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Objective: Biofilm infections in chronic wounds are common and pose a significant clinical challenge. This challenge was addressed by developing the SoftOx Biofilm Eradicator (SBE) composed of hypochlorous acid (HOCl) and acetic acid with strong broad-spectrum antimicrobial activity. Approach: First-in-human study investigating the safety and tolerability as primary endpoints and wound size effect and antimicrobial efficacy as secondary endpoints of SBE treatment in chronic leg wound patients. The study was divided into two as follows: a randomized, double-blinded, Single Ascending Dose (SAD) phase ( n = 16 SBE; n = 4 placebo), where patients were treated with SBE or saline (placebo) only once, followed by an open-label, Multiple Ascending Dose (MAD) phase ( n = 8), where patients were treated with SBE once daily or twice daily over five days. Reporting is according to CONSORT guidelines. Results: SBE was safe and well-tolerated in chronic leg wound patients. There were no significant differences in pain during and after treatment with SBE or the placebo. The SBE treatment reduced bioburden in wounds compared to baseline, with 98% and 49% median reduction after SBE or placebo treatment, respectively. A dose-dependent trend in absolute wound size reduction was observed in the MAD groups with a median (min, max) change of -2.99 (-14.25, -1.5) cm 2 in the once-daily and -10.48 (-17.95, -0.38) cm 2 in the twice-daily group, respectively. Innovation and Conclusion: This study demonstrated the safe use of HOCl-based SBE in chronic leg wounds with promising trends of immediate antimicrobial action and beneficial effect on wound healing.

Objective: Chronic wounds are costly and difficult to treat, resulting in morbidity and even mortality in some cases due to a high methicillin-resistant Staphylococcus aureus (MRSA) burden contributing to chronicity. We aimed to observe the antimicrobial activity and healing-promoting effect of a novel photosensitizer Shengtaibufen (STBF)-mediated antibacterial photodynamic therapy (PDT) on MRSA-infected chronic leg ulcers., Patients and Methods: This was a retrospective, comparative, single-center clinical study. A total of 32 patients with chronic lower limb wounds infected with MRSA from January 2022 to December 2023 were finally included in this study by searching the electronic medical records of the dermatology department of Huadong Hospital, including a group of red light combined with iodophor (control+iodophor, n=16, receiving red light once a week for 8 weeks and routine dressing change with iodophor once a day) and a group of STBF-mediated PDT (STBF-PDT) combined with iodophor (STBF-PDT+iodophor, n=16, receiving STBF-PDT and routine dressing change with iodophor once a day). STBF-PDT was performed once a week (1 mg/ml STBF, 1 h incubation, 630 nm red light, 80 J/cm 2 ) for 8 weeks. The primary endpoints included wound clinical signs, wound size, wound-related pain, re-epithelialization score, MRSA load and wound-related quality of life (wound-QoL). Any adverse events were also recorded., Results: We found that STBF-PDT+iodophor could effectively alleviate clinical infection symptoms, accelerate wound closure, reduce average biological burden and improve wound-QoL without severe adverse events in comparison to the control+iodophor group. The STBF-PDT+iodophor group obtained a mean percentage reduction of 65.22% in wound size (from 18.96±11.18 cm 2 to 6.59±7.94 cm 2 ) and excellent re-epithelialization scores, as compared with a decrease of 30.17% (from 19.23±9.80 cm 2 to 13.43±9.32 cm 2 ) for the control+iodophor group. Significant differences in wound area were observed at week 6 (p=0.028*) and week 8 (p=0.002**). The bacterial load decreased by 99.86% (from 6.45 × 10 7 ±2.69 × 10 7 to 8.94 × 10 4 ±1.92 × 10 5 CFU/cm 2 , p<0.0001) in the STBF-PDT+iodophor group and 1.82% (from 6.61 × 10 7 ±2.13 × 10 7 to 6.49 × 10 7 ±2.01 × 10 7 CFU/cm 2 , p=0.029) in the control+iodophor group. The wound-QoL in STBF-PDT+iodophor group had a 51.62% decrease in overall score (from 29.65±9.33 at the initial to 14.34±5.17 at week 8, p<0.0001) compared to those receiving red light and routine wound care (from 30.73±17.16 to 29.32±15.89 at week 8, p=0.003). Moreover, patients undergoing STBF-PDT+iodophor exhibited great improvements in all domains of wound-QoL (physical, psychological and everyday-life), whereas the control+iodophor group ameliorated in only one field (everyday-life)., Conclusion: Our data confirmed that a novel photosensitizer, STBF-mediated PDT, when combined with iodophor, served as a potential modality for MRSA infection and a possible therapy for other drug-resistant microorganisms, and as a promising alternative for chronic cutaneous infectious diseases., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Hydroxyuria is a common medication for treating blood system diseases, but ulcers in the lower limbs caused by this medication are often rare and not often suspected. We reported an elderly patient with lower limb ulcers caused by hydroxyurea treatment for primary thrombocytosis. When hydroxide is used, close observation of skin lesions and prompt handling of any skin disruption should prevent ulcers., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Kodamaea ohmeri is an emerging fungus recognised as an important pathogen in immunocompromised hosts, responsible for life-threatening infections., Case Presentation: We describe a case of a 69-year-old immunocompetent man with a long history of leg skin ulcers infected by K. ohmeri. This is the first case of leg wounds infected by K. ohmeri in an immunocompetent patient. The infection was successfully treated with voriconazole 200 mg daily., Conclusion: Though rare, K. ohmeri should be considered in patients with skin ulcers that are poorly responsive to medical treatment, even if not immunocompromised., (© 2024 S. Karger AG, Basel.)

