Diagnosis of infection in the foot of patients with diabetes: A systematic review.

BACKGROUND: Securing an early accurate diagnosis of diabetic foot infections and assessment of their severity are of paramount importance since these infections can cause great morbidity and potential mortality and present formidable challenges in surgical and antimicrobial treatment. METHODS: In June 2022, we searched the literature using PubMed and EMBASE for published studies on the diagnosis of diabetic foot infection (DFI). On the basis of pre-determined criteria, we reviewed prospective controlled, as well as non-controlled, studies in English. We then developed evidence statements based on the included papers. RESULTS: We selected a total of 64 papers that met our inclusion criteria. The certainty of the majority of the evidence statements was low because of the weak methodology of nearly all of the studies. The available data suggest that diagnosing diabetic foot infections on the basis of clinical signs and symptoms and classified according to the International Working Group of the Diabetic Foot/Infectious Diseases Society of America scheme correlates with the patient's likelihood of the need for hospitalisation, lower extremity amputation, and risk of death. Elevated levels of selected serum inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive protein and procalcitonin are supportive, but not diagnostic, of soft tissue infection. Culturing tissue samples of soft tissues or bone, when care is taken to avoid contamination, provides more accurate microbiological information than culturing superficial (swab) samples. Although non-culture techniques, especially next-generation sequencing, are likely to identify more bacteria from tissue samples including bone than standard cultures, no studies have established a significant impact on the management of patients with DFIs. In patients with suspected diabetic foot osteomyelitis, the combination of a positive probe-to-bone test and elevated ESR supports this diagnosis. Plain X-ray remains the first-line imaging examination when there is suspicion of diabetic foot osteomyelitis (DFO), but advanced imaging methods including magnetic resonance imaging (MRI) and nuclear imaging when MRI is not feasible help in cases when either the diagnosis or the localisation of infection is uncertain. Intra-operative or non-per-wound percutaneous biopsy is the best method to accurately identify bone pathogens in case of a suspicion of a DFO. Bedside percutaneous biopsies are effective and safe and are an option to obtain bone culture data when conventional (i.e. surgical or radiological) procedures are not feasible. CONCLUSIONS: The results of this systematic review of the diagnosis of diabetic foot infections provide some guidance for clinicians, but there is still a need for more prospective controlled studies of high quality.

IWGDF/IDSA guidelines on the diagnosis and treatment of diabetes-related foot infections (IWGDF/IDSA 2023).

The International Working Group on the Diabetic Foot (IWGDF) has published evidence-based guidelines on the management and prevention of diabetes-related foot diseases since 1999. The present guideline is an update of the 2019 IWGDF guideline on the diagnosis and management of foot infections in persons with diabetes mellitus. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used for the development of this guideline. This was structured around identifying clinically relevant questions in the P(A)ICO format, determining patient-important outcomes, systematically reviewing the evidence, assessing the certainty of the evidence, and finally moving from evidence to the recommendation. This guideline was developed for healthcare professionals involved in diabetes-related foot care to inform clinical care around patient-important outcomes. Two systematic reviews from 2019 were updated to inform this guideline, and a total of 149 studies (62 new) meeting inclusion criteria were identified from the updated search and incorporated in this guideline. Updated recommendations are derived from these systematic reviews, and best practice statements made where evidence was not available. Evidence was weighed in light of benefits and harms to arrive at a recommendation. The certainty of the evidence for some recommendations was modified in this update with a more refined application of the GRADE framework centred around patient important outcomes. This is highlighted in the rationale section of this update. A note is also made where the newly identified evidence did not alter the strength or certainty of evidence for previous recommendations. The recommendations presented here continue to cover various aspects of diagnosing soft tissue and bone infections, including the classification scheme for diagnosing infection and its severity. Guidance on how to collect microbiological samples, and how to process them to identify causative pathogens, is also outlined. Finally, we present the approach to treating foot infections in persons with diabetes, including selecting appropriate empiric and definitive antimicrobial therapy for soft tissue and bone infections; when and how to approach surgical treatment; and which adjunctive treatments may or may not affect the infectious outcomes of diabetes-related foot problems. We believe that following these recommendations will help healthcare professionals provide better care for persons with diabetes and foot infections, prevent the number of foot and limb amputations, and reduce the patient and healthcare burden of diabetes-related foot disease.

Interventions in the management of diabetes-related foot infections: A systematic review.

