An integrated personalized assistive devices approach to reduce the risk of foot ulcer recurrence in diabetes (DIASSIST): study protocol for a multicenter randomized controlled trial.

BACKGROUND: Preventing foot ulcers in people with diabetes can increase quality of life and reduce costs. Despite the availability of various interventions to prevent foot ulcers, recurrence rates remain high. We hypothesize that a multimodal treatment approach incorporating various footwear, self-management, and education interventions that matches an individual person's needs can reduce the risk of ulcer recurrence with beneficial cost-utility. The aim of this study is to assess the effect on foot ulcer recurrence, footwear adherence, and cost-utility of an integrated personalized assistive devices approach in high-risk people with diabetes. METHODS: In a parallel-group multicenter randomized controlled trial, 126 adult participants with diabetes mellitus type 1 or 2, loss of protective sensation based on the presence of peripheral neuropathy, a healed plantar foot ulcer in the preceding 4 years, and possession of any type of custom-made footwear will be included. Participants will be randomly assigned to either enhanced therapy or usual care. Enhanced therapy consists of usual care and additionally a personalized treatment approach including pressure-optimized custom-made footwear, pressure-optimized custom-made footwear for indoor use, at-home daily foot temperature monitoring, and structured education, which includes motivational interviewing and personalized feedback on adherence and self-care. Participants will be followed for 12 months. Assessments include barefoot and in-shoe plantar pressure measurements; questionnaires concerning quality of life, costs, disease, and self-care knowledge; physical activity and footwear use monitoring; and clinical monitoring for foot ulcer outcomes. The study is powered for 3 primary outcomes: foot ulcer recurrence, footwear adherence, and cost-utility, the primary clinical, patient-related, and health-economic outcome respectively. DISCUSSION: This is the first study to integrate multiple interventions for ulcer prevention into a personalized state-of-the-art treatment approach and assess their combined efficacy in a randomized controlled trial in people with diabetes at high ulcer risk. Proven effectiveness, usability, and cost-utility will facilitate implementation in healthcare, improve the quality of life of high-risk people with diabetes, and reduce treatment costs. TRIAL REGISTRATION: ClinicalTrials.gov NCT05236660. Registered on 11 February 2022.

Concordance between culture, Molecular Culture and Illumina 16S rRNA gene amplicon sequencing of bone and ulcer bed biopsies in people with diabetic foot osteomyelitis.

BACKGROUND: In clinical practice the diagnosis of diabetic foot osteomyelitis (DFO) relies on cultures of bone or ulcer bed (UB) biopsies, of which bone biopsy is reference standard. The slow growth or fastidious nature of some bacteria, hamper expeditious detection and identification. Rapid molecular techniques may solve both issues, but their additional value for everyday practice is unknown. We investigated the concordance between conventional culture, the molecular techniques Molecular Culture (MC), and illumina 16S rRNA gene amplicon (16S) sequencing in people with DFO. METHODS: In the BeBoP trial, bone and UB biopsies were obtained from people with DFO who visited Amsterdam UMC. These biopsies were analysed using 1) conventional culture, 2)MC, a rapid broad range PCR analysing the 16S-23S ribosomal-interspace-region, and 3) 16S sequencing, and evaluated concordance among these techniques. RESULTS: We analysed 20 samples (11 bone and 9 UB) of 18 people. A total of 84 infectious agents were identified, 45 (54%) by all techniques, an additional 22 (26.5%, overall 80.5%) by both MC and 16S, and the remaining 16 species by culture and MC or 16S, or by a single method only. MC and 16S identified anaerobes not detected by culturing in 5 samples, and the presence of bacteria in 7 of 8 culture-negative (6 bone, 2 UB) samples. CONCLUSION: The high level of concordance between MC and 16S and the additional ability of molecular techniques to detect various bacteria not detected by culturing opens up prospects for routine use of fast molecular techniques, in clinical settings including DFO. TRIAL REGISTRATION: The BeBoP trial is retrospectively registered on 05-03-2019 in Netherlands Trial Register: NL 7582.