The current report presents two cases with leg ulcers related to Behçet's disease (BD) resistant to conventional immunosuppressive therapy (CIST) but successfully treated with adalimumab (ADA). BD, which can affect vessels of any size and type, is a systemic vasculitis. In the vascular system, veins are the most predominantly affected blood vessels, with deep vein thrombosis and recurrent superficial vein thrombophlebitis being the most common vascular signs of the disease in the lower extremities. Leg ulcers, commonly associated with vasculitis or deep vein thrombosis, are rare in patients with BD. Conventional immunosuppressive therapy is very critical to prevent relapses and diminish the risk of post-thrombotic syndrome. In patients with BD-associated venous thrombosis (deep vein thrombosis or superficial vein thrombophlebitis) resistant to these treatments, tumour necrosis factor-α inhibitors can be used alone or in combination with traditional disease-modifying antirheumatic drugs. In view of such information, add-on adalimumab treatment was considered appropriate for both patients. Response to this intervention was highly satisfying for the patients at the end of the 6-month treatment. Nonetheless, it warrants further studies directly evaluating the efficacy of tumour necrosis factor-α inhibitors alone in leg ulcers in BD., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Background: Leg ulcers associated with major sickle cell disease (SCLU) are a chronic, painful complication, often treated by autologous skin graft. The analgesic effect of skin grafting in SCLU is poorly studied. The aim of this study was to evaluate the effect of skin grafting on the pain and healing of SCLU., Methods: Patients hospitalized for SCLU skin grafting were included in a retrospective and prospective observational cohort, between 2019 and 2023: 53 autologous pinch grafts were performed on a total of 35 SCLUs in 25 sickle cell patients. The primary endpoint was the evaluation of the analgesic effect of the skin graft, measured by visual analog scale (VAS) and weekly cumulative analgesic consumption between day (D)0, D7 and D30. Wound healing was assessed by variation in wound areas between D0 and D30., Results: Twenty-five patients with a median age range of 45.5years old were included, 68% were men, SS genotype was present in 96% of the cases. At D7, a significant decrease in VAS and consumption of analgesics of all classes was observed. At D30, only a significant decrease in VAS and consumption of mild opioids was present, as well as a significant reduction in wound surface area compared with D0., Conclusion: Pinch grafts have a significant early analgesic effect in the management of patients with SCLU, and significantly notice reduction of wound surface area within one month., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: Venous leg ulcers (VLUs) are the most severe manifestation of chronic venous disease, with long healing time and a high recurrence rate. It imposes a heavy burden on patients, their families, and the health care system. Chronic inflammation triggered by sustained venous hypertension is now recognized as the hallmark of chronic venous disease. The anti-inflammatory effect of pentoxifylline may offer a promising avenue to treat VLUs. However, current evidence of pentoxifylline for VLUs is relatively small and of low quality. The aim of this study is to evaluate the efficacy and safety of pentoxifylline for VLUs in the Chinese population., Methods: This is a randomized, double-blinded, double-dummy, multi-center, placebo-controlled clinical trial. A total of 240 patients will be randomized to receive pentoxifylline (400 mg, twice daily) or placebo for 24 weeks. All participants will receive diosmin treatment and standard care of VLUs and other comorbidities. The primary outcome is the difference in the wound healing rate within 12 weeks between pentoxifylline and placebo. Secondary outcomes include (1) percent wound size changes at 12 weeks, (2) the levels of TNF-α and IL-6, (3) venous clinical severity score and chronic venous insufficiency quality of life score, and (4) ulcer recurrence within 24 weeks., Discussion: This study would evaluate the efficacy and safety of pentoxifylline for VLUs in the Chinese population. If confirmed, it wound offer another effective and safe therapeutic option for treatment of VLUs., Trial Registration: The trial was registered at the Chinese Clinical Trial Registry (No. ChiCTR-2100053053). Registered on 10 November, 2021, https://www.chictr.org.cn/showproj.aspx?proj=137010., (© 2023. The Author(s).)

Background: The treatment of leg ulcers is an enormous problem worldwide. Chronic venous ulceration affects 1% of the population and often has a protracted course. Recurrence rate is high, ranging up to 69% in the first year after healing., Objectives: To determine whether topical application of low-dose topical recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) is safe in venous leg ulcer treatment, and whether it accelerates healing rates and reduces recurrence rates., Materials and Methods: Consecutive patients with chronic venous leg ulcers received topical treatment with low-dose rhu GM-CSF (10 µg/mL 0.9% sodium chloride solution; 1.0-2.3 µg rhu GM-CSF/cm 2 ) in combination with treatment of venous insufficiency. All patients were previously treated with other topical wound remedies for several weeks (median 8 weeks) without success., Results: In 119 of 130 patients, the wounds healed completely (91.5%). No local or systemic adverse reactions were observed. The mean time to healing was 24 weeks (median 14 weeks). Median follow-up of the 119 patients with healed ulcers was 84 months. The recurrence rates were 5.2% after 1 year, 18.9% after 4 years and 32.0% after 10 years., Conclusions: Topical low-dose rhu GM-CSF proved to be safe and highly effective. Healing rates were comparable to those reported in the ESCHAR study (Effects of Surgery and Compression on Healing And Recurrence in venous ulceration) and recurrence rates were the lowest reported in the literature. Topical therapy with rhu GM-CSF can be applied in an outpatient setting and does not require hospitalization., (© 2022. The Author(s).)

