Osteomyelitis is a devastating disease caused by microbial infection of bone. While the frequency of infection following elective orthopedic surgery is low, rates of reinfection are disturbingly ...high.
is responsible for the majority of chronic osteomyelitis cases and is often considered to be incurable due to bacterial persistence deep within bone. Unfortunately, there is no consensus on clinical classifications of osteomyelitis and the ensuing treatment algorithm. Given the high patient morbidity, mortality, and economic burden caused by osteomyelitis, it is important to elucidate mechanisms of bone infection to inform novel strategies for prevention and curative treatment. Recent discoveries in this field have identified three distinct reservoirs of bacterial biofilm including:
abscess communities in the local soft tissue and bone marrow, glycocalyx formation on implant hardware and necrotic tissue, and colonization of the osteocyte-lacuno canalicular network (OLCN) of cortical bone. In contrast,
intracellular persistence in bone cells has not been substantiated in vivo, which challenges this mode of chronic osteomyelitis. There have also been major advances in our understanding of the immune proteome against
, from clinical studies of serum antibodies and media enriched for newly synthesized antibodies (MENSA), which may provide new opportunities for osteomyelitis diagnosis, prognosis, and vaccine development. Finally, novel therapies such as antimicrobial implant coatings and antibiotic impregnated 3D-printed scaffolds represent promising strategies for preventing and managing this devastating disease. Here, we review these recent advances and highlight translational opportunities towards a cure.
Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of ...protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.
Osteomyelitis is a devastating complication of orthopaedic surgery and commonly caused by Staphylococcus aureus (S. aureus) and Group B Streptococcus (GBS, S. agalactiae). Clinically, S. aureus ...osteomyelitis is associated with local inflammation, abscesses, aggressive osteolysis, and septic implant loosening. In contrast, S. agalactiae orthopaedic infections generally involve soft tissue, with acute life‐threatening vascular spread. While preclinical models that recapitulate the clinical features of S. aureus bone infection have proven useful for research, no animal models of S. agalactiae osteomyelitis exist. Here, we compared the pathology caused by these bacteria in an established murine model of implant‐associated osteomyelitis. In vitro scanning electron microscopy and CFU quantification confirmed similar implant inocula for both pathogens (~105 CFU/pin). Assessment of mice at 14 days post‐infection demonstrated increased S. aureus virulence, as S. agalactiae infected mice had significantly greater body weight, and fewer CFU on the implant and in bone and adjacent soft tissue (p < 0.05). X‐ray, µCT, and histologic analyses showed that S. agalactiae induced significantly less osteolysis and implant loosening, and fewer large TRAP+ osteoclasts than S. aureus without inducing intraosseous abscess formation. Most notably, transmission electron microscopy revealed that although both bacteria are capable of digesting cortical bone, S. agalactiae have a predilection for colonizing blood vessels embedded within cortical bone while S. aureus primarily colonizes the osteocyte lacuno‐canalicular network. This study establishes the first quantitative animal model of S. agalactiae osteomyelitis, and demonstrates a vasculotropic mode of S. agalactiae infection, in contrast to the osteotropic behavior of S. aureus osteomyelitis.
Background:
Conventional bacterial cultures frequently fail to identify the dominant pathogen in polymicrobial foot infections, in which Staphylococcus aureus is the most common infecting pathogen. ...Previous work has shown that species-specific immunoassays may be able to identify the main pathogen in musculoskeletal infections. We sought to investigate the clinical applicability of a S. aureus immunoassay to accurately identify the infecting pathogen and monitor its infectivity longitudinally in foot infection. We hypothesized that this species-specific immunoassay could aid in the diagnosis of S. aureus and track the therapeutic response in foot infections.