Cold plasma treatment is safe for diabetic foot ulcers and decreases Staphylococcus aureus bacterial load.

AIM: Cold atmospheric plasma (CAP) has antimicrobial properties. We studied the safety of a novel CAP device (PLASOMA prototype; Plasmacure, The Netherlands) that is simple to use and could be applied at a patient's home for the treatment of diabetic foot ulcers (DFUs). Secondary objectives were to investigate the effect of CAP on bacterial load and on ulcer size. METHOD: We included subjects with non-infected, superficial DFUs and treated them with CAP on a daily basis for 10 days. The primary endpoint was the occurrence of serious adverse device effects (SADE). We defined safety as: ≤10% of patients experiencing a SADE other than infection (non-infectious SADE), and ≤60% of patients developing infection of the foot (infectious serious adverse event (SAE)). RESULTS: We enrolled 20 patients. No SADE occurred, but three infectious SAEs occurred at the site of application within one month of treatment; three SAEs unrelated to treatment occurred, and 55% of subjects reported transient mild adverse device effects. Staphylococcus aureus bacterial load decreased directly after CAP application (p=0.01). The mean decrease of ulcer surface area was 43% (95% confidence interval: 20.2%-65.9%). CONCLUSION: CAP treatment in DFUs was safe and well tolerated. Ulcer size and Staphylococcus aureus colonisation decreased during treatment.

Effect of Prior Antibiotic Use on Culture Results in People with Diabetes and Foot Osteomyelitis.

BACKGROUND: Antibiotic use prior to biopsy acquisition in people with diabetes and osteomyelitis of the foot (DFO) might influence bacterial yield in cultures or induce bacterial resistance. Obtaining reliable culture results is pivotal to guide antibiotics for conservative treatment of DFO. METHODS: We prospectively analysed cultures of ulcer bed and percutaneous bone biopsies of people with DFO and investigated if antibiotics administered prior to (<2 months up to 7 days) biopsy acquisition led to more negative cultures or increased resistance in virulent bacteria. We calculated relative risks (RR) and 95% confidence intervals (CIs). We stratified analyses according to biopsy type (ulcer bed or bone). RESULTS: We analysed bone and ulcer bed biopsies of 64 people, of whom 29 received prior antibiotics, and found that prior antibiotics did not lead to a higher risk of at least one negative culture (RR 1.3, (CI 0.8-2.0), nor did prior treatment increase the risk of a specific type of negative culture (RR for bone cultures 1.15, (CI 0.75-1.7), RR for ulcer bed cultures 0.92 (CI 0.33-2.6)) or both cultures (RR 1.3 (CI 0.35-4.7), and neither did it increase the risk of antibiotic resistance in the combined bacterial results of ulcer bed and bone cultures (RR 0.64, (CI 0.23-1.8)). CONCLUSIONS: Antibiotics administered up to 7 days before obtaining biopsies in people with DFO do not influence culture yield regardless of biopsy type, nor are they associated with more antibiotic resistance.

The association between bacteria and outcome and the influence of sampling method, in people with a diabetic foot infection.