The optimal approaches to managing diabetic foot infections remain a challenge for clinicians. Despite an exponential rise in publications investigating different treatment strategies, the various agents studied generally produce comparable results, and high-quality data are scarce. In this systematic review, we searched the medical literature using the PubMed and Embase databases for published studies on the treatment of diabetic foot infections from 30 June 2018 to 30 June 2022. We combined this search with our previous literature search of a systematic review performed in 2020, in which the infection committee of the International Working Group on the Diabetic Foot searched the literature until June 2018. We defined the context of the literature by formulating clinical questions of interest, then developing structured clinical questions (Patients-Intervention-Control-Outcomes) to address these. We only included data from controlled studies of an intervention to prevent or cure a diabetic foot infection. Two independent reviewers selected articles for inclusion and then assessed their relevant outcomes and methodological quality. Our literature search identified a total of 5,418 articles, of which we selected 32 for full-text review. Overall, the newly available studies we identified since 2018 do not significantly modify the body of the 2020 statements for the interventions in the management of diabetes-related foot infections. The recent data confirm that outcomes in patients treated with the different antibiotic regimens for both skin and soft tissue infection and osteomyelitis of the diabetes-related foot are broadly equivalent across studies, with a few exceptions (tigecycline not non-inferior to ertapenem [±vancomycin]). The newly available data suggest that antibiotic therapy following surgical debridement for moderate or severe infections could be reduced to 10 days and to 3 weeks for osteomyelitis following surgical debridement of bone. Similar outcomes were reported in studies comparing primarily surgical and predominantly antibiotic treatment strategies in selected patients with diabetic foot osteomyelitis. There is insufficient high-quality evidence to assess the effect of various recent adjunctive therapies, such as cold plasma for infected foot ulcers and bioactive glass for osteomyelitis. Our updated systematic review confirms a trend to a better quality of the most recent trials and the need for further well-designed trials to produce higher quality evidence to underpin our recommendations.

MRSA infection, re-infection and clinical outcomes in diabetic foot infections.

The aim was to investigate methicillin-resistant Staphylococcus aureus (MRSA) incidence, conversion and outcomes in diabetic foot infections (DFIs). This is a pooled patient-level analysis of combined data sets from two randomised clinical trials including 219 patients admitted to the hospital with moderate or severe DFIs. Intraoperative bone and tissue cultures identified bacterial pathogens. We identified pathogens at index infections and subsequent re-infections. We identified MRSA conversion (MSSA to MRSA) in re-infections. MRSA incidence in index infections was 10.5%, with no difference between soft tissue infections (STIs) and osteomyelitis (OM). MRSA conversion occurred in 7.7% of the re-infections in patients who initially had MSSA in their cultures. Patients with re-infection were 2.2 times more likely to have MRSA compared to the first infection (10.5% vs. 25.8%, relative risk [RR] = 2.2, p = 0.001). Patients with MRSA had longer antibiotic treatment during the 1-year follow-up, compared to other pathogens (other 49.8 ± 34.7 days, MRSA 65.3 ± 41.5 days, p = 0.04). Furthermore, there were no differences in healing, time to heal, length of stay, re-infection, amputation, re-ulceration, re-admission, surgery after discharge and amputation after discharge compared to other pathogens. The incidence of MRSA at the index was 10.5% with no difference in STI and OM. MRSA incidence was 25.8% in re-infections. The RR of having MRSA was 2.2 times higher in re-infections. Patients with MRSA used more antibiotics during the 1-year follow-up. Furthermore, there were no differences in clinical outcomes compared to other bacterial pathogens.

The infected diabetic foot: Analysis of diabetic and non-diabetic foot infections.

The aim of this study was to compare outcomes of moderate and severe foot infections in people with and without diabetes mellitus (DM). We retrospectively evaluated 382 patients (77% with DM and 23% non-DM). We collected demographic data, co-morbidities and one-year outcomes including healing, surgical interventions, number of surgeries, length of stay, re-infection and re-hospitalisation. DM patients required more surgeries (2.3 ± 2.2 vs. 1.7 ± 1.3, p = 0.01), but did not have a longer hospital length of stay during the index hospitalisation (DM 10.9 days ±9.2 vs. non-DM = 8.8 days ±5.8, p = 0.43). After the index hospitalisation, DM patients had increased rates of re-hospitalisation for any reason (63.3% vs. 35.2%, CI 1.9-5.2, OR 3.2, p < 0.01), re-infection at the index wound infection site (48% vs. 30.7%, CI 1.3-3.5, OR 2.1, p < 0.01), re-hospitalisation for a foot pathology (47.3% vs. 29.5%, CI 1.3-3.6, OR 2.1, p < 0.01), and longer times to ulcer healing (151.8 days ±108.8 vs. 108.8 ± 90.6 days, p = 0.04). Patients with DM admitted to hospital with foot infections have worse clinical outcomes during the index hospitalisation and are more likely to have re-infection and re-admission to hospital in the next year.

