synuclein protein aggregates and deteriorated dopaminergic neurons that are linked to altered REM sleep, circadian rhythms, and clock gene dysfunction. This review highlights the importance of understanding the functional role of glymphatic system disturbance in neurodegenerative disorders and the subsequent clinical and neuropathological effects on disease progression. Future research initiatives utilizing noninvasive brain imaging methods in human subjects with PD are warranted, as in vivo identification of functional biomarkers in glymphatic system functioning may improve clinical diagnosis and treatment of PD.

Information processing deficit in older adults with HIV infection: A comparison with Parkinson's disease.

OBJECTIVE: Individuals with HIV treated with antiretroviral therapy can expect to reach average life span, making them susceptible to combined disease and aging effects on cognitive and motor functions. Slowed processing speed in HIV is a concern for cognitive and everyday functioning and is sensitive to declines in aging. We hypothesized that information processing (IP) deficits, over and above that expected with normal aging, would occur in older HIV patients similar to those observed in Parkinson's disease (PD) patients, with both conditions affecting frontostriatal pathways. METHOD: Groups comprised 26 individuals with HIV infection, 29 with mild-to-moderate PD, and 21 healthy controls (C). Speed of IP was assessed with the oral version of the Symbol Digit Modalities Test and the color naming condition of the Golden Stroop Task. RESULTS: The HIV group was impaired on speed of IP tasks compared with both the C and PD groups. Even after controlling for normal aging effects, older age in the HIV group correlated with IP slowing. Slower IP speed was associated with poorer general cognitive ability and more extrapyramidal motor signs in older HIV-infected individuals. CONCLUSIONS: The notable effects of impaired IP speed, over and above neurotypical age-related declines, indicate that older HIV-infected individuals may have an enhanced vulnerability for developing nonmotor and motor symptoms despite antiretroviral therapy. Assessing for oral IP speed may provide the unique opportunity to identify early signs of progressive clinical declines in HIV. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Fully implantable, battery-free wireless optoelectronic devices for spinal optogenetics.

The advent of optogenetic tools has allowed unprecedented insights into the organization of neuronal networks. Although recently developed technologies have enabled implementation of optogenetics for studies of brain function in freely moving, untethered animals, wireless powering and device durability pose challenges in studies of spinal cord circuits where dynamic, multidimensional motions against hard and soft surrounding tissues can lead to device degradation. We demonstrate here a fully implantable optoelectronic device powered by near-field wireless communication technology, with a thin and flexible open architecture that provides excellent mechanical durability, robust sealing against biofluid penetration and fidelity in wireless activation, thereby allowing for long-term optical stimulation of the spinal cord without constraint on the natural behaviors of the animals. The system consists of a double-layer, rectangular-shaped magnetic coil antenna connected to a microscale inorganic light-emitting diode (µ-ILED) on a thin, flexible probe that can be implanted just above the dura of the mouse spinal cord for effective stimulation of light-sensitive proteins expressed in neurons in the dorsal horn. Wireless optogenetic activation of TRPV1-ChR2 afferents with spinal µ-ILEDs causes nocifensive behaviors and robust real-time place aversion with sustained operation in animals over periods of several weeks to months. The relatively low-cost electronics required for control of the systems, together with the biocompatibility and robust operation of these devices will allow broad application of optogenetics in future studies of spinal circuits, as well as various peripheral targets, in awake, freely moving and untethered animals, where existing approaches have limited utility.

Multiple sclerosis-related white matter microstructural change alters the BOLD hemodynamic response.

Multiple sclerosis (MS) results in inflammatory damage to white matter microstructure. Prior research using blood-oxygen-level dependent (BOLD) imaging indicates MS-related alterations to brain function. What is currently unknown is the extent to which white matter microstructural damage influences BOLD signal in MS. Here we assessed changes in parameters of the BOLD hemodynamic response function (HRF) in patients with relapsing-remitting MS compared to healthy controls. We also used diffusion tensor imaging to assess whether MS-related changes to the BOLD-HRF were affected by changes in white matter microstructural integrity. Our results showed MS-related reductions in BOLD-HRF peak amplitude. These MS-related amplitude decreases were influenced by individual differences in white matter microstructural integrity. Other MS-related factors including altered reaction time, limited spatial extent of BOLD activity, elevated lesion burden, or lesion proximity to regions of interest were not mediators of group differences in BOLD-HRF amplitude. Results are discussed in terms of functional hyperemic mechanisms and implications for analysis of BOLD signal differences.

Asynchrony in executive networks predicts cognitive slowing in multiple sclerosis.

OBJECTIVE: Cognitive slowing is a core neuropsychological symptom of Multiple Sclerosis (MS). We aimed to assess the extent to which cognitive slowing in MS was predicted by changes in dorsolateral prefrontal networks. METHOD: We assessed patients with relapsing-remitting MS and healthy controls (HCs) on measures of processing speed. Participants underwent a functional MRI while performing a processing speed task to allow assessment of task-based connectivity. RESULTS: Patients were slower than HCs on the processing speed tasks. Patients showed attenuated connectivity between right and left dorsolateral prefrontal cortex (DLPFC) and task-relevant brain regions compared to HCs during processing speed task performance. Patients' connectivity with DLPFC in these group-disparate networks accounted for significant variability in their performance on processing speed measures administered both in and out of the imaging environment. Specifically, patients who had stronger functional connections with DLPFC in group-disparate networks performed faster than patients with weaker connections with DLPFC in group-disparate networks. CONCLUSION: Results suggest that MS-related cognitive slowing can be accounted for by systemic alterations in executive functional networks.

Soft, stretchable, fully implantable miniaturized optoelectronic systems for wireless optogenetics.

Optogenetics allows rapid, temporally specific control of neuronal activity by targeted expression and activation of light-sensitive proteins. Implementation typically requires remote light sources and fiber-optic delivery schemes that impose considerable physical constraints on natural behaviors. In this report we bypass these limitations using technologies that combine thin, mechanically soft neural interfaces with fully implantable, stretchable wireless radio power and control systems. The resulting devices achieve optogenetic modulation of the spinal cord and peripheral nervous system. This is demonstrated with two form factors; stretchable film appliqués that interface directly with peripheral nerves, and flexible filaments that insert into the narrow confines of the spinal epidural space. These soft, thin devices are minimally invasive, and histological tests suggest they can be used in chronic studies. We demonstrate the power of this technology by modulating peripheral and spinal pain circuitry, providing evidence for the potential widespread use of these devices in research and future clinical applications of optogenetics outside the brain.