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IntroductionEndogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF.MethodsWe reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy.ResultsWe discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events.DiscussionWe identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need.

Chronic limb-threatening ischemia (CLTI) causes significant morbidity with profound negative effects on health-related quality of life. As the prevalence of peripheral artery disease and diabetes continue to rise in our aging population, the public health impact of CLTI has escalated. Patient-reported outcome measures (PROMs) have become common and important measures for clinical evaluation in both clinical care and research. PROMs are important for the measurement of clinical effectiveness and cost effectiveness and for shared decision-making on treatment options. However, the PROMs used to describe the experience of patients with CLTI are heterogeneous, incomplete, and lack specific applicability to the underlying disease processes and diverse populations. For example, certain PROMs exist for patients with extremity wounds, and other PROMs exist for patients with pain, and still others exist for patients with vascular disease. Despite this multiplicity of tools, no single PROM encompasses all of the components necessary to describe the experiences of patients with CLTI. This significant unmet need is evident from both published reports and contemporary large-scale clinical trials in the field. In this systematic review, we review the current use of PROMs for patients with CLTI in clinical practice and in research trials and highlight the gaps that need to be addressed to develop a unifying PROM instrument for CLTI.

The Wound Healing Foundation (WHF) recognised a need for an unbiased consensus on the best treatment of chronic wounds. A panel of 13 experts were invited to a virtual meeting which took place on 27 March 2021. The proceedings were organised in the sub-sections diagnosis, debridement, infection control, dressings, grafting, pain management, oxygen treatment, outcomes and future needs. Eighty percent or better concurrence among the panellists was considered a consensus. A large number of critical questions were discussed and agreed upon. Important takeaways included that wound care needs to be simplified to a point that it can be delivered by the patient or the patient's family. Another one was that telemonitoring, which has proved very useful during the COVID-19 pandemic, can help reduce the frequency of interventions by a visiting nurse or a wound care center. Defining patient expectations is critical to designing a successful treatment. Patient outcomes might include wound specific outcomes such as time to heal, wound size reduction, as well as improvement in quality of life. For those patients with expectations of healing, an aggressive approach to achieve that goal is recommended. When healing is not an expectation, such as in patients receiving palliative wound care, outcomes might include pain reduction, exudate management, odour management and/or other quality of life benefits to wound care.

BackgroundIn 2007, we reported a summary of data comparing diabetic foot complications to cancer. The purpose of this brief report was to refresh this with the best available data as they currently exist. Since that time, more reports have emerged both on cancer mortality and mortality associated with diabetic foot ulcer (DFU), Charcot arthropathy, and diabetes-associated lower extremity amputation.MethodsWe collected data reporting 5-year mortality from studies published following 2007 and calculated a pooled mean. We evaluated data from DFU, Charcot arthropathy and lower extremity amputation. We dichotomized high and low amputation as proximal and distal to the ankle, respectively. This was compared with cancer mortality as reported by the American Cancer Society and the National Cancer Institute.ResultsFive year mortality for Charcot, DFU, minor and major amputations were 29.0, 30.5, 46.2 and 56.6%, respectively. This is compared to 9.0% for breast cancer and 80.0% for lung cancer. 5 year pooled mortality for all reported cancer was 31.0%. Direct costs of care for diabetes in general was $237 billion in 2017. This is compared to $80 billion for cancer in 2015. As up to one-third of the direct costs of care for diabetes may be attributed to the lower extremity, these are also readily comparable.ConclusionDiabetic lower extremity complications remain enormously burdensome. Most notably, DFU and LEA appear to be more than just a marker of poor health. They are independent risk factors associated with premature death. While advances continue to improve outcomes of care for people with DFU and amputation, efforts should be directed at primary prevention as well as those for patients in diabetic foot ulcer remission to maximize ulcer-free, hospital-free and activity-rich days.

