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Our understanding of mitochondrial signaling in the nervous system has been limited by the technical challenge of analyzing mitochondrial function in vivo. In the transparent genetic model Caenorhabditis elegans, we were able to manipulate and measure mitochondrial reactive oxygen species (mitoROS) signaling of individual mitochondria as well as neuronal activity of single neurons in vivo. Using this approach, we provide evidence supporting a novel role for mitoROS signaling in dendrites of excitatory glutamatergic C. elegans interneurons. Specifically, we show that following neuronal activity, dendritic mitochondria take up calcium (Ca2+) via the mitochondrial Ca2+ uniporter (MCU-1) that results in an upregulation of mitoROS production. We also observed that mitochondria are positioned in close proximity to synaptic clusters of GLR-1, the C. elegans ortholog of the AMPA subtype of glutamate receptors that mediate neuronal excitation. We show that synaptic recruitment of GLR-1 is upregulated when MCU-1 function is pharmacologically or genetically impaired but is downregulated by mitoROS signaling. Thus, signaling from postsynaptic mitochondria may regulate excitatory synapse function to maintain neuronal homeostasis by preventing excitotoxicity and energy depletion.

Objective: New treatment options are emerging for chronic wounds, which represent a growing problem because of population ageing and increasing burden of chronic disease. While promising, the existing evidence for advanced modalities is commonly derived from small and/or poorly controlled studies and clear criteria for selecting patients, who are likely to benefit from these expensive options are lacking. In this study, we develop and validate a machine learning model to predict if a chronic wound, independent of etiology, is expected to heal within 12 weeks to identify cases in potential need of advanced treatment options. Approach: Retrospective analysis of electronic health record data from 2014 to 2018 covering 532 wound care clinics in the United States and 261,398 patients with 620,356 unique wounds. Prediction of 12-week healing trajectories with a machine learning model. Results: The best-performing model in a training dataset of a randomly drawn 75% subset of wounds contained variables for patient demographics, comorbidities, wound characteristics at initial presentation, and changes in wound dimensions over time, with the latter group being the most influential predictors. The final machine learning model had a high predictive accuracy with area under the receiver operating characteristic curves of 0.9 and 0.92 after 4 and 5 weeks of treatment, respectively. Innovation: A machine learning model can identify chronic wounds at risk of not healing by week 12 with high accuracy in the early weeks of treatment. Conclusions : If embedded in real-world care, the generated information could be able to guide effective and efficient treatment decisions.

Actin in neuronal processes is both stable and dynamic. The origin & functional roles of the different pools of actin is not well understood. We find that mutants that lack mitochondria, ric-7 and mtx-2; miro-1 , in neuronal processes also lack dynamic actin. Mitochondria can regulate actin dynamics upto a distance ~80 μm along the neuronal process. Absence of axonal mitochondria and dynamic actin does not markedly alter the Spectrin Membrane Periodic Skeleton (MPS) in touch receptor neurons (TRNs). Restoring mitochondria inTRNs cell autonomously restores dynamic actin in a sod-2 dependent manner. We find that dynamic actin is necessary and sufficient for the localization of gap junction proteins in the TRNs and for the C. elegans gentle touch response. We identify an in vivo mechanism by which axonal mitochondria locally facilitate actin dynamics through reactive oxygen species that we show is necessary for electrical synapses & behaviour.