PURPOSE: Different bacteria lead to divers diabetic foot infections (DFIs), and some bacteria probably lead to higher amputation and mortality risks. We assessed mortality and amputation risk in relation to bacterial profiles in people DFI and investigated the role of sampling method. METHODS: We included people (> 18 years) with DFI in this retrospective study (2011-2020) at a Dutch tertiary care hospital. We retrieved cultures according to best sampling method: (1) bone biopsy; (2) ulcer bed biopsy; and (3) swab. We aggregated data into a composite determinant, consisting of unrepeated bacteria of one episode of infection, clustered into 5 profiles: (1) Streptococcus and Staphylococcus aureus; (2) coagulase-negative Staphylococcus, Cutibacterium, Corynebacterium and Enterococcus; (3) gram-negative; (4) Anaerobic; and (5) less common gram-positive bacteria. We calculated Hazard Ratio's (HR's) using time-dependent-Cox regression for the analyses and investigated effect modification by sampling method. RESULTS: We included 139 people, with 447 person-years follow-up and 459 episodes of infection. Sampling method modified the association between bacterial profiles and amputation for profile 2. HR's (95% CI's) for amputation for bacterial profiles 1-5: 0.7 (0.39-1.1); stratified analysis for profile 2: bone biopsy 0.84 (0.26-2.7), ulcer bed biopsy 0.89 (0.34-2.3), swab 5.9*(2.9-11.8); 1.3 (0.78-2.1); 1.6 (0.91-2.6); 1.6 (0.58-4.5). HR's (95% CI's) for mortality for bacterial profiles 1-5: 0.89 (0.49-1.6); 0.73 (0.38-1.4); 2.6*(1.4-4.8); 1.1(0.58-2.2); 0.80(0.19-3.3). CONCLUSIONS: In people with DFI, there was no association between bacterial profiles in ulcer bed and bone biopsies and amputation. Only in swab cultures, low-pathogenic bacteria (profile 2), were associated with a higher amputation risk. Infection with gram-negative bacteria was associated with a higher mortality risk. This study underlined the possible negative outcome of DFI treatment based on swabs cultures.

Using a BonE BiOPsy (BeBoP) to determine the causative agent in persons with diabetes and foot osteomyelitis: study protocol for a multicentre, randomised controlled trial.

BACKGROUND: Diabetic foot osteomyelitis (DFO) poses a major disease burden. It can generally be treated with long-term antibacterial therapy. International guidelines recommend to base antibacterial therapy choices on percutaneous bone biopsy culture, while in practice, therapy is frequently based on (less invasive) ulcer bed cultures. It is currently unknown if treatment outcomes of DFO differ depending on the chosen diagnostic strategy. METHODS: The BeBoP trial is a multicentre; randomised controlled; physician-, researcher- and subject-blinded; clinical trial comparing two diagnostic strategies in persons with DFO. Culture-directed antibacterial therapy will be based on either percutaneous bone biopsy culture results (intervention group) or ulcer bed biopsy culture results (comparison group). We will enrol 80 subjects with diabetes mellitus (≥ 18 years) and DFO, and we will use block randomisation stratified per centre to randomise them in a 1:1 allocation. The primary outcome is remission of DFO 12 months after enrolment. The secondary outcomes are the time to remission, signs of inflammation or ulceration at the primary location of infection at 6 and 12 months, microbiological and molecular profiles of culture outcomes, surgical interventions including amputation, total antibacterial therapy duration, infection-free survival days, adverse events, quality of life and survival. We will compare the outcomes by intention-to-treat and per-protocol analysis. DISCUSSION: We aim to compare clinical remission in persons with DFO treated with antibacterial therapy based on either percutaneous bone biopsy culture results or ulcer bed biopsy culture results. TRIAL REGISTRATION: Netherlands Trial Register NL 7582 . Registered on 05 March 2019.

When Limb Surgery Has Become the Only Life-Saving Therapy in FOP: A Case Report and Systematic Review of the Literature.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease in which heterotopic ossification (HO) is formed in muscles, tendons and ligaments. Traumatic events, including surgery, are discouraged as this is known to trigger a flare-up with risk of subsequent HO. Anesthetic management for patients with FOP is challenging. Cervical spine fusion, ankylosis of the temporomandibular joints, thoracic insufficiency syndrome, restrictive chest wall disease, and sensitivity to oral trauma complicate airway management and anesthesia and pose life-threatening risks. We report a patient with FOP suffering from life-threatening antibiotic resistant bacterial infected ulcers of the right lower leg and foot. The anesthetic, surgical and postoperative challenges and considerations are discussed. In addition, the literature on limb surgeries of FOP patients is systemically reviewed. The 44 year-old female patient was scheduled for a through-knee amputation. Airway and pulmonary evaluation elicited severe abnormalities, rendering standard general anesthesia a rather complication-prone approach in this patient. Thus, regional anesthesia, supplemented with intravenous analgosedation and N2O-inhalation were performed in this case. The surgery itself was securely planned to avoid any unnecessary tissue damage. Postoperatively the patient was closely monitored for FOP activity by ultrasound and [18F]PET/CT-scan. One year after surgery, a non-significant amount of HO had formed at the operated site. The systematic review revealed seventeen articles in which thirty-two limb surgeries in FOP patients were described. HO reoccurrence was described in 90% of the cases. Clinical improvement due to improved mobility of the operated joint was noted in 16% of the cases. It should be noted, though, that follow-up time was limited and no or inadequate imaging modalities were used to follow-up in the majority of these cases. To conclude, if medically urgent, limb surgery in FOP is possible even when general anesthesia is not preferred. The procedure should be well-planned, alternative techniques or procedures should be tested prior to surgery and special attention should be paid to the correct positioning of the patient. According to the literature recurrent HO should be expected after surgery of a limb, even though it was limited in the case described.