Competing Interests: Conflicts of interest None disclosed.

Introduction: Nonhealing ulcers are difficult to manage because they deviate from the normal wound healing process. The standard treatment with saline dressings is not efficient in treating patients with such wounds; advanced wound care dressings are needed. Chitosan-based advanced wound dressings are gaining popularity because of their unique characteristics, such as absorbency, conformability, and pain alleviation at the wound bed. A case of an ulcer that developed after cellulitis and healed with application of a chitosan-based dressing is presented., Case Report: An 81-year-old female with hypertension was admitted to the hospital with a high-grade fever, generalized weakness, anorexia, and right lower limb pain with redness. Venous insufficiency in the right lower limb in the form of early insufficiency at the right saphenofemoral and saphenopopliteal junctions along with right leg varicosities was evident on color Doppler ultrasound. A diagnosis of cellulitis was made; the patient was treated with antibiotics and discharged from the hospital. The cellulitis progressed, and an incision and drainage of the right leg was performed on the second admission. The patient was admitted twice more, and the wound was surgically debrided twice and antibiotics were administered. During this period, the patient was treated with saline dressing changes for almost 4 weeks. Because the wound was nonhealing and infected during the fourth hospital admission, chitosan-based dressings were used. Daily dressing changes for 10 days resulted in 100% granulation tissue. Later, the patient underwent skin grafting and was eventually discharged., Conclusions: The use of chitosan-based dressings resulted in progression to complete granulation, along with the management of exudate, pain, and Pseudomonas infection. The results of this case suggest patients with nonhealing ulcers may benefit from early use of advanced wound care dressings.

Objective . To identify the bacterial isolates and their antibiotics susceptibility pattern among patients with lower limb ulcers admitted at a tertiary hospital in northern Tanzania. Methodology. A cross-sectional study was conducted between April and July 2018 at the Kilimanjaro Christian Medical Centre. Questionnaire was used to obtain the demographics and clinical information of participants. Wound samples were collected and culture method used to identify the bacteria and their susceptibility patterns. Results. Out of 65 participants, 55 (84.6%) had positive aerobic bacterial growth. Twelve (18 %) participants had more than one bacterium. Fifty-nine (88.1%) were gram-negative bacteria. Proteus vulgaris (13, 19.9%), Pseudomonas spp (10, 14.8%), and Staphylococcus aureus (8, 11.7%) were the common isolates. Out of 59 gram-negative bacterial, 47 (78%) were sensitive to amikacin. Staph were sensitive to oxacillin (75%; n = 8) and vancomycin (50%; n = 8). Gram-negative were common isolates and were resistant to amoxicillin/clavulanic acid but sensitive to amikacin. Conclusion . The observed resistance to antibiotics calls for continuous monitoring of the resistance pattern to guide the empirical management of patients with leg ulcer.

Background: Venous leg ulcers (VLUs) often take a very long time to heal. Timolol maleate has been reported as displaying efficacy in healing of VLUs., Objectives: To evaluate the efficacy of timolol maleate gel in the management of hard-to-heal VLUs and to assess its safety as a topical agent during 12 weeks of use in combination with conventional treatment., Methods: A prospective, phase-II randomised-controlled trial with a sample size based on Fleming's one-stage design (P0=0.25, P1=0.45, alpha=0.1, beta=0.2) was planned. Patients with VLUs present for ≥24 weeks and with ≥50% granulation tissue were included. One drop of sustained-release timolol gel (Timoptol® LP 0.5%, Santen, Tampere, Finland) per 6 cm 2 VLU area was applied every 2 days for 12 weeks in timolol-treated patients, as adjuvant therapy to the standard care protocol (interface dressing and multilayer venous compression). Controls received standard care alone. The primary endpoint was to obtain ≥40% reduction in ulcer area at week 12 (W12)., Results: Forty-three patients were randomised to the study, with 40 receiving at least one treatment and included in the analysis: 21 timolol-treated patients and 19 controls (females: 70%; median age: 72.5 [range 35-93] years). At W12, ≥40% ulcer-area reduction was achieved in 14/21 (67%) timolol-treated patients vs. 6/19 (32%) controls. No serious adverse events occurred. Local wound infections not requiring systemic antibiotics occurred in 5 cases in the timolol group and in one case in the controls., Conclusions: These results support the benefit and safety of using timolol maleate to manage hard-to-heal VLUs, but confirmation is required in a larger multicentre randomised phase-III study., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Introduction: Topical applications of hyaluronic acid (HA)-containing formulations, based on the complex and vital role of HA in all stages of the wound-healing process, are routinely used with standard therapy to promote faster healing of chronic wounds. However, evidence to guide clinical decisions on the use of topical HA in the healing of vascular leg ulcers is limited., Objective: This study compared the efficacy and safety of topical application of a hyaluronic acid cream vs a neutral comparator (identical cream without HA) in treating subjects with chronic leg ulcers of vascular origin., Materials and Methods: This was a prospective, multicenter double-blind randomized controlled trial. One hundred sixty-eight subjects with chronic leg ulcers of venous or mixed (venous and arterial) origin were randomized to receive either topical applications of 0.2% HA cream or neutral comparator cream for a maximum of 20 weeks. The primary efficacy endpoint was complete ulcer healing (100% reepithelialization of the wound area centrally assessed at 20 weeks or before and confirmed 3 weeks later). In both groups, topical treatment was associated with standard therapy (ulcer cleansing and optimized compression)., Results: The proportion of subjects with centrally assessed complete healing of the target ulcer that was confirmed 3 weeks later (primary efficacy endpoint) was substantially higher in the HA cream group (31.3%) than in the neutral cream group (14.8%; P =.009). Results in the full analysis, per protocol, and as assessed by the investigator were consistent with primary results. No significant difference in treatment effect was observed when subjects were stratified according to baseline ulcer size (≤20 cm2 or >20 cm2) regardless of topical treatment. Safety and tolerability were comparable between treatments., Conclusions: Treatment of subjects with chronic leg ulcers of venous or mixed origin with HA cream is safe, well tolerated, and results in a higher rate of healing than a neutral comparator cream.