Methods:
From July 2015 to July 2019, 83 infected foot ulcer patients undergoing surgical intervention (debridement or amputation) were recruited and blood was drawn at 0, 4, 8, and 12 weeks. Whole blood was analyzed for S. aureus–specific serum antibodies (mix of historic and new antibodies) and plasmablasts were isolated and cultured to quantify titers of newly synthesized antibodies (NSAs). Anti–S. aureus antibody titers were compared with culture results to assess their concordance in identifying S. aureus as the pathogen. The NSA titer changes at follow-ups were compared with wound healing status to evaluate concordance between evolving host immune response and clinically resolving or relapsing infection.
Results:
Analysis of serum for anti–S. aureus antibodies showed significantly increased titers of 3 different anti–S. aureus antibodies, IsdH (P = .037), ClfB (P = .025), and SCIN (P = .005), in S. aureus culture-positive patients compared with culture-negative patients. Comparative analysis of combining antigens for S. aureus infection diagnosis increased the concordance further. During follow-up, changes of NSA titers against a single or combination of S. aureus antigens significantly correlated with clinically resolving or recurring infection represented by wound healing status.
Conclusion:
In the management of foot infection, the use of S. aureus–specific immunoassay may aid in diagnosis of the dominant pathogen and monitoring of the host immune response against a specific pathogen in response to treatment. Importantly, this immunoassay could detect recurrent foot infection, which may guide a surgeon’s decision to intervene.
Level of Evidence:
Level II, prospective comparative study.
•Patient Reported Outcomes Measurement Information System (PROMIS) data reveal diabetic foot ulcer patients’ physical function averaging two standard deviations below the U.S. average.•Our findings ...indicate that surgical interventions do not necessarily improve physical function in diabetic foot ulcer population.•We introduce a predictive model to estimate post-operative physical function.•This proposed equation can aid in patients understanding of expected post-operative physical function and modifiable factors to optimize functional outcome.
Infected diabetic foot ulcer (DFU) patients present with an impaired baseline physical function (PF) that can be further compromised by surgical intervention to treat the infection. The impact of surgical interventions on Patient Reported Outcomes Measurement Information System (PROMIS) PF within the DFU population has not been investigated. We hypothesize that preoperative PROMIS scores (PF, Pain Interference (PI), Depression) in combination with relevant clinical factors can be utilized to predict postoperative PF in DFU patients.
DFU patients from a single academic physician’s practice between February 2015 and November 2018 were identified (n = 240). Ninety-two patients met inclusion criteria with complete follow-up and PROMIS computer adaptive testing records. Demographic and clinical factors, procedure performed, and wound healing status were collected. Spearman's rank correlation coefficient, Chi-Squared tests and multidimensional modelling were applied to all variables’ pre- and postoperative values to assess patients’ postoperative PF.
The mean age was 60.5 (33–96) years and mean follow-up was 4.7 (3−12) months. Over 70 % of the patients’ initial PF were 2–3 standard deviations below the US population (n = 49; 28). Preoperative PF (p < 0.01), PI (p < 0.01), Depression (p < 0.01), CRF (p < 0.02) and amputation level (p < 0.04) showed significant univariate correlation with postoperative PF. Multivariate model (r = 0.55) showed that the initial PF (p = 0.004), amputation level (p = 0.008), and wound healing status (p = 0.001) predicted postoperative PF.
Majority of DFU patients present with poor baseline PF. Preoperative PROMIS scores (PF, PI, Depression) are predictive of postoperative PROMIS PF in DFU patients. Postoperative patient’s physical function can be assessed by PFpostoperative = 29.42 + 0.34 (PFinitial) – 5.87 (Not Healed) – 2.63 (Amputation Category). This algorithm can serve as a valuable tool for predicting post-operative physical function and setting expectations.