Rationale and design of the RAPID-WATER-FLOW trial: Radiolabeled perfusion to identify coronary artery disease using water to evaluate responses of myocardial FLOW.

OBJECTIVES: The objective of this study was to determine the diagnostic performance of 15O-water positron emission tomography (PET) myocardial perfusion imaging to detect coronary artery disease (CAD) using the truth-standard of invasive coronary angiography (ICA) with fractional flow reserve (FFR) or instantaneous wave-Free Ratio (iFR) or coronary computed tomography angiogram (CCTA). BACKGROUND: 15O-water has a very high first-pass extraction that allows accurate quantification of myocardial blood flow and detection of flow-limiting CAD. However, the need for an on-site cyclotron and lack of automated production at the point of care and relatively complex image analysis protocol has limited its clinical use to date. METHODS: The RAPID WATER FLOW study is an open-label, multicenter, prospective investigation of the accuracy of 15O-water PET to detect obstructive angiographic and physiologically significant stenosis in patients with suspected CAD. The study will include the use of an automated system for producing, dosing, and injecting 15O-water and enrolling approximately 215 individuals with suspected CAD at approximately 10 study sites in North America and Europe. The primary endpoint of the study is the diagnostic sensitivity and specificity of the 15O-water PET study using the truth-standard of ICA with FFR or iFR to determine flow-limiting stenosis, or CCTA to rule out CAD and incorporating a quantitative analytic platform developed for the 15O-water PET acquisitions. Sensitivity and specificity are to be considered positive if the lower bound of the 95% confidence interval is superior to the threshold of 60% for both, consistent with prior registration studies. Subgroup analyses include assessments of diagnostic sensitivity, specificity, and accuracy in female, obese, and diabetic individuals, as well as in those with multivessel disease. All enrolled individuals will be followed for adverse and serious adverse events for up to 32 hours after the index PET scan. The study will have >90% power (one-sided test, α = 0.025) to test the hypothesis that sensitivity and specificity of 15O-water PET are both >60%. CONCLUSIONS: The RAPID WATER FLOW study is a prospective, multicenter study to determine the diagnostic sensitivity and specificity of 15O-water PET as compared to ICA with FFR/iFR or CCTA. This study will introduce several novel aspects to imaging registration studies, including a more relevant truth standard incorporating invasive physiologic indexes, coronary CTA to qualify normal individuals for eligibility, and a more quantitative approach to image analysis than has been done in prior pivotal studies. CLINICAL TRIAL REGISTRATION INFORMATION: Clinical-Trials.gov (#NCT05134012).

The infected diabetic foot: Modulation of traditional biomarkers for osteomyelitis diagnosis in the setting of diabetic foot infection and renal impairment.

The objective of this paper was to investigate erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP) in diagnosing pedal osteomyelitis (OM) in patients with and without diabetes, and with and without severe renal impairment (SRI). This was a retrospective cohort study of patients with moderate and severe foot infections. We evaluated three groups: Subjects without diabetes (NDM), subjects with diabetes and without severe renal insufficiency (DM-NSRI), and patients with diabetes and SRI (DM-SRI). SRI was defined as eGFR <30. We evaluated area under the curve (AUC), cutoff point, sensitivity and specificity to characterize the accuracy of ESR and CRP to diagnose OM. A total of 408 patients were included in the analysis. ROC analysis in the NDM group revealed the AUC for ESR was 0.62, with a cutoff value of 46 mm/h (sensitivity, 49.0%; specificity, 76.0%). DM-NSRI subjects showed the AUC for ESR was 0.70 with the cutoff value of 61 mm/h (sensitivity, 68.9%; specificity 61.8%). In DM-SRI, the AUC for ESR was 0.67, with a cutoff value of 119 mm/h (sensitivity, 46.4%; specificity, 82.40%). In the NDM group, the AUC for CRP was 0.55, with a cutoff value of 6.4 mg/dL (sensitivity, 31.3%; specificity, 84.0%). For DM-NSRI, the AUC for CRP was 0.70, with a cutoff value of 8 mg/dL (sensitivity, 49.2%; specificity, 80.6%). In DM-SRI, the AUC for CRP was 0.62, with a cutoff value of 7 mg/dL (sensitivity, 57.1%; specificity, 67.7%). While CRP demonstrated relatively consistent utility, ESR's diagnostic cutoff points diverged significantly. These results highlight the necessity of considering patient-specific factors when interpreting ESR results in the context of OM diagnosis.