To investigate whether the addition of human recombinant epidermal growth factor (h-EGF) to 2% carboxymethyl cellulose gel is more effective in diabetic wound healing than standard treatment, a pilot, double-blind, randomized and controlled clinical trial with therapeutic intervention was performed at a university hospital. The sample consisted of 25 patients (14 in the intervention group that used rh-EGF and 11 in the control group that used 2% carboxymethyl cellulose gel). Data were tabulated in SPSS and analysed by intention to treat, without loss or exclusion of participants. Twenty-five subjects participated with a mean age of 60.6 years, a predominance of males in both groups and 100% prevalence of type-2 diabetes. Within 12 weeks, complete wound healing occurred in three ulcers in the intervention group versus one ulcer in the control group. The percent reduction in the wound area was significantly higher in the intervention group than in the control group (p = 0.049). Concerning the types of tissue, an increase in granulation and epithelial tissue and a reduction in exudate levels were observed in both groups. Decreased slough occurred only in the intervention group. No participant experienced serious or local adverse events during the study period. This study shows that h-EGF is effective, with a statistically significant reduction in wound area, improvement of tissue quality, and safe treatment of chronic wounds. In addition, this study demonstrated that blinding of participants during research using h-EGF is feasible., (© 2021 The Wound Healing Society.)

Many patients with venous leg ulcers do not reach complete healing with compression treatment alone, which is current standard care. This clinical trial HEAL LL-37 was a phase IIb double-blind, randomized, placebo-controlled study, with the aim to evaluate the efficacy and safety of a new drug LL-37 for topical administration, in combination with compression therapy, in 148 patients suffering from hard-to-heal venous leg ulcers. The study had three arms, consisting of two groups treated with LL-37 at concentrations of 0.5 or 1.6 mg/mL, and a placebo cohort. Patients had a mean age of 67.6 years, a median ulcer duration of 20.3 months, and a mean wound size at the time of randomization of 11.6 cm 2 . Efficacy analysis performed on the full study population did not identify any significant improvement in healing in patients treated with LL-37 as compared with the placebo. In contrast, a post hoc analysis revealed statistically significant improvement with LL-37 treatment in several interrelated healing parameters in the subgroup of patients with large target wounds (a wound area of at least 10 cm 2 at randomization), which is a known negative prognostic factor for healing. The study drug was well tolerated and safe in both dose strengths. In summary, this clinical trial did not detect any significant differences in healing of venous lower leg ulcers in the entire study cohort comparing patients treated with LL-37 versus placebo. A subgroup analysis provided an interesting observation that LL-37 could offer a treatment benefit in patients with large ulcers, exigently warranting a further study adequately powered to statistically assess the treatment outcome in this patient group., (© 2021 Promore Pharma AB. Wound Repair and Regeneration published by Wiley Periodicals LLC on behalf of The Wound Healing Society.)

An understanding of the consequences of oxidative/halogenative stress triggered by neutrophil activation is impossible without considering NETosis. NETosis, formation of neutrophil extracellular traps (NETs), is known to promote microthrombus formation and impair wound healing in type 2 diabetes mellitus (T2DM) patients. Therefore, there is a need to search for drugs and treatment approaches that could prevent excessive NET formation. We aimed to evaluate the effect of vitamin D3 in combination with omega-3 polyunsaturated fatty acids (vitamin D3/omega-3 PUFAs) on NETosis in T2DM patients with purulent necrotizing lesions of the lower extremities. Patients and healthy subjects had vitamin D3 deficiency. Patients received, beyond standard treatment, 6000 IU of vitamin D3 and 480 mg of omega-3 PUFAs, and healthy subjects 1000 IU of vitamin D3 and 240 mg of omega-3 PUFAs daily for seven days. Neutrophil activation in ex vivo blood by phorbol-12-myristate-13-acetate (PMA) was used as a NETosis model. The percentage of blood NETs relative to leukocytes (NET background ) before vitamin D3/omega-3 PUFA supplementation was 3.2%-4.9% in healthy subjects and 1.7%-10.8% in patients. These values rose, respectively, to 7.7%-9.1% and 4.0%-17.9% upon PMA-induced NETosis. In addition, the leukocyte count decreased by 700-1300 per 1  μ L in healthy subjects and 700-4000 per 1  μ L in patients. For both patients and healthy subjects, taking vitamin D3/omega-3 PUFAs had no effect on NET background but completely inhibited PMA-induced NET formation, though neutrophils exhibited morphological features of activation. Also, leukocyte loss was reduced (to 500 per 1  μ L). For patients on standard treatment alone, changes occurred neither in background NETs and leukocytes nor in their amount after PMA stimulation. The decreased ability of neutrophils to generate NETs, which can be achieved by vitamin D3/omega-3 PUFA supplementation, could have a positive effect on wound healing in T2DM patients and reduce the incidence and severity of complications., Competing Interests: The authors declare no competing financial and nonfinancial interests., (Copyright © 2021 Liliya Yu. Basyreva et al.)