Objective: The objective of this study was to assess patient, wound, care, and reflux characteristics of venous leg ulcers (VLUs) to update and improve knowledge of disease etiology, identify barriers to healing, and improve treatment., Methods: Patients diagnosed with VLUs treated at the Stanford Advanced Wound Care Center between 2018 and 2019 were identified from the Healogics iHeal database. We identified 327 VLU entries, of which 133 were patients who had multiple or recurring wounds. An additional 27 patients were labeled as misdiagnosis, resulting in a final patient sample of 167. Patient demographics, wound, care, and ultrasound data for these patients were extracted from the Stanford electronic medical records regarding characteristics. The initial data analysis suggested possible differences in VLU characteristics depending on patient age and body mass index (BMI), which was then further analyzed., Results: Of the 167 VLU patients assessed, 53.9% were male and 46.1% were female. The mean age was 74.7 years, and the average BMI was 30.2 kg/m 2 , including 41.1% of patients with a BMI over 30 kg/m 2 . Approximately 50% of wounds were presented in multiples, had cellulitis, or were recurring, and 39.5% were caused by trauma. Most common venous reflux patterns on duplex ultrasound examination were below-knee great saphenous vein reflux and calf perforator reflux, which was identified in 37.7% and 29.3% of the patients, respectively. Axial great saphenous vein reflux was detected in 14.4% of patients. When looking at the patient sample under 60 years of age, 67.7% were male, 61.3% presented with venous skin changes, and 51.6% had diabetes. In the patients older than 60, only 51.9% were male, 37.6% presented with venous skin changes, and 31.6% had diabetes. BMI was greater in the patients under age 60, with an average of 39.2 kg/m 2 , compared with 28.2 kg/m 2 in those above 60. Of the patients with a BMI ≥30 kg/m 2 , 64.3% had multiple wounds, 61.4% had recurring wounds, and 56.5% had venous skin changes. In contrast, in patients with BMI <30 kg/m 2 , 47.4% had multiple wounds, 39.2% had recurring wounds, and 32.0% had venous skin changes., Conclusions: VLU pathology appears to differ depending on patient demographics and characteristics. Different drivers may influence disease cause, progression, and prognosis, making a standard approach to VLUs difficult. Our findings suggest that identifying different subtypes of VLUs and adapting an algorithm of care with a personalized treatment may help optimize management of these patients., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Patients with sickle cell disease and/or (rarely) trait are at increased risk for developing recurrent episodes of priapism, also known as stuttering priapism, and major ischemic priapism. Treatment of acute ischemic priapism is reactive; whereas ideal management consists of preventative approaches to ultimately promote the best improvement in patient's quality of life. Leg ulcers in patients with sickle cell disease (SCD) are quite common, with ∼20 % of patients with HBSS reporting either having an active or a past ucler. They can be confused with venous ulcers, with lower extremity hyperpigmentation confounding further the diagnosis. Several factors believed to contribute to the development of leg ulcers in patients with SCD are discussed in this article. Sickle cell liver disease (SCLD) occurs because of a wide variety of insults to the liver that happen during the lifetime of these patients. SCLD includes a range of complications of the hepatobiliary system and is increasing in prevalence with the aging adult sickle population. Liver nodular regenerative hyperplasia (NRH) is more common than realized and underappreciated as a diagnosis and requires liver biopsy with reticulin staining. Undiagnosed, the insidious damage from liver NRH can lead to noncirrhotic portal hypertension or cirrhosis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Chronic ulcers are associated with significant morbidity and mortality. Typical ulcers are due to venous insufficiency, diabetes, ischemia, pressure, and lymphedema. A chronic ulcer that does not respond to standard therapies should be reevaluated for potential atypical etiologies. Atypical ulcers are less common and more difficult to diagnose due to a wide range of possible etiologies, including inflammatory (autoimmune), neoplastic, vasculopathy, hematologic, infectious, drug-induced, or external. No standardized approach to the management of complex atypical ulcers exists. In this review, a stepwise approach to atypical ulcers is proposed with the aim of assisting physicians in their identification and diagnosis. If perfusion is adequate and there are no signs of infection, then the authors recommend obtaining an ulcer biopsy for microbiologic, DIF, and histopathologic evaluation as the criterion standard for diagnosis. Laboratory testing, including an autoimmune panel, a hypercoagulable panel, and an infectious diseases panel, can further aid in diagnosis. Atypical ulcers often require multidisciplinary care, with input from specialists in rheumatology, dermatology, infectious diseases, wound care, vascular surgery, hematology, and oncology. Effective communication within the health care team is essential for accurate diagnosis and management of atypical ulcers. Active dialogue between providers can improve consult efficiency and ultimately lower the cost of care.

Objectives: To evaluate the association between clinics' wound healing performance and clinic-level measures of care continuity, clinical quality, and sociodemographic characteristics of the population in their catchment areas., Study Design: In this cross-sectional analysis, we analyzed electronic health records for 180,336 chronic wounds from 480 wound care clinics during the 2018 calendar year., Methods: We measured healing performance using a clinic's observed to expected (O/E) ratio, which is based on the rate at which chronic wounds were predicted to heal within 12 weeks given its case mix and the actual healing rate. We compared the top and bottom quintiles, in terms of the O/E ratio, of clinics. Multivariable regression was used to estimate the effect of the clinic-level measures on the O/E ratio., Results: Clinics in the top quintile had higher rates of care continuity and quality measures, as well as a lower proportion of disadvantaged populations in their catchment areas. In the regression model, 10% increases in a clinic's rate of weekly provider visits, nurse visits, and debridement were associated with 2.5%, 3.0% and 0.7% increases, respectively, in the O/E ratio. The weekly provider visit rate had a greater marginal effect when the proportion of African American residents in the clinic's catchment area was larger., Conclusions: Clinic-level measures of care continuity, clinical quality, and sociodemographic composition of their catchment areas' population explain a meaningful part of differences in clinics' wound healing performance. Better care continuity appears to have a greater beneficial effect in disadvantaged populations.