IWGDF/IDSA Guidelines on the Diagnosis and Treatment of Diabetes-related Foot Infections (IWGDF/IDSA 2023).

The International Working Group on the Diabetic Foot (IWGDF) has published evidence-based guidelines on the management and prevention of diabetes-related foot diseases since 1999. The present guideline is an update of the 2019 IWGDF guideline on the diagnosis and management of foot infections in persons with diabetes mellitus. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was used for the development of this guideline. This was structured around identifying clinically relevant questions in the P(A)ICO format, determining patient-important outcomes, systematically reviewing the evidence, assessing the certainty of the evidence, and finally moving from evidence to the recommendation. This guideline was developed for healthcare professionals involved in diabetes-related foot care to inform clinical care around patient-important outcomes. Two systematic reviews from 2019 were updated to inform this guideline, and a total of 149 studies (62 new) meeting inclusion criteria were identified from the updated search and incorporated in this guideline. Updated recommendations are derived from these systematic reviews, and best practice statements made where evidence was not available. Evidence was weighed in light of benefits and harms to arrive at a recommendation. The certainty of the evidence for some recommendations was modified in this update with a more refined application of the GRADE framework centred around patient important outcomes. This is highlighted in the rationale section of this update. A note is also made where the newly identified evidence did not alter the strength or certainty of evidence for previous recommendations. The recommendations presented here continue to cover various aspects of diagnosing soft tissue and bone infections, including the classification scheme for diagnosing infection and its severity. Guidance on how to collect microbiological samples, and how to process them to identify causative pathogens, is also outlined. Finally, we present the approach to treating foot infections in persons with diabetes, including selecting appropriate empiric and definitive antimicrobial therapy for soft tissue and bone infections; when and how to approach surgical treatment; and which adjunctive treatments may or may not affect the infectious outcomes of diabetes-related foot problems. We believe that following these recommendations will help healthcare professionals provide better care for persons with diabetes and foot infections, prevent the number of foot and limb amputations, and reduce the patient and healthcare burden of diabetes-related foot disease.

Hypoxia induces heart regeneration in adult mice.

The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the lasting and severe effects of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium, and the adult heart is capable of modest self-renewal. In both of these scenarios, cardiomyocyte renewal occurs via the proliferation of pre-existing cardiomyocytes, and is regulated by aerobic-respiration-mediated oxidative DNA damage. Therefore, we reasoned that inhibiting aerobic respiration by inducing systemic hypoxaemia would alleviate oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals. Here we report that, in mice, gradual exposure to severe systemic hypoxaemia, in which inspired oxygen is gradually decreased by 1% and maintained at 7% for 2 weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Notably, we find that exposure to hypoxaemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Genetic fate-mapping analysis confirms that the newly formed myocardium is derived from pre-existing cardiomyocytes. These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxaemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.

Comparison of BMIPP-SPECT/CT to 18FDG-PET/CT for Imaging Brown or Browning Fat in a Preclinical Model.

Obesity is a leading cause of preventable death and morbidity. To elucidate the mechanisms connecting metabolically active brown adipose tissue (BAT) and metabolic health may provide insights into methods of treatment for obesity-related conditions. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) is traditionally used to image human BAT activity. However, the primary energy source of BAT is derived from intracellular fatty acids and not glucose. Beta-methyl-p-iodophenylpentadecanoic acid (BMIPP) is a fatty acid analogue amenable to in vivo imaging by single photon emission computed tomography/CT (SPECT/CT) when radiolabeled with iodine isotopes. In this study, we compare the use of 18FDG-PET/CT and 125I-BMIPP-SPECT/CT for fat imaging to ascertain whether BMIPP is a more robust candidate for the non-invasive evaluation of metabolically active adipose depots. Interscapular BAT, inguinal white adipose tissue (iWAT), and gonadal white adipose tissue (gWAT) uptake of 18FDG and 125I-BMIPP was quantified in mice following treatment with the BAT-stimulating drug CL-316,243 or saline vehicle control. After CL-316,243 treatment, uptake of both radiotracers increased in BAT and iWAT. The standard uptake value (SUVmean) for 18FDG and 125I-BMIPP significantly correlated in these depots, although uptake of 125I-BMIPP in BAT and iWAT more closely mimicked the fold-change in metabolic rate as measured by an extracellular flux analyzer. Herein, we find that imaging BAT with the radioiodinated fatty acid analogue BMIPP yields more physiologically relevant data than 18FDG-PET/CT, and its conventional use may be a pivotal tool for evaluating BAT in both mice and humans.