OBJECTIVE: Diabetes affects 537 million people globally, with 34% expected to develop foot ulceration in their lifetime. Diabetes-related foot ulceration causes strain on health care systems worldwide, necessitating provision of high-quality evidence to guide their management. Given heterogeneity of reported outcomes, a core outcome set (COS) was developed to standardize outcome measures in studies assessing treatments for diabetes-related foot ulceration. RESEARCH DESIGN AND METHODS: The COS was developed using Core Outcome Measures in Effectiveness Trials (COMET) methodology. A systematic review and patient interviews generated a long list of outcomes that were rated by patients and experts using a nine-point Likert scale (from 1 [not important] to 9 [critical]) in the first round of the Delphi survey. Based on predefined criteria, outcomes without consensus were reprioritized in a second Delphi round. Critical outcomes and those without consensus after two Delphi rounds were discussed in the consensus meeting where the COS was ratified. RESULTS: The systematic review and patient interviews generated 103 candidate outcomes. The two consecutive Delphi rounds were completed by 336 and 176 respondents, resulting in an overall second round response rate of 52%. Of 37 outcomes discussed in the consensus meeting (22 critical and 15 without consensus after the second round), 8 formed the COS: wound healing, time to healing, new/recurrent ulceration, infection, major amputation, minor amputation, health-related quality of life, and mortality. CONCLUSIONS: The proposed COS for studies assessing treatments for diabetes-related foot ulceration was developed using COMET methodology. Its adoption by the research community will facilitate assessment of comparative effectiveness of current and evolving interventions. [ABSTRACT FROM AUTHOR]

Aims: Incorrectly fitting footwear (IFF) poses a risk of trauma to at‐risk feet with diabetes. The aim of this systematic review was to summarise and assess the evidence that IFF is a statistically significant cause of ulceration. Methods: We searched PubMed, Scopus, Web of Science and Google Scholar for English‐language peer‐reviewed studies reporting the number or percentage of people with diabetes‐related foot ulceration (DFU) attributed to wearing IFF and included a physical examination of the footwear worn. Two independent reviewers assessed the risk of bias using the Newcastle–Ottawa scale. Results: 4318 results were retrieved excluding duplicates with 45 studies shortlisted. Ten studies met the inclusion criteria with most rated as fair (n = 6) or good (n = 3). There is some evidence that DFU is significantly associated with IFF, but this is limited: only 3 of 10 included studies found a statistically significant percentage of those with DFU were wearing IFF or inappropriate footwear which included fastening, material, type or fit (15.0%–93.3%). Risk of bias in these three studies ranged from 'fair' to 'poor'. IFF definitions were often unreported or heterogeneous. Only one study reported IFF‐related ulcer sites: 70% were at plantar hallux/toes and 10% at plantar metatarsal heads. Conclusions: There is some evidence that IFF is a cause of DFU, but further research is needed, which defines IFF, and methodically records footwear assessment, ulcer location and physical activity. Researchers need to uncover why IFF is worn and if this is due to economic factors, a need for footwear education or other reasons. [ABSTRACT FROM AUTHOR]

Objective: Several national and international guidelines recommend lipidocolloid technology with a nano-oligosaccharide factor (TLC-NOSF) dressings (UrgoStart dressing range, Laboratoires Urgo, France) for treating patients with chronic wounds. However, these dressings are still often reported as second-line options, potentially leading to loss of opportunity for patients and additional costs for payers. This review aimed to explore the reported wound healing and patient outcomes as well as the related costs when the dressings were used as first-line treatment in patients with different types of chronic wounds. Method: A systematic review of the literature was conducted. Databases (MEDLINE, Embase, Emcare, and Google Scholar) were searched up to 1 February 2024, without any language or time period limitations. Studies were eligible if the evaluated dressings had been used as a first-line treatment for chronic wounds, that is, as an integral part of the standard of care (SoC) at the patient's first presentation and/or in recent wounds. The main evaluation criteria included: wound healing rate; time to reach wound closure; change in patients' quality of life (QoL); and associated costs. The quality of evidence of the included studies was appraised using well-recognised risk-of-bias tools suitable for different study designs. A narrative synthesis describes the findings in three sections depending on the type of comparison. This report followed the principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: A total of 17 studies published between 2017 and 2024 met the eligibility criteria. A comparative analysis between TLC-NOSF dressings and standard dressings, both of which were used as first-line treatment, was reported in nine studies. A comparative analysis between the use of TLC-NOSF dressings as first-line and second-line treatments was reported in eight studies, and five studies reported a systematic use of the TLC-NOSF dressing as first-line treatment without a control group. Overall, the included studies had a relatively low risk of bias for the respective types of evidence. Data of 10,191 patients of both sexes and different age groups with a total of 10,203 wounds (diabetic foot ulcers, leg ulcers, pressure injuries, and other types of chronic wounds) were included in the analysis: 7775 treated with the evaluated dressing and 2428 treated with a comparator dressing. The data suggested that using TLC-NOSF as a first-line treatment for chronic wounds consistently resulted in significantly higher healing rates, shorter healing times, and cost savings compared with standard dressings used under similar conditions. Real-life evidence confirmed the results obtained in clinical trials and economic models, within similar ranges, regardless of the settings involved or of the characteristics of the patients and wounds treated. The wound healing rates ranged around 70-80% by week 20/24 and time-to-heal was reported on average around seven weeks, with slightly longer times reported in wounds with a more severe prognosis. Furthermore, the dressings were shown to improve patient QoL, and were well tolerated and accepted, supporting a wider adoption approach. Conclusion: The results of this review are aligned with the current guidelines recommending the use of TLC-NOSF dressings in the treatment of patients with chronic wounds. They support its wider implementation as a first-line treatment and as an integral part of SoC for these wounds in the daily practice of all centres involved in their management. [ABSTRACT FROM AUTHOR]