Objective: To evaluate the effectiveness of topical ozone therapy as an adjuvant treatment in the healing of lower limb ulcers through a systematic literature review., Data Sources: Three databases were used to search for studies conducted in the period up to and including September 2020: PubMed, Scopus, and the Web of Science., Study Selection: The search identified 44 studies, 7 of which met the eligibility criteria and were evaluated., Data Extraction: Study design, study location, number of patients, patient age, type of control, wound type, intervention type, equipment used to generate ozone (ozone generation), evaluation methodology, and main results were extracted from each study., Data Synthesis: A total of 506 patients 18 years or older with chronic wounds, such as venous or diabetic ulcers, on the lower limbs were enrolled. The majority of studies addressed diabetic foot ulcers., Conclusions: The ozone therapy protocols demonstrated a healing effect in all included studies, and none reported adverse effects. This reinforces the need for more controlled and randomized clinical trials to determine the effectiveness of this treatment and establish clinical criteria for its use., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Study aimed to find out best option (systemic or local antimicrobial or combination of both) for treating venous leg ulcer infection. Patients' files were reviewed retrospectively. Participants were divided into three groups. First group was treated by systemic antibiotics only (SABG). Second group received local antibiotics only (LABG). Third group was treated by combination of both (SLABG). Treatment strategies were compared based on multiple parameters using Pearson chi-squared test & relative risk (RR). 456 participants identified: 153 in SABG, 152 in LABG and 151 in SLABG. It was found that SLABG group was statistically significantly better than other single treatment strategies regarding all parameters (except bacterial resistance): (i) ulcer healing within usual duration (10-14 days) was 2.4 time higher (RR 2.4, 95% CI: 1.84, 3.12), (ii) probability of not recurring ulcer was 2.6 time higher (iii) probability of not getting increased wound size, abscess,cellulites was 5 times higher (iv) probability of not developing septicemia was 40% higher (v) probability of not requiring surgical intervention was 30% higher (vi) fewer patients needed prolonged hospitalization & lower cost was 8 times more likely (vii) patients were 3 times more satisfied during treatment .Probability of bacterial resistance was six times higher with SLABG and 5 times higher with SABG compared to LABG. For RR & CI values for all above parameters, see results below Ultimately, combination of both systemic and local antimicrobials may be best option to treat venous leg ulcer infection with out- weight with emergence of antibiotic-resistance microorganism.

Competing Interests: The authors declare no conflict of interest.

Introduction: Hyaluronic acid (HA)-containing formulations routinely are utilized along with standard therapy to promote faster healing of chronic wounds; evidence to guide clinical decisions on the use of topical HA in the healing of vascular leg ulcers is limited., Objective: This study compared the efficacy and safety of an HA-impregnated gauze pad with an identical gauze pad without HA in the treatment of chronic leg ulcers of vascular origin., Materials and Methods: A prospective, multicenter, multinational, parallel-group, randomized, double-blind, clinical study was conducted between June 13, 2017, and December 31, 2018. Adults with 1 or more chronic leg ulcers of venous or mixed origin between 2 months and 4 years' duration were eligible to participate. Participants were randomized to treatment consisting of standard care (ie, ulcer cleansing, debridement/anesthesia as necessary, and optimized compression) and either application of a gauze pad containing 0.05% HA or a neutral comparator once daily for a maximum of 20 weeks. The primary efficacy endpoint was complete ulcer healing (100% reepithelialization of the wound area centrally assessed by 1 independent and experienced assessor blinded with respect to the treatment applied, as shown on digital photographs taken under standardized conditions at or before 20 weeks and confirmed 3 weeks later). Secondary efficacy endpoints included the percentage of completely healed target ulcers, residual area of target ulcer relative to baseline, the condition of the periulcerous skin, the total amount of analgesics used, the incidence of infection at the ulcer site of the target ulcer, patient adherence to treatment, time to achieve complete healing as centrally assessed, and pain intensity as measured by a visual analog scale., Results: Among the 168 participants (82 in the HA gauze pad group and 86 in the neutral gauze pad group), 33 (39.8%) in the HA group experienced complete healing of the target ulcer, which was significantly higher than the neutral comparator group (15, 18.5%; P = .002). Results in the full analysis and per-protocol sets were consistent with the primary results; no significant difference was noted in outcomes when participants' wounds were stratified according to baseline ulcer size., Conclusions: HA delivered in a gauze pad formulation could be a beneficial treatment for chronic leg ulcers of venous or mixed origin.

Objective: The purpose of this research is to investigate the effect of low-frequency contact ultrasonic debridement therapy (LFCUD) in hard-to-heal wounds with suspected biofilm, and compare the effect with or without a surfactant antimicrobial on bacterial colony counts and wound healing rates., Method: A single-blinded randomised controlled trial (RCT) will investigate the combination of LFCUD and the antiseptic polyhexamethylene biguanide with a surfactant betaine (referred to in this paper as PHMB) as a topical solution post-treatment and in a sustained dressing, compared with use of LFCUD alone. Potential participants from a community wound clinic (n=50) will be invited to take part in the 12-week trial. Wound swabs and tissue samples will be analysed for bacterial type and quantity, before and after treatments, using traditional culture techniques and advanced molecular methods. Wound healing, pain, quality of life and biofilm (via a specifically designed tool) will also be measured., Discussion: Bacteria have the potential to cause a hard-to-heal wound, particularly when antibiotics are too frequently and unnecessarily prescribed, resulting in antibiotic-resistant microorganisms. Appropriate care is vital when caring for hard-to-heal wounds to avoid these scenarios. With no simple laboratory method available to identify or treat wound biofilm, clinicians rely on their expertise in wound management. This study aims to provide in vivo evidence on the effectiveness of PHMB, to prevent the reformation of biofilm when applied after LFCUD. The aim is to provide evidence-based and more cost-effective wound care.