The effect of physical training on workload, upper leg muscle function and muscle areas in patients with chronic heart failure.

OBJECTIVE: To investigate the effect of physical training (PTr) on upper leg muscle area, muscle strength and muscle endurance expressed as upper leg muscle function (ULMF) in relation to exercise performance in CHF. DESIGN: Randomised to a training (TG) or control group (CG). SETTING: Outpatient cardiac rehabilitation centre of community hospital. PATIENTS: 77 CHF patients (59 men and 18 women), NYHA class II/III, age 59.8+/-9.3 years, LVEF 27+/-8%. Sixteen patients dropped out during the intervention period, 61 patients (M/F:46/15) completed the study. INTERVENTION: PTr (combined strength and endurance exercises) four times per week, twice supervised and twice at home, during 26 weeks. MAIN OUTCOME MEASURES: LVEF, body composition, daily physical activity, exercise performance, upper leg muscle area and isokinetic leg muscle variables. RESULTS: Workload and peak oxygen consumption decreased in the CG (-4.1% and -4%) but increased in the TG (+5% and +4%) following PTr (p<0.05, ANOVA repeated measures). Hamstrings area decreased in the CG and did not change in the TG (p<0.05, ANOVA repeated measures). ULMF improved in the TG, but remained unchanged in the CG (+13.0% and 0.0, respectively, p<0.05; ANOVA repeated measures). At baseline and after intervention nearly 60% of the variance in maximal workload was explained by ULMF and quadriceps muscle area (multiple regression analysis). CONCLUSIONS: In CHF patients, home-based training in conjunction with a supervised strength and endurance training program is safe, feasible and effective and does not require complex training equipment. Physical training prevented loss of hamstrings muscle mass and improved exercise performance by enhancing muscle strength and endurance.

Determinants of maximal exercise performance in chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is characterized by symptoms like fatigue, dyspnoea and limited exercise performance. It has been postulated that maximal exercise performance (Wmax) is predominantly limited by skeletal muscle function and less by heart function. AIM: To study the interrelation between most relevant muscle and anthropometrical variables and Wmax in CHF patients in order to develop a model that describes the impact of these variables for maximal exercise performance. DESIGN: In 77 patients with CHF Wmax was assessed by incremental cycle ergometry until exhaustion (20 Watt/3 min). Peak torque (strength) and total work (endurance) for the quadriceps and hamstrings were assessed by isokinetic dynamometry. Isometric strength was measured by hand dynamometry. Relevant muscle areas were calculated by computerized tomography scan. RESULTS: Significant correlations between Wmax and isokinetic muscle parameters (peak torque and total work) ranged from 0.41-0.65 (P<0.01). Other significant relationships (P<0.01) with Wmax were obtained for age (r=-0.22), gender (r=0.45), fat free mass (FFM) (r=0.51), quadriceps muscle area (r=0.73), hamstrings muscle area (r=0.50), upper leg muscle function (i.e., a combination of muscle strength and muscle endurance) (r=0.71) and isometric strength (r=0.63). Multiple regression analysis showed that upper leg muscle function and quadriceps muscle area could predict 57% of the variance in Wmax. CONCLUSION: Muscle strength and muscle endurance, combined with quadriceps muscle area are the main predictors of maximal exercise performance in patients with CHF.