Diagnostic imaging of the diabetic foot: an EANM evidence-based guidance.

PURPOSE: Consensus on the choice of the most accurate imaging strategy in diabetic foot infective and non-infective complications is still lacking. This document provides evidence-based recommendations, aiming at defining which imaging modality should be preferred in different clinical settings. METHODS: This working group includes 8 nuclear medicine physicians appointed by the European Association of Nuclear Medicine (EANM), 3 radiologists and 3 clinicians (one diabetologist, one podiatrist and one infectious diseases specialist) selected for their expertise in diabetic foot. The latter members formulated some clinical questions that are not completely covered by current guidelines. These questions were converted into statements and addressed through a systematic analysis of available literature by using the PICO (Population/Problem-Intervention/Indicator-Comparator-Outcome) strategy. Each consensus statement was scored for level of evidence and for recommendation grade, according to the Oxford Centre for Evidence-Based Medicine (OCEBM) criteria. RESULTS: Nine clinical questions were formulated by clinicians and used to provide 7 evidence-based recommendations: (1) A patient with a positive probe-to-bone test, positive plain X-rays and elevated ESR should be treated for presumptive osteomyelitis (OM). (2) Advanced imaging with MRI and WBC scintigraphy, or [18F]FDG PET/CT, should be considered when it is needed to better evaluate the location, extent or severity of the infection, in order to plan more tailored treatment. (3) In a patient with suspected OM, positive PTB test but negative plain X-rays, advanced imaging with MRI or WBC scintigraphy + SPECT/CT, or with [18F]FDG PET/CT, is needed to accurately assess the extent of the infection. (4) There are no evidence-based data to definitively prefer one imaging modality over the others for detecting OM or STI in fore- mid- and hind-foot. MRI is generally the first advanced imaging modality to be performed. In case of equivocal results, radiolabelled WBC imaging or [18F]FDG PET/CT should be used to detect OM or STI. (5) MRI is the method of choice for diagnosing or excluding Charcot neuro-osteoarthropathy; [18F]FDG PET/CT can be used as an alternative. (6) If assessing whether a patient with a Charcot foot has a superimposed infection, however, WBC scintigraphy may be more accurate than [18F]FDG PET/CT in differentiating OM from Charcot arthropathy. (7) Whenever possible, microbiological or histological assessment should be performed to confirm the diagnosis. (8) Consider appealing to an additional imaging modality in a patient with persisting clinical suspicion of infection, but negative imaging. CONCLUSION: These practical recommendations highlight, and should assist clinicians in understanding, the role of imaging in the diagnostic workup of diabetic foot complications.

A multidisciplinary team reduces in-hospital clinical complications and mortality in patients with diabetic foot ulcers.

AIMS: The current study aims to evaluate the effectiveness of a multidisciplinary diabetic foot team (MDFT) in the management of in-patients affected by diabetic foot problems. MATERIALS AND METHODS: The study was a retrospective observational study. Consecutive patients with a diabetic foot problem requiring hospitalisation were included. All patients were managed by a MDFT led by diabetologists according to the guidance. The rate of in-hospital complications (IHCs), major amputation, and survival were recorded at the end of patient's hospitalisation. IHC was defined as any new infection different from wound infection, cardiovascular events, acute renal injury, severe anaemia requiring blood transfusion, and any other clinical problem not present at the assessment. RESULTS: Overall, 350 patients were included. The mean age was 67.9 ± 12.6 years, 254 (72.6%) were males, 323 (92, 3%) showed Type 2 diabetes with a mean duration of 20.2 ± 9.6 years; 224 (64%) had ischaemic diabetic foot ulcers (DFUs) and 299 (85.4%) had infected DFUs. IHCs were recorded in 30/350 (8.6%) patients. The main reasons for IHCs were anaemia requiring blood transfusion (2.8%), pneumonia (1.7%), acute kidney failure (1.1%). Patients with IHCs showed a higher rate of major amputation (13.3 vs. 3.1%, p = 0.02) and mortality (16.7 vs. 0.6%, p < 0.0001) in comparison to those without. Ischaemic heart disease (IHD) and wound duration at the assessment (>1 month) were independent predictors of IHC, whereas IHCs, heart failure, and dialysis were independent predictors of in-hospital mortality. CONCLUSIONS: The multidisciplinary management of diabetic foot problems leads to an IHC rate of 8%. The risk of IHCs is higher in patients with IHD and long wound duration.