Purpose: The recent SENZA-PDN study showed that high-frequency (10kHz) spinal cord stimulation (SCS) provided significant, durable pain relief for individuals with painful diabetic neuropathy (PDN), along with secondary benefits, including improved sleep quality and HRQoL. Given that metabolic factors and chronic neuropathic pain are related, we evaluated potential secondary effects of 10kHz SCS on hemoglobin A1c (HbA1c) and weight in SENZA-PDN participants with type 2 diabetes (T2D). Patients and Methods: This analysis included 144 participants with T2D and lower limb pain due to PDN who received 10kHz SCS during the SENZA-PDN study. Changes in HbA1c, weight, pain intensity, and sleep were evaluated over 24 months, with participants stratified according to preimplantation HbA1c (> 7% and > 8%) and body mass index (BMI; ≥ 30 and ≥ 35 kg/m2). Results: At 24 months, participants with preimplantation HbA1c > 7% and > 8% achieved clinically meaningful and statistically significant mean reductions in HbA1c of 0.5% (P = 0.031) and 1.1% (P = 0.004), respectively. Additionally, we observed a significant mean weight loss of 3.1 kg (P = 0.003) across all study participants. In subgroups with BMI ≥ 30 and ≥ 35 kg/m2, weight reductions at 24 months were 4.1 kg (P = 0.001) and 5.4 kg (P = 0.005), respectively. These reductions were accompanied by a mean pain reduction of 79.8% and a mean decrease in pain interference with sleep of 65.2% at 24 months across all cohorts. Conclusion: This is the first study of SCS to demonstrate long-term, significant, and clinically meaningful reductions in HbA1c and weight in study participants with PDN and T2D, particularly among those with elevated preimplantation HbA1c and BMI. Although the mechanism for these improvements has yet to be established, the results suggest possible direct and indirect metabolic benefits with 10kHz SCS in addition to durable pain relief. Trial Registration: ClincalTrials.gov Identifier, NCT03228420. [ABSTRACT FROM AUTHOR]

Diabetic foot complications that lead to lower extremity amputations pose a significant challenge to the entire global health system. In this multicentre clinical trial, 26 patients with chronic Wagner one diabetic foot ulcers (DFUs) were treated with a unique human keratin matrix graft applied either weekly or bi‐weekly, in addition to standard of care. The hypothesis was that bi‐weekly application would be similar to weekly application. The primary endpoint was complete wound closure by 12 weeks, and secondary endpoints included healing time, percent area reduction and weekly changes in peripheral neuropathy, pain and quality of life. In the intent‐to‐treat population, 77% (10/13) of DFUs treated with bi‐weekly application healed compared with 69% (9/13) treated with weekly application. The mean time to heal within 12 weeks in the bi‐weekly group was 61 days and in the weekly group was 54 days. The mean percent area reduction at 12 weeks was 94.7% in the bi‐weekly group compared with 84.8% in the weekly group. The number of grafts used in the bi‐weekly group was 3.9 compared with 6.2 in the weekly group. The results of this trial confirm our hypothesis that whether bi‐weekly or weekly application of the unique keratin matrix graft is used to treat nonhealing indolent DFUs, there is a high rate of complete healing. Based on these results, future studies should be conducted that further investigate the use of this novel human keratin matrix graft for the treatment of chronic DFUs. [ABSTRACT FROM AUTHOR]