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.
Background
Skeletal muscle wasting (SMW) in cancer patients is associated with increased morbidity, mortality, treatment intolerance and discontinuation, and poor quality of life. This is ...particularly true for patients with pancreatic ductal adenocarcinoma (PDAC), as over 85% experience SMW, which is responsible for ~30% of patient deaths. While the established paradigm to explain SMW posits that muscle catabolism from systemic inflammation and nutritional deficiencies, the cause of death, and the cellular and molecular mechanisms responsible remain to be elucidated. To address this, we investigated the relationship between tumour burden and survival in the KCKO murine PDAC model.
Methods
Female C57BL/6J mice 6–8 weeks of age underwent orthotopic injection with KCKO‐luc tumour cells. Solid tumour was verified on Day 5, post‐tumour inoculation. In vivo, longitudinal lean mass and tumour burden were assessed via dual‐energy X‐ray absorptiometry and IVIS imaging, respectively, and total body weight was assessed, weekly. Animals were sacrificed at a designated end point of ‘failure to thrive’. After sacrifice, lower limb hind muscles were harvested for histology and RNA extraction.
Results
We found a strong correlation between primary tumour size and survival (r2 = 0.83, P < 0.0001). A significant decrease in lower limb lean mass was first detected at Day 38 post‐implantation vs. no tumour controls (NTCs) (P < 0.0001). SMW was confirmed by histology, which demonstrated a 38%, 32.7%, and 39.9% decrease in fibre size of extensor digitorum longus, soleus, and tibialis anterior muscles, respectively, in PDAC mice vs. NTC (P < 0.002). Histology also revealed a 67.6% increase in haematopoietic cells within the muscle of PDAC mice when compared with NTC. Bulk RNAseq on muscles from PDAC mice vs. NTC revealed significant increases in c/ebpβ/Δ, il‐1, il‐6, and tnf gene expression. Pathway analyses to identify potential upstream factors revealed increased adipogenic gene expression, including a four‐fold increase in igfbp‐3. Histomorphometry of Oil Red‐O staining for fat content in tibialis anterior muscles demonstrated a 95.5% increase in positively stained fibres from PDAC mice vs. NTC.
Conclusions
Together, these findings support a novel model of PDAC‐associated SMW and mortality in which systemic inflammation leads to inflammatory cell infiltration into skeletal muscle with up‐regulated myocellular lipids.
Academic hospitals contribute to health care through patient care, research, and teaching; however, their outcomes may not be equivalent to nonacademic hospitals. Multivariate analysis of variance is ...used to compare publicly reported data on patient satisfaction, readmission rates, mortality rates, and hospital-acquired injury scores between 1906 academic and nonacademic hospitals, while controlling for hospital-level covariates. Results show that academic hospitals have higher levels of patient satisfaction on 7 of the 11 measures and are equivalent to nonacademic hospitals on the remaining 4 measures. Academic hospitals have lower pneumonia mortality rates than nonacademic hospitals, with no difference for other mortality or disease-specific readmissions. However, academic hospitals have a slightly higher overall readmission rate. Infection rates were equivalent between academic and nonacademic hospitals for central line-associated bloodstream infections, pressure ulcers, and wound dehiscence for abdominal and pelvic injuries, but academic hospitals have higher catheter-associated urinary tract infection rates.
The evaluation of the risk of recurring heart failure events (HFEs) was a pre-specified substudy of MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization ...Therapy).
There are limited data regarding the effect of cardiac resynchronization therapy with a defibrillator (CRT-D) on the occurrence of recurring heart failure episodes after a first post-implantation HFE.
Data with regard to recurring HFEs were prospectively collected for all 1,820 MADIT-CRT participants. The CRT-D versus defibrillator-only risk for nonfatal first- and subsequent-HFEs was assessed by Cox proportional hazards and Andersen-Gill proportional intensity regression modeling, respectively, in efficacy analyses recognizing active device-type during follow-up.
Multivariate analysis showed that CRT-D was associated with a significant reduction in the risk of a first HFE (hazard ratio HR: 0.54, 95% confidence interval CI: 0.44 to 0.67, p < 0.001) and with a similar magnitude of reduction in the risk of HFEs subsequent to a first post-enrollment event (HR: 0.62, 95% CI: 0.45 to 0.85, p = 0.003). The benefit of CRT-D for the prevention of first and subsequent HFEs was pronounced among patients with left bundle branch block (HR: 0.38, 95% CI: 0.29 to 0.49, p < 0.001; and HR: 0.50, 95% CI: 0.33 to 0.76, p = 0.001, respectively) and nonsignificant in non-left bundle branch block patients (HR: 1.12, 95% CI: 0.77 to 1.64, p = 0.55; and HR: 0.99, 95% CI: 0.58 to 1.69, p = 0.96, respectively; p values for interaction: p < 0.001 and p = 0.06, respectively). The occurrences of first and second HFEs were associated with 7- and nearly 19-fold respective increases in the risk of subsequent mortality.