Objective: The aim of the study was to analyze bacterial flora in venous leg ulcers, empiric and targeted antibiotic therapy, and factors influencing healing time., Materials and Methods: Data from 30 patients with venous leg ulcers were retrospectively analyzed. Collected data included: sociodemographic data, wounds information, number of comorbidities, results of the microbiological examination, and empiric and targeted antibiotic therapy. To compare the empiric and targeted treatment in terms of their compatibility, the group of patients was divided into the four subgroups: NEA (no empiric antibiotics), NA (no antibiotics), ETA+ (compatibility of empiric and targeted antibiotic), ETA- (no compatibility of empiric and targeted antibiotic)., Results: The average ulcer healing time was 163.4 ± 97.1 (range 51.0 to 426.0) days and increased by 28 days with each additional bacterial strain in the ulcer (p = 0.041). Healing time did not differ between the four groups. Staphylococcus aureus and Pseudomonas aeruginosa were the most frequent bacteria. Amoxicillinium/acidum clavulanicum was the most common empirical antibiotic and amoxicillinium/acidum clavulanicum, and levofloxacinum was the most common targeted antibiotic., Conclusions: Venous leg ulcer healing time was prolonged with each subsequent bacterial strain in the ulcer, and it was independent from systemic antibiotic therapy.

Chronic leg ulcers effect millions of people around the world. It is imperative to search for effective treatments for such challenging ulcers. We report the success of aminolevulinic acid-mediated antimicrobial photodynamic therapy (A-PDT) to enhance wound healing of chronic ulcers for 3 patients who were refractory to conventional treatments. These ulcers healed after one to three sessions of A-PDT and there was no recurrence for more than 29 months. Interestingly, no bacteria were isolated from the ulcers after A-PDT treatment. In vitro, A-PDT also inactivated all bacteria isolated from the patients. A-PDT conditioned medium containing IL-6 enhanced keratinocyte migration. The results suggest in addition to bactericidal effects, A-PDT also alters the wound microenvironment. A-PDT may be an effective treatment for patients with recalcitrant infected ulcers., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: A score to identify local wound infections was developed by a panel of experts from seven European countries. The Therapeutic Index for Local Infections (TILI) score was designed for health professionals who are not specialised in wound care. This study was carried out to test the validity of the TILI score in everyday practice., Method: Content validity was analysed by means of evaluation by a panel of experts, individually and face-to-face, followed by a European multicentred, retrospective, observational study. Participating clinicians sent anonymised copies of completed TILI scores for patients with leg ulcers along with a photograph of the wound for analysis by two blinded reviewers. Concordance (Kappa index) and convergent criterion validity (sensitivity, specificity, accuracy, Youden's J Index and receiver operator characteristic (ROC) or area under the curve (AUC) curve) were calculated to construct validity and reliability., Results: A total of 307 patients with leg ulcers from seven institutions in five European countries were included in this retrospective analysis. It was shown that the diagnosis of local wound infection could be documented well with five of the six clinical criteria included in the TILI score. By summing up these facultative criteria in comparison with any direct criteria that may be present, there would have been an indication for local antiseptic wound therapy in 22% of patients examined., Conclusions: The results show that the TILI score is concordant with the expert assessment of patients and with good diagnostic characteristics. Thus, the easy-to-use TILI score can now be used in the daily routine practice of health professionals to diagnose local wound infections.

Background: Chronic venous insufficiency (CVI) is a condition in which veins are unable to transport blood unidirectionally towards the heart. CVI usually occurs in the lower limbs. It might result in considerable discomfort, with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is the second update of a review first published in 2005., Objectives: To assess the efficacy and safety of phlebotonics administered orally or topically for treatment of signs and symptoms of lower extremity CVI., Search Methods: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and Clinicaltrials.gov trials register up to 12 November 2019. We searched the reference lists of the articles retrieved by electronic searches for additional citations. We also contacted authors of unpublished studies., Selection Criteria: We included randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of phlebotonics (rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, French maritime pine bark extract, grape seed extract and aminaftone) in patients with CVI at any stage of the disease., Data Collection and Analysis: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardized mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence intervals (CIs) and percentage of heterogeneity (I 2 ). Outcomes of interest were oedema, quality of life (QoL), assessment of CVI and adverse events. We used GRADE criteria to assess the certainty of the evidence., Main Results: We identified three new studies for this update. In total, 69 RCTs of oral phlebotonics were included, but only 56 studies (7690 participants, mean age 50 years) provided quantifiable data for the efficacy analysis. These studies used different phlebotonics (28 on rutosides, 11 on hidrosmine and diosmine, 10 on calcium dobesilate, two on Centella asiatica, two on aminaftone, two on French maritime pine bark extract and one on grape seed extract). No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria. Moderate-certainty evidence suggests that phlebotonics probably reduce oedema slightly in the lower legs, compared with placebo (RR 0.70, 95% CI 0.63 to 0.78; 13 studies; 1245 participants); and probably reduce ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; 15 studies; 2010 participants). Moderate-certainty evidence shows that phlebotonics probably make little or no difference in QoL compared with placebo (SMD -0.06, 95% CI -0.22 to 0.10; five studies; 1639 participants); and similarly, may have little or no effect on ulcer healing (RR 0.94, 95% CI 0.79 to 1.13; six studies; 461 participants; low-certainty evidence). Thirty-seven studies reported on adverse events. Pooled data suggest that phlebotonics probably increase adverse events slightly, compared to placebo (RR 1.14, 95% CI 1.02 to 1.27; 37 studies; 5789 participants; moderate-certainty evidence). Gastrointestinal disorders were the most frequently reported adverse events. We downgraded our certainty in the evidence from 'high' to 'moderate' because of risk of bias concerns, and further to 'low' because of imprecision., Authors' Conclusions: There is moderate-certainty evidence that phlebotonics probably reduce oedema slightly, compared to placebo; moderate-certainty evidence of little or no difference in QoL; and low-certainty evidence that these drugs do not influence ulcer healing. Moderate-certainty evidence suggests that phlebotonics are probably associated with a higher risk of adverse events than placebo. Studies included in this systematic review provided only short-term safety data; therefore, the medium- and long-term safety of phlebotonics could not be estimated. Findings for specific groups of phlebotonics are limited due to small study numbers and heterogeneous results. Additional high-quality RCTs focusing on clinically important outcomes are needed to improve the evidence base., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