Pathophysiology and Molecular Imaging of Diabetic Foot Infections.

Diabetic foot infection is the leading cause of non-traumatic lower limb amputations worldwide. In addition, diabetes mellitus and sequela of the disease are increasing in prevalence. In 2017, 9.4% of Americans were diagnosed with diabetes mellitus (DM). The growing pervasiveness and financial implications of diabetic foot infection (DFI) indicate an acute need for improved clinical assessment and treatment. Complex pathophysiology and suboptimal specificity of current non-invasive imaging modalities have made diagnosis and treatment response challenging. Current anatomical and molecular clinical imaging strategies have mainly targeted the host's immune responses rather than the unique metabolism of the invading microorganism. Advances in imaging have the potential to reduce the impact of these problems and improve the assessment of DFI, particularly in distinguishing infection of soft tissue alone from osteomyelitis (OM). This review presents a summary of the known pathophysiology of DFI, the molecular basis of current and emerging diagnostic imaging techniques, and the mechanistic links of these imaging techniques to the pathophysiology of diabetic foot infections.

The Infected Diabetic Foot: Re-evaluating the Infectious Diseases Society of America Diabetic Foot Infection Classification.

BACKGROUND: We provide evidence to revise the Infectious Diseases Society of America (IDSA) diabetic foot infection classification by adding a separate tier for osteomyelitis and evaluating if moderate and severe infection criteria improve the classification's ability to direct therapy and determine outcomes. METHODS: We retrospectively evaluated 294 patients with moderate and severe infections. Osteomyelitis was confirmed by bone culture or histopathology. Soft tissue infection (STI) was based on negative bone culture, magnetic resonance imaging, or single-photon emission computed tomography. We stratified STI and osteomyelitis using IDSA criteria for moderate and severe infections and compared outcomes and complications. RESULTS: Osteomyelitis patients had greater antibiotic duration (32.5 ± 46.8 vs 63.8 ± 55.1 days; P < .01), surgery frequency (55.5% vs 99.4%; P < .01), number of surgeries (2.1 ± 1.3 vs 3.3 ± 2.3; P < .01), amputations (26.3% vs 83.4%; P < .01), reinfection (38.0% vs 56.7%; P < .01), and length of stay (14.5 ± 14.9 vs 22.6 ± 19.0 days; P < .01). There were no differences in moderate and severe STI outcomes except for infection readmissions (46.2% vs 25.0%; P = .02), and acute kidney injury (31.2% vs 50.0%; P = .03). There were no differences in moderate and severe osteomyelitis except the number of surgeries (2.8 ± 2.1 vs 4.1 ± 2.5; P < .01) and length of stay (18.6 ± 17.5 vs 28.2 ± 17.7; P < .01). CONCLUSIONS: The IDSA classification better reflects outcomes if risk categories are stratified by STI or osteomyelitis and moderate and severe infections are not categorized separately.

Randomized clinical study to compare negative pressure wound therapy with simultaneous saline irrigation and traditional negative pressure wound therapy for complex foot infections.