Objective: To evaluate the impact of COVID-19-related disruptions on care continuity and outcomes of chronic wounds., Design: Retrospective cohort study., Setting and Participants: Electronic medical records for 152,225 chronic wounds from a network of 488 wound care clinics in 45 US states and the District of Columbia., Methods: Wound and patient characteristics, the number of chronic wounds newly seen at the clinics, and 12-week healing rates were compared between the first 2 quarters of 2019 and 2020. Multivariable regression models were constructed to evaluate whether the pandemic was associated with a statistically significant change in the probability of 12-week wound healing after risk adjustment., Results: During the pandemic, wound and patient characteristics did not change compared to the previous year. Case volume dropped as much as 40% in April 2020 but returned to the previous year's level by June. No systematic changes in measures of care continuity were observed. Unadjusted 12-week healing rates remained stable at 0.502 in 2019 and 0.503 in 2020. Likewise, risk-adjusted 12-week healing rates were 0.504 and 0.505 in 2019 and 2020, respectively, but the difference was not statistically significant. States with stricter lockdowns saw a greater decline in case volume. However, the pandemic was not associated with a statistically significant change in the probability of 12-week wound healing in most states. The percentage of wounds with 1 or more telehealth visits increased from 0.14% in 2019 to 1.04% in 2020., Conclusions and Implications: Despite COVID-19-related disruptions, our results suggest that wound care clinics maintained standards of care and outcomes for patients who sought care. This positive result should not detract from the problem that the number of new wounds seen at the clinics dropped sharply. Further research should evaluate outcomes in patients with unattended chronic wounds., (Copyright © 2021 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Chronic wounds represent a highly prevalent but little recognized condition with substantial implications for patients and payers. While better wound care products and treatment modalities are known to improve healing rates, they are inconsistently used in real-world practice. Predicting healing rates of chronic wounds and comparing to actual rates could be used to detect and reward better quality of care. We developed a prediction model for chronic wound healing. Approach: We analyzed electronic medical records (EMRs) for 620,356 chronic wounds of various etiologies in 261,398 patients from 532 wound care clinics in the United States. Patient-level and wound-level parameters influencing wound healing were identified from prior research and clinician input. Logistic regression and classification tree models to predict the probability of wound healing within 12 weeks were developed using a random sample of 70% of the wounds and validated in the remaining data. Results: A total of 365,659 (58.9%) wounds were healed by week 12. The logistic and classification tree models predicted healing with an area under the curve of 0.712 and 0.717, respectively. Wound-level characteristics, such as location, area, depth, and etiology, were more powerful predictors than patient demographics and comorbidities. Innovation: The probability of wound healing can be predicted with reasonable accuracy in real-world data from EMRs. Conclusion: The resulting severity adjustment model can become the basis for applications like quality measure development, research into clinical practice and performance-based payment.

The present status of clinical leg ulcer healing research was reviewed by 25 experts over 2 days on September 28 and 29, 2015. Multiple clinical effectiveness reviews were presented suggesting that published clinical wound healing research often does not meet present (2015) evidence based standards. Specific areas requiring remediation were highlighted and approaches to overcoming existing challenges were proposed. Participants using anonymous voting technology developed an action plan to resolve perceived deficiencies. Statements were accepted if 75% of participants agreed. Older patients with a high frequency of comorbid conditions posed particular difficulties in designing clinical research protocols and better diagnostic categorization is necessary A standardized model template for collecting information about diagnosis and evaluation of the effect of interventions on healing of all types of leg ulcers was considered a high priority. Such a model template could be modified depending on the specific etiology of the leg ulcers. Generally agreed on quantifiable standards to establish degree of morbidity was considered a high priority. There was universal agreement that sources of funding and conflicts of interest needed to be disclosed in presentations and all publications. All clinical research studies should be registered with appropriate authorities. There was substantial enthusiasm for a clinical research network with quality standards for membership and an advisory research core available to investigators. Such a network should be funded and actively managed to insure long-term viability. The governance of such an entity needs to be established by the wound care community. The present trend to integrate patients into the clinical research process was endorsed and there was enthusiasm to develop patient advocacy for wound healing research., (© 2016 by the Wound Healing Society.)