Researchers investigated pain perception in patients with diabetic foot ulcers (DFUs) by analyzing pre- and postoperative physical function (PF), pain interference (PI), and depression domains of the ...Patient-Reported Outcome Measurement Information System (PROMIS). They hypothesized that
) because of painful diabetic peripheral neuropathy (DPN), a majority of patients with DFUs would have high PROMIS PI scores unchanged by operative intervention, and
) the initially assessed PI, PF, and depression levels would be correlated with final outcomes. Seventy-five percent of patients with DFUs reported pain, most likely because of painful DPN. Those who reported high PI and low PF were likely to report depression. PF, PI, and depression levels were unchanged after operative intervention or healing of DFUs.
Category:
Diabetes
Introduction/Purpose:
Diabetic foot ulcers (DFU) is a prevalent problem that can lead to devastating results such as limb loss if left untreated. Nevertheless, the prolonged ...treatment course can limit the patient’s overall function and quality of life. Utilization of Patient-Reported Outcomes Measurement Information System (PROMIS) in Orthopaedic practice has previously shown that preoperative PROMIS scores can predict postoperative outcomes in foot and ankle surgeries. However, PROMIS assessment has not been used to determine the impact of surgical treatment for DFU on patients’ physical function. We sought to investigate the impact of preoperative PROMIS scores (Physical Function (PF), Pain Interference (PI), Depression (D)), demographic and laboratory values on postoperative PF in this unique patient population.
Methods:
From an academic orthopaedic surgeon’s practice, we identified infected DFU patients who underwent surgical interventions between February 2015 and November 2018 using ICD-10 code E11.621 (n=240). Patients with at least 3 consecutive visits, 3 month minimum post-surgical follow up and completed PROMIS Computer Adaptive Testing (CAT) assessments for each visit were included (n=92). Demographic data, BMI, medical comorbidities, Hemoglobin A1C, procedure performed, and wound healing status were collected. Amputation level was categorized as the following: 0 = irrigation & debridement (I&D) (n=39), 1 = forefoot amputations (n=46), 2 = mid/hindfoot amputations (n=14), 3 = Syme or above amputations (n=12). Uni- and multivariate analysis were performed to identify factors affecting the post-operative PF within the cohort. Spearman’s rank correlation coefficient, Chi-Squared tests and multidimensional modelling were applied to all variables’ pre-operative and post-operative time points. Based on the results, we formulated a numeric equation to predict post-surgical PROMIS PF.
Results:
The mean age was 60.5 (33-96) and 4.7 (3-12) months follow up. Mean preoperative PF, PI, and D changed from 34.4, 58.7, 51.4 to postoperative 36.1, 58.8, 51.1, respectively (ΔPF = 1.7, ΔPI=0.1, ΔD = -0.3). Preoperative PF (p < 0.01), PI (p < 0.01), depression (p < 0.01), chronic renal failure (p < 0.02) and amputation level (p < 0.04) showed significant univariate correlation with post-operative PF. Multivariate model (r = 0.6) revealed postoperative PF is predicted by initial PF (p = 0.094), depression (p= 0.008), amputation level (p = 0.002), and wound healing status (p = 0.001). The model had greater prediction power than the best univariate association (Δr = +0.17). Follow up length was not significant (p = 0.08).
Conclusion:
This study demonstrates that preoperative PROMIS scores combined with clinical factors can predict postoperative PF in DFU patients. Postoperative PF is predicted by: PFlongest_FU = 45.4 +0.20 PFinitial -0.21 Dinitial -6.1 (Heal =1) -2.9 (Amputation Category, 1-3). Additional diseased states not captured in this study and psychosocial variables may improve prediction power of the multivariate model. 70% of the patients’ initial PF were 1 to 2 standard deviations below the US population (n = 49; 28). Therefore, the reported model may serve as a valuable tool for patient education, setting expectations and post-surgical PF prediction in infected DFU patients.