Results of a prospective observational study of autologous peripheral blood mononuclear cell therapy for no-option critical limb-threatening ischemia and severe diabetic foot ulcers.

BACKGROUND: Cell therapy with autologous peripheral blood mononuclear cells (PB-MNCs) may help restore limb perfusion in patients with diabetes mellitus and critical limb-threatening ischemia (CLTI) deemed not eligible for revascularization procedures and consequently at risk for major amputation (no-option). Fundamental is to establish its clinical value and to identify candidates with a greater benefit over time. Assessing the frequency of PB circulating angiogenic cells and extracellular vesicles (EVs) may help in guiding candidate selection. METHODS: We conducted a prospective, non-controlled, observational study on no-option CLTI diabetic patients that underwent intramuscular PB-MNCs therapy, which consisted of more cell treatments repeated a maximum of three times. The primary endpoint was amputation rate at 1 year following the first treatment with PB-MNCs. We evaluated ulcer healing, walking capability, and mortality during the follow-up period. We assessed angiogenic cells and EVs at baseline and after each cell treatment, according to primary outcome and tissue perfusion at the last treatment [measured as transcutaneous oxygen pressure (TcPO2)]. RESULTS: 50 patients were consecutively enrolled and the primary endpoint was 16%. TcPO2 increased after PB-MNCs therapy (17.2 ± 11.6 vs 39.1 ± 21.8 mmHg, p < .0001), and ulcers healed with back-to-walk were observed in 60% of the study population (88% of survivors) during follow-up (median 1.5 years). Patients with a high level of TcPO2 (≥ 40 mmHg) after the last treatment showed a high frequency of small EVs at enrollment. CONCLUSIONS: In no-option CLTI diabetic patients, PB-MNCs therapy led to an improvement in tissue perfusion, a high rate of healing, and back-to-walk. Coupling circulating cellular markers of angiogenesis could help in the identification of patients with a better clinical benefit over time.

Endovascular treatment of calcific lesions of the common femoral artery using atherectomy device associated with scoring balloon angioplasty in diabetic patients with high "major amputation" risk.

OBJECTIVES: To investigate the outcomes of patients with calcific lesions in the common femoral artery undergoing endovascular procedures with atherectomy device and scoring balloon angioplasty combined with treatment of steno-occlusive disease of the remaining arterial districts of the lower limb. METHODS: Between January 2015 and December 2018, 11 diabetic patients at high risk for "major amputation", with calcific lesions of the common femoral artery and ischemic ulcers requiring endovascular treatment were retrospectively evaluated. Technical success was defined as revascularization of the common femoral artery with a residual stenosis lower than 30%. Primary endpoints were an immediate increase of perilesional transcutaneous oxygen pressure (TCPO2) > 40 mmHg, ulcerative lesions improvement up to healing or skin flaps re-epithelialization after minor amputation, limb rescue with rejected major amputation, and resolution of rest pain if present. RESULTS: The success rate of the revascularization procedures was 100%. No patient underwent surgical conversion. One case of peri-operative bleeding at the brachial access site was observed. There were no cases of arterial dissection or undesired distal embolization. The average baseline value of perilesional TCPO2 was 21.8 ± 9.2 mmHg. The mean TCPO2 value was 57.4 ± 7.2 mmHg three days after the procedure (P < 0.05), and 51.2 ± 9.8 mmHg 15 days after (P < 0.05). Minor amputations were performed in five patients with advanced ulcerative lesions. No major amputations were performed in the follow-up period. At 14 months follow-up, one patient developed new occlusion of the CFA for extension from the external iliac artery and underwent a new endovascular procedure. We observed an overall primary patency rate of 91% and a primary assisted patency rate of 100% in our 18-month follow-up. CONCLUSIONS: Endovascular approach for severely calcified atherosclerotic lesions of the common femoral artery seems to represent a valid therapeutic option associated with promising results in terms of clinical outcome and low complication rates.

Peripheral arterial disease in patients with renal-diabetic foot ulcers.