The aim of this study was to compare the efficacy of different negative pressure wound therapy (NPWT) devices and NPWT with and without simultaneous irrigation in patients admitted to hospital with moderate and severe foot infections. Ninety patients were randomized in a 12-week prospective, randomized noninferiority trial to compare wound healing in patients with moderate and severe infected foot wounds treated with NPWT after surgery. Inclusion criteria included ABI > 0.5 or toe pressures >30 PVR/mmHg, >18 years of age and exclusion included active Charcot arthropathy, collagen vascular disease, HIV, and hypercoagulable state. We compared two different traditional devices, NPWT-K (KCI, VAC Ulta) and NPWT-C (Cardinal, PRO), and NPWT-I with saline irrigation (Cardinal, PRO). All patients had therapy delivered at 125 mmHg continuous pressure. In patients who received simultaneous saline irrigation (NPWT-I), the administration rate was 15 ml per hour. The primary outcome was the proportion of healed wounds in 12 weeks. Secondary outcomes included surgical wound closure, number of surgeries, length of stay, and time to wound healing. Continuous data was presented as mean ± standard deviation. Analysis of variance was used to compare continuous variables and chi-square to compare dichotomous variables with an alpha of 0.05. There were no differences in outcomes among NPWT-I, NPWT-C, and NPWT-K groups in proportion of healed wounds (63.3%, 50.0%, 46.7% p = 0.39), surgical wound closure (83.3%, 80.0%, 63.3%, p = 0.15), number of surgeries (2.0 ± 0.49, 2.4 ± 0.77, 2.4 ± 0.68, p = 0.06), length of stay (16.3 ± 15.7, 14.7 ± 7.4, 15.3 ± 10.5 days, p = 0.87), time to wound healing (46.2 ± 22.8, 40.9 ± 18.8, 45.9 ± 28.3 days, p = 0.78). We did not identify any significant differences in clinical outcomes or adverse events between patients treated with different NPWT devices or NPWT with and without irrigation.

Clinical Outcomes of Foot Infections in Patients Without Diabetes.

The aim of this study was to report clinical outcomes of moderate and severe foot infections in patients without diabetes. Medical records of 88 nondiabetic patients with foot infections treated at a safety net hospital were retrospectively reviewed. Patients were grouped by the presence of soft-tissue infection (STI) or osteomyelitis (OM). The diagnosis of OM was determined by positive bone culture or histopathology. STIs were defined by negative bone biopsy or negative imaging with magnetic resonance imaging or computed tomography/dual-modality radiolabeled white blood cell single-photon emission computed tomography. Patient outcomes were recorded ≤1 year after admission. Eighty-eight nondiabetic patients admitted to our institution for moderate or severe foot infections were included, 45 OM and 43 STI. No differences were noted in patient characteristics except that OM patients had a higher prevalence of neuropathy (66.7% versus 39.5%, p = .02). OM patients required surgery more often (97.8% versus 67.4%, p < .01), a greater number of surgeries (2.0 ± 1.2 versus 1.4 ± 1.3, p = .02), and more amputations (75.6% versus 11.6%, p < .01) than STI patients. OM patients had a higher proportion of wounds that healed (82.2% versus 62.8%, p = .04). There were no significant differences in reinfection (35.6% versus 25.6%, p = .36), foot-related readmission to hospital (35.6% versus 23.3%, p = .25), or total duration of antibiotics (13.9 ± 10.2 versus 13.5 ± 12.9, p = .87) between OM and STI patients. In conclusion, OM patients required more surgeries and amputations than patients with STIs; however, they had similar rates of reinfection and readmission within a year after the index hospitalization.

Translation of Quantitative Imaging Biomarkers into Clinical Chest CT.

Quantitative imaging has been proposed as the next frontier in radiology as part of an effort to improve patient care through precision medicine. In 2007, the Radiological Society of North America launched the Quantitative Imaging Biomarkers Alliance (QIBA), an initiative aimed at improving the value and practicality of quantitative imaging biomarkers by reducing variability across devices, sites, patients, and time. Chest CT occupies a strategic position in this initiative because it is one of the most frequently used imaging modalities, anatomically encompassing the leading causes of mortality worldwide. To date, QIBA has worked on profiles focused on the accurate, reproducible, and meaningful use of volumetric measurements of lung lesions in chest CT. However, other quantitative methods are on the verge of translation from research grounds into clinical practice, including (a) assessment of parenchymal and airway changes in patients with chronic obstructive pulmonary disease, (b) analysis of perfusion with dual-energy CT biomarkers, and (c) opportunistic screening for coronary atherosclerosis and low bone mass by using chest CT examinations performed for other indications. The rationale for and the key facts related to the application of these quantitative imaging biomarkers in cardiothoracic chest CT are presented. ©RSNA, 2019 See discussion on this article by Buckler (pp 977-980).

What are the Optimal Cutoff Values for ESR and CRP to Diagnose Osteomyelitis in Patients with Diabetes-related Foot Infections?