Category:
Diabetes, Midfoot/Forefoot
Introduction/Purpose:
Most diabetic foot ulcer (DFU) patients have peripheral neuropathy (PN), which presents with numbness, pain and weakness. DFU patient’s ...perceived pain and other clinical factors affecting their pain level have not been reported. Although high prevalence of depression among diabetes patients have been reported, its correlation with perception of pain has not been investigated in patients with ulcers. PROMIS (Patient-Reported Outcomes Measurement Information System) allows accurate quantification of patient’s physical function (PF), pain interference (PI) and Depression. We aimed to investigate 1) if DFU patient’s pre- and postoperative pain level correlate with demographic data/ laboratory values/surgical procedure and 2) if depression level and/or surgical intervention impacts pain.
Methods:
Prospectively collected PROMIS (PF, PI, D) assessments were obtained for patients who underwent surgical intervention for infected DFU between February 2015 and November 2018 (n=240). Patients who had at least 3 consecutive visits with a minimum follow up of 3 months and had completed all assessments for each visit were included (n=92). Demographic data, BMI, medical comorbidities, Hemoglobin A1C (A1C), procedure performed, wound healing status, PN, depression, and amputation level were collected. The mean follow-up duration was 4.7 (3-12) months. T-score distribution of initial PROMIS scores were calculated and compared to the US population. Chi-Square test and Minimum clinically important differences (MCID) were calculated to assess the co-occurrence of different PROMIS domains. We also analyzed other clinical factors and their influences on MCID changes in PROMIS domains.
Results:
The 92 patients were 80.4% male (n=74) and had an average age of 60.5 (33-96) and BMI of 34.1 (22.0-57.5). Irrigation and debridement (n=39), forefoot amputations (n=46), mid/hindfoot amputations (n=14) and Syme or above amputations (n=12) were performed. Mean pre-operative PF, PI, and depression PROMIS scores were 34.4, 58.7, and 51.4, respectively. Average scores at final follow up increased 1.7, decreased 0.1, and increased 0.2, respectively. Depression and PI were the most strongly associated co-occurrences (p=0.03) pre-operatively and remained significant (p<0.01) with respect to post-operative MCID. PF and PI also strongly co-occurred pre-operatively (p=0.04) and with post-operative MCID assessment (p=0.02). PF was affected by initial A1C (p=0.03) and wound healing status (p=0.03). PN was the only clinical factor found to affect PI (p=0.03).
Conclusion:
DFU patients with PN experience a significant amount of pain. Contrary to previous studies, we did not find a higher prevalence of depression in our DFU cohort compared to the average United States population. The study results do not indicate the origin of pain, which can be further investigated using other measures, such as PROMIS Neuropathic Pain Quality Scale. Surgical intervention did not significantly relieve pain in DFU patients. These findings may be referenced for pre-operative patient education and setting expectation for surgery.
Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, ...few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). To assess the clinical utility of GS, we compared its diagnostic yield against these three tests in 1,612 quartet families including an individual with ASD and in 295 prenatal families. Our GS analytic framework identified a diagnostic variant in 7.8% of ASD probands, almost 2-fold more than CMA (4.3%) and 3-fold more than ES (2.7%). However, when we systematically captured copy-number variants (CNVs) from the exome data, the diagnostic yield of ES (7.4%) was brought much closer to, but did not surpass, GS. Similarly, we estimated that GS could achieve an overall diagnostic yield of 46.1% in unselected FSAs, representing a 17.2% increased yield over karyotype, 14.1% over CMA, and 4.1% over ES with CNV calling or 36.1% increase without CNV discovery. Overall, GS provided an added diagnostic yield of 0.4% and 0.8% beyond the combination of all three standard-of-care tests in ASD and FSAs, respectively. This corresponded to nine GS unique diagnostic variants, including sequence variants in exons not captured by ES, structural variants (SVs) inaccessible to existing standard-of-care tests, and SVs where the resolution of GS changed variant classification. Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs.
We evaluated genome sequencing (GS) as a single test to displace the sequential application of karyotype, chromosomal microarray, and exome sequencing, three standard-of-care tests used for the assessment of autism and fetal structural anomalies. Our data suggest GS warrants consideration as a first-tier diagnostic approach for these two phenotypes.
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