OBJECTIVE: To describe the angiographic characteristics of peripheral arterial disease (PAD) in persons with diabetic foot ulcers (DFUs) on dialysis treatment. METHOD: The study is a retrospective analysis of patients with DFUs and PAD who had been referred to our diabetic foot clinic. All patients had been managed by a pre-set limb salvage protocol including revascularisation of the affected limb. Arterial lesions (stenosis between 50-99% and occlusions) were retrospectively evaluated through angiogram analysis. According to the presence or not of dialysis, patients were divided into two patient groups: renal-diabetic foot (RDF) and diabetic foot (DF). Distribution of PAD and immediate revascularisation outcome (technical revascularisation outcome) for RDF and DF were separately reported and compared. RESULTS: The sample included 239 patients: mean age was 71.8 years; 72.4% were male; 87.4% had type 2 diabetes; mean diabetes duration was 21.4 years; and the mean HbA1c was 63±22mmol/mol. The RDF group compared with the DF group reported higher numbers of vessels affected (n=5±1.6 versus 3.9±1.5, respectively, p<0.0001), greater involvement of the superficial femoral artery (90.2% versus 75.8%, respectively, p=0.003), the tibial-peroneal trunk (53.7% versus 25.5%, respectively, p=0.01), the anterior tibial artery (93.9% versus 80.9%, respectively, p=0.03) and below-the-ankle (BTA) arteries (70.7% versus 35.7%, respectively, p=0.0001). The RDF group showed a higher rate of revascularisation failure in comparison to DF patients (43.9% versus 15.3%, respectively, p<0.0001). BTA arterial disease (odds ratio 9.5; 95% Confidence Interval: 3.5-25.4; p=0.0001) resulted as the only independent predictor of revascularisation failure. CONCLUSION: In this study, RDF patients showed a widespread distribution of arterial lesions with a higher involvement of foot arteries in comparison with DF patients. BTA arterial disease was found to be an independent predictor of revascularisation failure.

Recessive mutations in the neuronal isoforms of DST, encoding dystonin, lead to abnormal actin cytoskeleton organization and HSAN type VI.

Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders, characterized by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. Several pathways have been implicated in the pathogenesis of neuronal degeneration in HSAN, while recent observations point to an emerging role of cytoskeleton organization and function. Here, we report novel biallelic mutations in the DST gene encoding dystonin, a large cytolinker protein of the plakin family, in an adult form of HSAN type VI. Affected individuals harbored the premature termination codon variant p.(Lys4330*) in trans with the p.(Ala203Glu) change affecting a highly conserved residue in an isoform-specific N-terminal region of dystonin. Functional studies showed defects in actin cytoskeleton organization and consequent delayed cell adhesion, spreading and migration, while recombinant p.Ala203Glu dystonin loses the ability to bind actin. Our data aid in the clinical and molecular delineation of HSAN-VI and suggest a central role for cell-motility and cytoskeletal defects in its pathogenesis possibly interfering with the neuronal outgrowth and guidance processes.

Endovascular Distal Plantar Vein Arterialization in Dialysis Patients With No-Option Critical Limb Ischemia and Posterior Tibial Artery Occlusion: A Technique for Limb Salvage in a Challenging Patient Subset.

PURPOSE: To detail a percutaneous technique for distal plantar venous arterialization in diabetic, end-stage renal disease (ESRD) patients with no-option critical limb ischemia (CLI). TECHNIQUE: After failure of standard intraluminal recanalization attempts, a subintimal approach through the posterior tibial artery (PTA) is begun using a 0.014-inch, 190- or 300-cm-long guidewire supported by a 2-×20-mm, low-profile balloon catheter positioned a short distance behind the narrow "U-shaped" loop in the guidewire. Typically, heavy calcification in the distal tortuous segment of the PTA prevents reentry to the arterial true lumen; however, an entry in the distal lateral or medial plantar vein from a subintimal channel in the plantar artery can be intentionally pursued as a bailout technique, pointing the tip of the guidewire opposite to the arterial wall calcifications. Venous access is confirmed by contrast injection through the balloon catheter. Once the guidewire is advanced in the distal lateral or medial plantar vein and a plantar arteriovenous fistula (AVF) has been created, the AV anastomosis and the occluded PTA segment are dilated with 0.014-inch balloon catheters. The technique has been attempted in 9 consecutive diabetic, ESRD patients (mean age 69 years; 5 men) with no-option CLI; an AVF was created between the PTA and plantar vein in 7 patients. The mean TcPO2 at 1 month was 30±17 mm Hg (vs 7.3±2.2 at baseline). Six ulcers healed over an average of 21±4 weeks. Three of the 9 patients had below-knee amputations. CONCLUSION: Although further investigations are required, distal plantar venous arterialization may represent a promising technique to improve recanalization rates and limb salvage in diabetic ESRD patients with extremely calcified PTA occlusions.