The presence of Kerstersia gyiorum in lower leg wounds has been reported in case studies from several countries., Objective: This study evaluated the antimicrobial susceptibility profile of K gyiorum isolated from a chronic wound., Methods: An 85-year-old woman with chronic venous insufficiency presented to an intermediate care unit in Niteroi City, Rio de Janeiro, Brazil, with an instep chronic wound of 14 cm² with wound duration of 6 months. K gyiorum was identified by matrix-assisted laser desorption ionization-time of flight, confirmed by 16S rRNA partial sequence analysis, and classified as resistant for ciprofloxacin by reagent strips(minimum inhibitory concentration [MIC] = 32 µg/mL) and the broth macrodilution method (MIC = 8 µg/mL). Intermediate resistance for ciprofloxacin was verified by microscan (MIC = 2 µg/mL)., Conclusion: The authors identified the first, to their knowledge, lower leg wound with K gyiorum in Brazil and verified that it was ciprofloxacin resistant.

Non-Uremic Calciphylaxis (NUC) is a rare condition that often manifests as intractable and painful integumentary wounds, afflicting patients with a high burden of co-morbidity. The Endocannabinoid System (ECS) is a ubiquitous signalling system that is theorised to be dysregulated within wound beds and associated peri-wound tissues. Preclinical research has shown that the dominant chemical classes derived from the cannabis plant, cannabinoids, terpenes, and flavonoids, interact with the integumentary ECS to promote wound closure and analgesia. This is a prospective open label cohort study involving two elderly Caucasian females with recalcitrant NUC leg ulcers of greater than 6 months duration. Topical Cannabis-Based Medicines (TCBM) composed of cannabinoids, terpenes, and flavonoids were applied daily to both the wound bed and peri-wound tissues until complete wound closure was achieved. Wounds were photographed regularly, and the digital images were subjected to planimetric analysis to objectively quantify the degree of granulation and epithelization. Analgesic utilisation, as a surrogate/proxy for pain scores, was also tracked. The cohort had a mean M3 multimorbidity index score of 3.31. Complete wound closure was achieved in a mean of 76.3 days. Additionally, no analgesics were required after a mean of 63 days. The treatments were well tolerated with no adverse reactions. The positive results demonstrated in very challenging wounds such as NUC, among highly complex patients, suggest that TCBM may have an even broader role within integumentary and wound management. This treatment paradigm warrants being trialled in other wound types and classes, and ultimately should be subjected to randomised controlled trials., (© 2020 The Authors. International Wound Journal published by Medicalhelplines.com Inc (3M) and John Wiley & Sons Ltd.)

Pembrolizumab, a programmed cell death protein 1 (PD1) inhibitor, has been known to be associated with several adverse reactions, including immune related adverse events. In less than one percent of patients, PD1 inhibitors have been linked to the development of connective tissue disease. Patients with previously known connective tissue disease are hypothesized to be at increased risk of flares in as many as 40% of cases. A 70-year-old man with a past medical history significant for rheumatoid arthritis in remission and stage IV lung adenocarcinoma presented to the dermatology clinic after one cycle of nivolumab and eight cycles of pembrolizumab exhibiting worsening, painful bilateral lower extremity ulcers for approximately one month. On the lower legs, three large black retiform eschars and bullous purpuric plaques were observed. Vasculitis is a rare complication of PD1 inhibitor therapy, with the majority of cases reported in literature either medium vessel or large vessel vasculitis. Only glucocorticoids have proven effective for PD1-induced vasculitis and these patients generally require multi-specialty management.

This study was aimed to evaluate whether silver-containing dressings were superior to other types of dressings in the treatment of venous leg ulcers (VLU) and their specific advantages.Eight databases (Cochrane Library, PubMed, Web of Science, Ovid-Medline, Wanfang, VIP, China Biology Medicine, and China National Knowledge Infrastructure) were systematically reviewed from inception to May 2019 for randomized controlled trials (RCTs). The primary outcome was complete wound healing, and the secondary outcomes included absolute wound size changes (change of cm area since baseline), relative changes (percentage change of area relative to baseline), and healing rate. Two reviewers independently evaluated the risk of bias using the Cochrane Collaboration assessment tool and extracted the data according to the predesigned table. All analyses were performed using the latest Review Manager Software (version 5.3).A total of 8 studies qualified and were included in the meta-analysis, including 1057 patients (experiment: 526, control: 531). Both complete wound healing and wound healing rates were reported in 5 studies. Two and 3 studies reported the effect of silver dressings on absolute and relative wound size changes, respectively. Most of the studies used intention-to-treat analysis.There was sufficient evidence that silver-containing dressings can accelerate the healing rate of chronic VLU and improve their healing in a short duration of time. However, compared with other dressings, clinical trials with long-term follow-up data are needed to confirm whether silver dressings have advantages regarding complete wound healing.