BACKGROUND: Distinguishing osteomyelitis from soft-tissue infection of the foot is important because osteomyelitis is associated with more operations, amputation, and prolonged antibiotic exposure. Both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are routinely ordered inflammatory biomarkers for evaluating foot infection. When initial evaluation is inconclusive, advanced imaging is indicated, and high clinical or radiographic suspicion of osteomyelitis may indicate bone biopsy to identify organisms and antibiotic sensitivity. Although ESR and CRP levels are helpful for distinguishing osteomyelitis from soft-tissue infections in patients with diabetes-related foot infections, parameters regarding optimal cutoff values for those tests have not, to our knowledge, been defined. QUESTIONS/PURPOSES: (1) What are the optimal cutoff values for ESR and CRP to differentiate osteomyelitis from soft-tissue infection in patients with diabetes-related foot infection? (2) Can a diagnostic algorithm be derived to guide interpretation of ESR and CRP to improve recognition of osteomyelitis in the setting of diabetic foot infection? METHODS: The medical records of 1842 patients between 18 and 89 years of age treated at our institution between January 1, 2010 and February 6, 2017 for foot infection were reviewed. For inclusion, patients must have had a diagnosis of diabetes mellitus, moderate or severe infection, ESR and CRP values within 72 hours of admission, either advanced imaging (MRI or single-positron emission computed tomography/computed tomography [SPECT/CT]) or bone biopsy during admission and must not have had comorbidities that could affect ESR and CRP, such as autoimmune disorders. As such, 1489 patients were excluded, and 353 patients were included in the study. Osteomyelitis was diagnosed by positive bone culture or histopathology. Osteomyelitis was considered to be absent if there was a negative MRI or SPECT/CT result, or negative bone culture and histology findings if imaging was inconclusive. We identified 176 patients with osteomyelitis and 177 with soft-tissue infection. A blinded investigator performed the statistics. Optimal cutoffs of ESR and CRP were determined using receiver operative characteristic (ROC) analysis. A diagnostic algorithm was determined using epidemiologic principles of screening evaluations. RESULTS: An ESR of 60 mm/h and a CRP level of 7.9 mg/dL were determined to be the optimal cutoff points for predicting osteomyelitis based on results of the ROC analysis. The ESR threshold of 60 mm/h demonstrated a sensitivity of 74% (95% confidence interval [CI], 67-80) and specificity of 56% (95% CI, 48-63) for osteomyelitis, whereas the CRP threshold of 7.9 mg/dL had a sensitivity of 49% (95% CI, 41-57) and specificity of 80% (95% CI, 74-86). If the ESR is < 30 mm/h, the likelihood of osteomyelitis is low. However, if ESR is > 60 mm/h and CRP level is > 7.9 mg/dL, the likelihood of osteomyelitis is high, and treatment of suspected osteomyelitis should be strongly considered. CONCLUSIONS: While ESR is better for ruling out osteomyelitis initially, CRP helps distinguish osteomyelitis from soft-tissue infection in patients with high ESR values. Further prospective studies addressing the prognostic value of ESR and CRP are needed, and a more comprehensive diagnostic algorithm should be developed to include other diagnostic tests such as probe-to-bone and imaging. LEVEL OF EVIDENCE: Level III, diagnostic study.

Imaging Metabolically Active Fat: A Literature Review and Mechanistic Insights.

Currently, obesity is one of the leading causes death in the world. Shortly before 2000, researchers began describing metabolically active adipose tissue on cancer-surveillance 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in adult humans. This tissue generates heat through mitochondrial uncoupling and functions similar to classical brown and beige adipose tissue in mice. Despite extensive research, human brown/beige fat's role in resistance to obesity in humans has not yet been fully delineated. FDG uptake is the de facto gold standard imaging technique when studying brown adipose tissue, although it has not been rigorously compared to other techniques. We, therefore, present a concise review of established and emerging methods to image brown adipose tissue activity in humans. Reviewed modalities include anatomic imaging with CT and magnetic resonance imaging (MRI); molecular imaging with FDG, fatty acids, and acetate; and emerging techniques. FDG-PET/CT is the most commonly used modality because of its widespread use in cancer imaging, but there are mechanistic reasons to believe other radiotracers may be more sensitive and accurate at detecting brown adipose tissue activity. Radiation-free modalities may help the longitudinal study of brown adipose tissue activity in the future.

Do SIRS Criteria Predict Clinical Outcomes in Diabetic Skin and Soft Tissue Infections?