Risk of contrast induced nephropathy in diabetic patients affected by critical limb ischemia and diabetic foot ulcers treated by percutaneous transluminal angioplasty of lower limbs.

BACKGROUND: The aim of this study is to evaluate the risk of contrast induced nephropathy (CIN) in diabetic patients with critical limb ischemia (CLI) and foot ulcers (FUs) treated by percutaneous transluminal angioplasty of lower limbs. METHODS: The study group was composed of 145 diabetic patients who underwent a limb salvage protocol because of CLI and FUs between 2012 and 2015. All patients received a prophylactic strategy against the administration of contrast medium. Serum creatinine (SCr) levels were evaluated the day of procedure and for 3 days after. CIN was considered in case of increase of 25% of SCr in comparison to baseline value or an absolute increase of at least 0.5 mg/dl without other interfering factors. RESULTS: CIN occurred in 9% (14/145) of the cases. In the 1-year follow-up SCr returned to baseline values in 10 patients (71 %), 3 patients died (21%), and 1 patient had a major cardiovascular event (7%). No patients required dialysis. The risk was independent of chronic kidney disease stage. The rate of contrast nephropathy in each stage (X = 0.27) was as follows: 3/20 (15%) in stage 2; 3/66 (4.6%) in stage 3, 7/51 (13.7%) in stage 4; and 1/8 (12.5%) in stage 5. At the univariate analysis factors predicting this risk were anemia (HR 95% 2.5 [CI 1.8-4.2] P = .039) and heart failure (HR 95% 2.6 [CI 2.1-4.6] P = .038), while any significant variable was found at multivariate analysis. CONCLUSIONS: Peripheral percutaneous transluminal angioplasty in diabetic patients with CLI and FUs can be performed with a good safety factor and a low risk of contrast medium toxicity.

Comparative Impact of Hypoglycemic Agents on Severity and Extent of Myocardial Ischemia in Patients With Type 2 Diabetes Mellitus Undergoing Myocardial Perfusion Scintigraphy.

BACKGROUND: Hypoglycemic agents differ in mechanism, efficacy, and profile. However, there is uncertainty on their impact on myocardial perfusion. We thus aimed to investigate whether individuals with type 2 diabetes mellitus treated with different drug classes exhibit different perfusion patterns at myocardial perfusion scintigraphy (MPS). METHODS AND RESULTS: We queried our administrative database for patients with diabetes mellitus without prior or recent myocardial infarction. The primary objective was to compare the severity and extent of ischemia at MPS, distinguishing patients according to management strategy. A total of 7592 patients were included [2336 (31%) on diet, 3611 (48%) on metformin, 749 (10%) on sulfonylureas, 449 (6%) on metformin plus sulfonylureas, 447 (6%) on metformin plus insulin]. Unadjusted analyses and analyses adjusting for baseline features suggested that sulfonylureas alone or in combination were associated with more severe ischemia than nonsulfonylurea regimens (P < 0.05), whereas combination regimens including metformin were associated with more extensive myocardial ischemia than the other regimens (P < 0.05 for both). However, no significant difference disfavoring either metformin or sulfonylurea regimens persisted after multivariable adjustment for baseline, stress, and angiographic characteristics (all P > 0.05). CONCLUSION: Several significant differences in baseline, stress, and scintigraphic features appear evident in patients with diabetes mellitus receiving different hypoglycemic agents or regimens.

Expression of the receptor activator of nuclear factor-kB ligand in peripheral blood mononuclear cells in patients with acute Charcot neuroarthropathy.

Introduction. The receptor activator of nuclear factor-kB (RANK), ligand (RANK-L) and osteoprotegerin (OPG) are implicated in the pathogenesis of acute Charcot neuroarthropathy (CN). Materials and Methods. This study aimed to investigate the expression of RANK-L and OPG in peripheral blood mononuclear cells (PBMC) from patients with acute CN. Results. We found that the expression of RANK-L was lower in patients with acute CN as compared with diabetic control subjects and healthy control participants; whereas OPG expression was not detected in patients and in both control groups. RANK-L expression at the onset of disease was inversely correlated with the index of polyunsaturation (PUI), a bone marrow MRS-derived measurable index that allows evaluation of disease activity in acute CN, and recovery time. Finally, the expression of RANK-L increased at the time of healing compared with the values found during the acute phase. Conclusions. In conclusion, our preliminary data provide a first step in applying analysis of RANK-L expression in peripheral blood cells to the diagnosis of acute CN. Based on our data we also suggest that analysis of RANK-L expression could be a complementary tool that can be employed to obtain quantitative parameters that may help clinicians to monitor disease activity in patients with acute CN.