Background: While skin carcinomas are reported in chronic ulcers and in patients treated with hydroxyurea (HU) for myeloproliferative neoplasms, no skin carcinoma has been reported in patients with sickle cell disease (SCD), presenting chronic skin ulcers or treated with HU. The objective was to estimate the risk of cutaneous malignant transformation in SCD patients with prolonged leg ulcers or under HU therapy., Results: In this cross-sectional study, the cohort consisted of 1543 patients. In the first series, 29 patients presented a total of 53 ulcers lasting more than two years. The median age was 35 ± 8.4 years old. The median duration for a single ulcer was 9.2 ± 7 years. None of the examined ulcers showed any suspicious area of malignant transformation. In the second series, 187 patients treated with HU for more than two years were identified. The median age was 31.3 ± 9.9 years old. The median duration of treatment with HU was 6 ± 3.2 years. No skin carcinoma or actinic keratosis was recorded., Conclusions: This study showed that skin carcinogenesis did not occur in our series of SCD patients exposed to transforming events such as long term HU treatment or prolonged leg ulcers.

A 9-year-old girl with no relevant past medical history presented to our department due to a painless solitary nodule on the anterior aspect of the left thigh. The lesion had appeared 18 months before and showed a gradual significant growth, along with recent ulceration. Examination revealed a 20-mm firm, well-circumscribed pink-violaceous nodule but a yellow hue and an ulcerated erythematous center.

Aim: An investigator-initiated clinical study was carried out to evaluate the therapeutic potency of SR-0379 for the treatment of leg ulcers in patients with Werner syndrome., Methods: A multicenter, open-label study was carried out from September 2017 to February 2018. The inclusion criteria for leg ulcers were: (i) leg ulcers in patients with Werner syndrome, diabetes or critical limb ischemia/venous stasis; and (ii) a wound size of >1 cm and <6 cm in diameter. Four individuals with Werner syndrome and diabetic ulcers, respectively, were enrolled. SR-0379 (0.1%) was sprayed on skin ulcers once per day for 4 weeks. Efficacy was evaluated by determining the rate of wound size reduction as a primary end-point at 4 weeks after the first treatment compared with the pretreatment wound size. As secondary end-points, the DESIGN-R score index, the 50% wound size reduction ratio, time to wound closure and quantification of wound bacteria were also evaluated. The safety of SR-0379 was evaluated during the study period., Results: The reduction rate of ulcer size treated with 0.1% SR-0379 was 22.90% (mean) in the Werner syndrome ulcers group (n = 4) and 35.70% (mean) in the diabetic ulcers group (n = 4), respectively. The DESIGN-R score decreased by 4.0 points in the Werner syndrome ulcers group and 4.3 points in the diabetic ulcers group. Two mild adverse events were reported in two patients, and causal relationships were denied in any events., Conclusion: Treatment with SR-0379 was safe, well-tolerated, and effective for leg ulcers of both Werner syndrome and diabetes patients. Geriatr Gerontol Int 2019; 19: 1118-1123., (© 2019 Japan Geriatrics Society.)

Introduction: Venous leg ulcers (VLUs), the most common leg ulceration worldwide, are caused by venous hypertension due to venous reflux, the failure of the calf muscle to pump, and venous flow obstruction. They are associated with a reduced quality of life, particularly in relation to pain and physical function. Hibiscus rosa-sinensis is commonly employed because of its many medicinal properties, and studies have shown Hibiscus contains phytochemicals that have antimicrobial, antioxidant, and anti-inflammatory properties that promote wound healing., Objective: The authors evaluate the efficacy and safety of 4% gumamela leaf extract ointment in the closure of VLUs among patients seen in a dermatology outpatient department in the Philippines., Materials and Methods: The study included male or female patients with leg ulcers confirmed by duplex scan to be venous in origin and willing to have elastic compression therapy. Patients were instructed to clean the wound with normal saline solution and to apply the extract twice daily. The study was conducted for 12 weeks or until wound closure. Wounds were evaluated and photographed at baseline and every subsequent 2 weeks. Efficacy of therapy was evaluated based on ulcer area size using planimetry method at each visit. Safety was assessed using a 4-point grading system to monitor possible adverse reactions, namely pruritus, rash, burning, and urticaria., Results: Twelve patients were included in the study; 5 patients had an initial ulcer area of ⟩ 10 cm2 and 7 had an initial ulcer area of ≤ 10 cm2. By the end of the study, 10 patients (83.3%) achieved complete ulcer closure in ⟨ 12 weeks, 1 patient (8.3%) had a decrease in ulcer area ⟩ 50% by week 12, and 1 patient (8.3%) had ⟨ 50% decrease in ulcer area at the end of the study., Conclusions: Data showed compression stockings with 4% gumamela leaf extract ointment application could close VLUs in ⟨ 12 weeks. Applied with compression stockings, the ointment shows potential use in VLU management.