The aim of this study was to assess whether systemic inflammatory response syndrome (SIRS) is correlated with outcomes in diabetic foot infections (DFIs). We retrospectively reviewed 137 diabetic patients admitted to the hospital with Infectious Diseases Society of America moderate and severe DFIs. We used SIRS criteria to define severe infection based on the presence of at least 2 of the following: heart rate >90 bpm, temperature >38°C or <36°C, respiratory rate >20 breaths per minute, and white blood cell count >12,000/mm3 or <4,000/mm3. Patients with severe DFI were significantly younger (median 49.6 versus 53.6 years, p = .04), less often had type 2 diabetes (88.6% versus 98.9%, p = .01), and less often had a history of previous amputation (15.9% versus 40.9%, p < .01). There were no differences in patients with severe infections defined by SIRS versus moderate infections in the need for surgery (47.7% versus 59.1%, p = .27), any amputation (20.5% versus 29.0%, p = .29), leg amputations (6.8% versus 7.5%, p = .88), duration of antibiotics (median ± standard deviation 34.1 ± 46.5 versus 31.9 ± 47.2 days, p = .47), or healing within 1 year (68.2% versus 66.7%, p = 1.00). Length of hospital stay was the only outcome variable that was significantly different in severe infections (median 12.7 ± 11.9 versus 7.8 ± 5.8 days, p = .02). Foot-related readmission was more common in moderate infections (46.2% versus 25.0%, p = .02). In conclusion, SIRS criteria for severe infections in diabetic patients with skin and soft tissue infections were not associated with a difference in outcomes other than longer hospital stay.

Erbium: Yttrium Aluminum Garnet Laser Accelerates Healing in Indolent Diabetic Foot Ulcers.

The objective of the study was to evaluate the effect of the erbium:yttrium aluminum garnet (YAG) laser on diabetic foot ulcers (DFUs) that had not responded to standard care. We retrospectively evaluated 22 nonhealing DFUs that received at least 4 weeks of standard wound care, demonstrated poor healing response, and subsequently were treated with an erbium:YAG laser. We measured the percent wound area reduction (PWAR) for the 4 weeks before initiating laser therapy and the PWAR for 4 weeks after the initiation of laser therapy. Erbium:YAG laser treatment consisted of 2 components: debridement and resurfacing. The laser settings were the same for all treatments. We used the paired t test to compare pretreatment with posttreatment wound area reduction. During the 4-week period before the initiation of laser therapy, the average PWAR was -33.6%. Four weeks after initiating treatment with the erbium:YAG laser, the average PWAR was 63.4% (p = .002) and 72.7% of wounds had ≥50% PWAR. By 12 weeks, 50% of wounds had healed. Erbium:YAG laser therapy accelerated DFU healing in a cohort of patients with ulcers that had been unresponsive to standard of care therapy.

Are We Misdiagnosing Diabetic Foot Osteomyelitis? Is the Gold Standard Gold?

To compare the incidence of osteomyelitis based on different operational definitions using the gold standard of bone biopsy, we prospectively enrolled 35 consecutive patients who met the criteria of ≥21 years of age and a moderate or severe infection based on the Infectious Diseases Society of America classification. Bone samples were obtained from all patients by percutaneous bone biopsy or intraoperative culture if the patient required surgery. Bone samples were analyzed for conventional culture, histology, and 16S ribosomal RNA genetic sequencing. We evaluated 5 definitions for osteomyelitis: 1) traditional culture, 2) histology, 3) genetic sequencing, 4) traditional culture and histology, and 5) genetic sequencing and histology. There was variability in the incidence of osteomyelitis based on the diagnostic criteria. Traditional cultures identified more cases of osteomyelitis than histology (68.6% versus 45.7%, p = .06, odds ratio [OR] 2.59, 95% confidence interval [CI] 0.98 to 6.87), but the difference was not significant. In every case that histology reported osteomyelitis, bone culture was positive using traditional culture or genetic sequencing. The 16S ribosomal RNA testing identified significantly more cases of osteomyelitis compared with histology (82.9% versus 45.7%, p = .002, OR 5.74, 95% CI 1.91 to 17.28) and compared with traditional cultures but not significantly (82.9% versus 68.6%, p = .17, OR 2.22, 95% CI 0.71 to 6.87). When both histology and traditional culture (68.6%) or histology and genetic sequencing cultures (82.9%) were used to define osteomyelitis, the incidence of osteomyelitis did not change. There is variability in the incidence of osteomyelitis based on how the gold standard of bone biopsy is defined in diabetic foot infections.