Non-healing foot ulcers in diabetic patients: general and local interfering conditions and management options with advanced wound dressings.

Medical knowledge about wound management has improved as recent studies have investigated the healing process and its biochemical background. Despite this, foot ulcers remain an important clinical problem, often resulting in costly, prolonged treatment. A non-healing ulcer is also a strong risk factor for major amputation. Many factors can interfere with wound healing, including the patient's general health status (i.e., nutritional condition indicated by albumin levels) or drugs such as steroids that can interfere with normal healing. Diabetic complications (i.e., renal insufficiency) may delay healing and account for higher amputation rates observed in diabetic patients under dialysis treatment. Wound environment (e.g., presence of neuropathy, ischaemia, and infection) may significantly influence healing by interfering with the physiological healing cascade and adding local release of factors that may worsen the wound. The timely and well-orchestrated release of factors regulating the healing process, observed in acute wounds, is impaired in non-healing wounds that are blocked in a chronic inflammatory phase without progressing to healing. This chronic phase is characterised by elevated protease activity (EPA) of metalloproteinases (MMPs) and serine proteases (e.g., human neutrophil elastase) that interfere with collagen synthesis, as well as growth factor release and action. EPA (mainly MMP 9, MMP-8 and elastase) and inflammatory factors present in the wound bed (such as IL-1, IL-6, and TNFa) account for the catabolic state of non-healing ulcers. The availability of wound dressings that modulate EPA has added new therapeutic options for treating non-healing ulcers. The literature confirms advantages obtained by reducing protease activity in the wound bed, with better outcomes achieved by using these dressings compared with traditional ones. New technologies also allow a physician to know the status of the wound bed environment, particularly EPA, in a clinical setting. These may be helpful in guiding a clinician's options in treating very difficult-to-heal ulcers.

From a Spark to a Flame: The Evolution of Diabetic Foot Disease in the Last Two Decades.

Despite many improvements have been achieved, diabetic foot disease (DFD) remains a clinical, social, and economic burden. In the last years, DFD showed an evolution of its characteristics with an increase of the ischaemic/neuro-ischaemic foot in comparison to the pure neuropathic foot. Simultaneously, there was and increased incidence of concomitant cardiovascular co-morbidities, which influences the higher fragility of patients with DFS. Peripheral arterial disease (PAD) in subjects with diabetic foot seems to show a more aggressive pattern, being more distal and difficult to treat. Untreatable PAD remains the unmet need for clinicians and the main risk factor of major amputation in patients with diabetic foot ulcers. Authors aimed to describe the evolution of diabetic foot patients in the last two decades, describing also the current and future treatment which may improve outcomes in the next generations.

The Appropriateness of Footwear in Diabetic Patients Observed during a Podiatric Examination: A Prospective Observational Study.

Background: Adequate compliance with wearing therapeutic footwear (TF) to prevent diabetic foot ulcers is known to be low. The primary aim of this study was to identify population awareness about the ulceration and/or recurrence risk according to footwear choice. The secondary aim was to evaluate the compliance level in footwear choice based on a patient's own risk. Methods: Forty podiatrists participated from 1 September 2017 to 31 August 2018, providing six-section forms which included personal data, risk classification, footwear characteristics and a knowledge questionnaire. Results: This study included 1507 patients. Those with active ulcers were excluded. A total of 43% of patients belonged to risk class 0, 19% to risk class 1, 19% to risk class 2 and 19% to risk class 3. A total of 58% had foot deformities. Conclusions: Nearly half of patients with a high risk of ulceration had knowledge of their own risk but the majority of them did not follow the recommendations. Only a small percentage (36%) of risk class 3 patients wore footwear suitable for their risk class. There was poor consideration of footwear choice among patients. We highlight critical issues in patient education and compliance with wearing footwear appropriate to their risk class.

Prevalence of Diabetes Mellitus and Clinical Differences in Patients with Severe Osteoporosis and Fragility Fractures.

Background: Diabetes mellitus (DM) and osteoporosis are two of the most widespread metabolic diseases in the world. The aim of this study is to investigate the prevalence of DM among patients affected by osteoporosis and fragility fractures, and to search for differences in clinical characteristics. Methods: This is a single-center retrospective, case-controlled study. A total of 589 patients attending CTO Bone Unit between 2 January 2010 and 31 May 2023, due to osteoporosis and fragility fractures, were divided into two groups, according to the diagnosis of DM. The clinical and bone characteristics of patients were compared. Results: Prevalence of DM was 12.7%. Compared to patients without DM, the median age at the time of first fracture was similar: 72 years ± 13.5 interquartile range (IQR) vs. 71 years ± 12 IQR; prevalence of combination of vertebral and hip fractures was higher (p = 0.008), as well as prevalence of males (p = 0.016). Bone mineral density (BMD) at all sites was higher in DM group; trabecular bone score (TBS), instead, was significantly lower (p < 0.001). Conclusions: Patients with fragility fractures and DM more frequently show combination of major fractures with higher BMD levels. In these patients, TBS could be a better indicator of bone health than BMD and, therefore, might be used as a diagnostic tool in clinical practice.

Diabetic Foot Osteomyelitis in Patients with and without Peripheral Arterial Disease: Two Different Diseases?

The aim of the current study was to evaluate the outcomes of patients with diabetic foot osteomyelitis (DFO), comparing subjects with and without peripheral arterial disease (PAD). The study is a prospective study including a population of patients affected by a DFO located in the forefoot. All patients were managed by a surgical conservative approach defined by the removal of the infected bone, in association with the antibiotic therapy. Patients were divided into two groups: those with PAD (neuro-ischaemic DFO) and those without (neuropathic DFO). After 1 year of follow-up, the following outcome were evaluated and compared between groups: healing, healing time, minor amputation, major amputation, hospitalization, need for surgical re-intervention. Overall, 166 patients were included, 87(52.4%) of them had neuro-ischaemic DFO and 79 (47.6%) neuropathic DFO. Patients with neuro-ischaemic DFO in comparison to neuropathic DFO were older (72.5 ± 9 vs 64.1 ± 15.5 years, P < .0001), had longer diabetes duration (21.8 ± 5.6 vs 16.4 ± 7.6 years, P < .0001), higher rate of dialysis (13.8 vs 1.3%, P = .001) and ischaemic heart disease (79.3 vs 12.7%, P < .0001). Outcomes for neuro-ischaemic DFO and neuropathic DFO were: healing (96.5 vs 97.5%, P = .7), healing time (7.8 ± 6.2 vs 5.7 ± 3.7 weeks, P = .01), minor amputation (16.1 vs 3.8%, P = .006), major amputation (0 vs 0%, ns), hospitalization (90.8 vs 51.9%, P < .0001), surgical re-intervention (14.9 vs 8.8%, P = .004) respectively. In addition, PAD resulted in an independent predictor of minor amputation, hospitalization, and surgical re-intervention. DFO in patients with PAD was characterized by longer healing time, more cases of minor amputation, hospitalization, and surgical re-intervention. PAD independently predicted the risk of minor amputation, hospitalization, and surgical re-intervention, while it was not associated with the healing rate.

Severe Hypocalcemia Occurring During the Hospitalization of a Patient Affected by Permanent Post-Surgical Hypoparathyroidism with Multimorbidity: A Case Report.

BACKGROUND: Patients with permanent hypoparathyroidism experience an impaired quality of life, due to acute and chronic complications that may affect several organs, with an increased risk of hospitalisation and death. Adequate and continuous replacement therapy with calcium and calcitriol is necessary to avoid symptoms and long-term complications related to hypocalcemia. CASE PRESENTATION: A 63 years old male, affected by permanent post-surgical hypoparathyroidism, was hospitalized in the cardiology department because of a dehiscence of the subcutaneous housing of the double-chambered implantable cardioverter-defibrillator. Chronic replacement therapy for hypoparathyroidism was poorly controlled and, during hospitalization, severe hypocalcemia occurred together with electrocardiographic and echocardiogram life-threatening alterations. CONCLUSION: Constant and targeted long-term replacement therapy with calcium and particularly calcitriol is necessary to avoid major consequences on patients' health, especially during acute events and in the presence of other comorbidities.

Thyroid Hormone Resistance: A 17-Year Follow-up Case Report.

BACKGROUND: Resistance to thyroid hormone is a rare syndrome characterized by peripheral resistance to thyroid hormones. It is caused by genetic dysfunction of thyroid receptor genes, with Thyroid hormone Receptor-beta (TRß) being the most prevalent. Affected patients show high thyroid hormone levels and non-suppressed Thyroid-stimulating Hormone (TSH). Syndrome manifestations vary from hyperthyroidism to hypothyroidism depending on the specific mutation. CASE PRESENTATION: We, herein, describe the case of a 24-year-old female with a diagnosis of resistance to thyroid hormone from the age of 7. The main symptoms the patients complained about were headaches, palpitations, hyperidrosis, and frequent evacuations with severe underweight. The patient's blood test showed high FT3 and FT4 levels with a non-suppressed TSH. We performed a disease complications screening that revealed mild osteoporosis and normal cardiac activity (the patient was already treated with bisoprolol). CONCLUSION: This case illustrates symptoms and complications of resistance to thyroid hormone syndrome, a rare and misdiagnosed condition. In this case report, we describe and explain longterm disease symptoms and their management. The long-term history of our patient's disease adds a more comprehensive evaluation of the syndrome and its consequences, contributing to new insights into the resistance to thyroid hormone syndrome and shedding light on personalized management of its manifestations.

Early Treatment of Acute Stage 0/1 Diabetic Charcot Foot Can Avoid Major Amputations at One Year.

Background: If unrecognized, Charcot neuro-osteoarthropathy (CNO) can be a devastating complication of diabetes. Methods: The aim of this retrospective study was to evaluate the outcomes in a cohort of diabetic patients diagnosed with active CNO managed in a tertiary level diabetic foot clinic (DFC). We included consecutive patients with active CNO, stage 0-1, according to the Eichenholtz-Shibata classification, who were referred from 1 January 2019 to 27 September 2022. Diagnosis of CNO was based on clinical signs and imaging (X-rays and magnetic resonance). All patients were completely offloaded by a total-contact cast (TCC) or removable knee-high device. Each patient was closely monitored monthly until CNO remission or another outcome. At 12 months of follow-up, the following outcomes were analyzed: remission, time to remission, major amputations (any above the ankle), and surgical indication. Results: Forty-three patients were included. The mean age was 57.6 ± 10.8 years; 65% were males and 88.4% had type 2 diabetes, with a mean duration of 20.6 ± 9.9 years. At baseline, 32.6% was affected by peripheral artery disease. Complete remission was recorded in 40/43 patients (93%), with a mean time to remission of 5.6 ± 1.5 months; major amputation and surgical indication occurred, respectively in 1/43 patients (2.3%) and 3/43 patients (7%). Conclusions: Early treatment of active Stage 0/1 CNO leads to high rates of remission and limb salvage.

Effectiveness of different advanced wound dressings versus standard of care for the management of diabetic foot ulcers: a meta-analysis of randomized controlled trials for the development of the Italian guidelines for the treatment of diabetic foot syndrome.

AIM: to assess the effects of advanced wound dressings (AWD) commonly used in the treatment of predominantly neuropathic diabetic foot ulcers (DFU) The present meta-analysis was designed to support the development of the Italian Guidelines for the Treatment of Diabetic Foot Syndrome (DFS). METHODS: A Medline and Embase search were performed up to April 1st, 2024 collecting all RCTs including diabetic patients or reporting subgroup analyses on diabetic patients with DFU comparing AWD with placebo/standard of care (SoC), with a duration of at least 12 weeks. Prespecified endpoints were: ulcer healing (principal), time-to-healing, frequency of dressings change, major and minor amputation, pain, and all-cause mortality. AWD assessed were: alginates; foam, hydrocolloids, hydrogels, hyaluronic acid, hemoglobin spray, silver-impregnated, sucrose octasulfate-impregnated, honey-impregnated, micro-organism-binding, and protease-modulating matrix dressings. Mantel-Haenzel Odds ratios and 95% confidence intervals (MH-OR, 95% CIs) were either calculated or extracted directly from the publications. Weighted mean differences (WMD) and 95% CIs were calculated for continuous variables. RESULTS: Fifteen studies fulfilled all inclusion criteria. Participants treated with AWD had a significantly higher ulcer healing rate and shorter time-to-healing in comparison with SoC/placebo (MH-OR 1.50 [0.80, 2.79], p = 0.20 and WMD:: - 24.38 [- 42.90, - 5.86] days, p = 0.010). No other significant effect on the above reported prespecified endpoints were observed. For the primary endpoint, the quality of evidence was rated as "moderate". CONCLUSIONS: In conclusion, AWD, particularly sucrose-octasulfate, hydrogels, hyaluronic acid, and honey dressings, can actively promote wound healing and shortening time-to-healing in patients with DFU.

Bypass surgery versus endovascular revascularization for occlusive infrainguinal peripheral artery disease: a meta-analysis of randomized controlled trials for the development of the Italian Guidelines for the treatment of diabetic foot syndrome.

To report a review and meta-analysis of all randomized controlled trials (RCTs) comparing bypass surgery (BS) and endovascular treatment (ET) in infrainguinal peripheral arterial disease (PAD) for several endpoints, such as major and minor amputation, major adverse limb events (MALEs), ulcer healing, time to healing, and all-cause mortality to support the development of the Italian Guidelines for the Treatment of Diabetic Foot Syndrome (DFS). A MEDLINE and EMBASE search was performed to identify RCTs, published since 1991 up to June 21, 2023, enrolling patients with lower limb ischemia due to atherosclerotic disease (Rutherford I-VI). Any surgical BS or ET was allowed, irrespective of the approach, route, or graft employed, from iliac to below-the-knee district. Primary endpoint was major amputation rate. Secondary endpoints were amputation-free survival major adverse limb events (MALEs), minor amputation rate, all-cause mortality, ulcer healing rate, time to healing, pain, transcutaneous oxygen pressure (TcPO2) or ankle-brachial index (ABI), quality of life, need for a new procedure, periprocedural serious adverse events (SAE; within 30 days from the procedure), hospital lenght of stay, and operative time. Twelve RCTs were included, one enrolled two separate cohorts of patients, and therefore, the studies included in the analyses were 13. Participants treated with ET had a similar rate of major amputations to participants treated with BS (MH-OR 0.85 [0.60, 1.20], p = 0.36); only one trial reported separately data on patients with diabetes (N = 1), showing no significant difference between ET and BS (MH-OR: 0.67 [0.09, 5.13], p = 0.70). For minor amputation, no between-group significant differences were reported: MH-OR for ET vs BS: 0.83 [0.21, 3.30], p = 0.80). No significant difference in amputation-free survival between the two treatment modalities was identified (MH-OR 0.94 [0.59, 1.49], p = 0.80); only one study reported subgroup analyses on diabetes, with a non-statistical trend toward reduction in favor of ET (MH-OR 0.62 [0.37, 1.04], p = 0.07). No significant difference between treatments was found for all-cause mortality (MH-OR for ET vs BS: 0.98 [0.80, 1.21], p = 0.88). A significantly higher rate of MALE was reported in participants treated with ET (MH-OR: 1.44 [1.05, 1.98], p = 0.03); in diabetes subgroup analysis showed no differences between-group for this outcome (MH-OR: 1.34 [0.76, 2.37], p = 0.30). Operative duration and length of hospital stay were significantly shorter for ET (WMD: - 101.53 [- 127.71, - 75.35] min, p < 0.001, and, - 4.15 [- 5.73, - 2.57] days, p < 0.001 =, respectively). ET was associated with a significantly lower risk of any SAE within 30 days in comparison with BS (MH-OR: 0.60 [0.42, 0.86], p = 0.006). ET was associated with a significantly higher risk of reintervention (MH-OR: 1.57 [1.10, 2.24], p = 0.01). No significant between-group differences were reported for ulcer healing (MH-OR: 1.19 [0.53, 2.69], p = 0.67), although time to healing was shorter (- 1.00 [0.18, 1.82] months, p = 0.02) with BS. No differences were found in terms of quality of life and pain. ABI at the end of the study was reported by 7 studies showing a significant superiority of BS in comparison with ET (WMD: 0.09[0.02; 0.15] points, p = 0.01). The results of this meta-analysis showed no clear superiority of either ET or BS for the treatment of infrainguinal PAD also in diabetic patients. Further high-quality studies are needed, focusing on clinical outcomes, including pre-planned subgroup analyses on specific categories of patients, such as those with diabetes and detailing multidisciplinary team approach and structured follow-up.