In the MADIT-CRT trial, the benefit of cardiac resynchronization therapy for the reduction in recurring HFEs was maintained after the occurrence of a first post-enrollment event. The occurrence of HFEs greatly increased the risk of death. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy; NCT00180271).
Genetic ablation of cyclooxygenase-2 (COX-2) in mice is known to impair fracture healing. To determine if teriparatide (human PTH1–34) can promote healing of Cox-2-deficient fractures, we performed ...detailed in vivo analyses using a murine stabilized tibia fracture model. Periosteal progenitor cell proliferation as well as bony callus formation was markedly reduced in Cox-2−/− mice at day 10 post-fracture. Remarkably, intermittent PTH1–34 administration increased proliferation of periosteal progenitor cells, restored callus formation on day 7, and enhanced bone formation on days 10, 14 and 21 in Cox-2-deficient mice. PTH1–34 also increased biomechanical torsional properties at days 10 or 14 in all genotypes, consistent with enhanced bony callus formation by radiologic examinations. To determine the effects of intermittent PTH1–34 for callus remodeling, TRAP staining was performed. Intermittent PTH1–34 treatment increased the number of TRAP positive cells per total callus area on day 21 in Cox-2−/− fractures. Taken together, the present findings indicate that intermittent PTH1–34 treatment could compensate for COX-2 deficiency and improve impaired fracture healing in Cox-2-deficient mice.
•Fracture healing, as assessed using a murine stabilized tibia fracture model, was impaired in Cyclooxygenase-2 (Cox-2)-deficient mice.•PTH1-34 improved callus volume and biomechanical properties during the early phases of healing in Cox-2-deficient tibial fractures.•PTH1-34 increased periosteal progenitor cell proliferation, bone callus formation, and callus remodeling.
We address an optimization problem that requires deciding the location of a set of facilities, the allocation of customers to those facilities under capacity constraints, and the allocation of ...customers to trucks at those facilities under truck travel-distance constraints. We present a hybrid approach that combines integer and constraint programming using logic-based Benders decomposition. Computational experiments demonstrate that the Benders model is able to find and prove optimal solutions up to three orders-of-magnitude faster than an existing integer programming approach; it also finds better feasible solutions in less time when compared with an existing tabu search algorithm.
Abstract Huntington disease is an autosomal-dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive ...decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins that result in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state, resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease.
Calls for early exposure of all undergraduates to research have led to the increased use and study of course-based research experiences (CREs). CREs have been shown to increase measures of ...persistence in the sciences, such as science identity, scientific self-efficacy, project ownership, scientific community values, and networking. However, implementing CREs can be challenging and resource-intensive. These barriers may be partly mitigated by the use of short-term CRE modules rather than semester- or year-long projects. One study has shown that a CRE module captures some of the known benefits of CREs as measured by the Persistence in the Sciences (PITS) survey. Here, we used this same survey to assess outcomes for introductory biology students who completed a semester of modular CREs based on faculty research at an R1 university. The results indicated levels of self-efficacy, science community values, and science identity similar to those previously reported for students in the Science Education Alliance-Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) full-semester CRE. Scores for project ownership (content) were between previously reported traditional lab and CRE scores, while project ownership (emotion) and networking were similar to those of traditional labs. Our results suggest that modular CREs can lead to significant gains in student affect measures that have been linked to persistence in the sciences in other studies. Although gains were not as great in all measures as with a semester-long CRE, implementation of modular CREs may be more feasible and offers the added benefits of exposing students to diverse research fields and lab techniques.
Histomorphometric analysis of histologic sections of normal and diseased bone samples,such as healing allografts and fractures,is widely used in bone research.However,the utility of traditional ...semi-automated methods is limited because they are labor-intensive and can have high interobserver variability depending upon the parameters being assessed,and primary data cannot be re-analyzed automatically.Automated histomorphometry has long been recognized as a solution for these issues,and recently has become more feasible with the development of digital whole slide imaging and computerized image analysis systems that can interact with digital slides.Here,we describe the development and validation of an automated application（algorithm）using Visiopharm＇s image analysis system to quantify newly formed bone,cartilage,and fibrous tissue in healing murine femoral allografts in high-quality digital images of H＆E/alcian blue-stained decalcified histologic sections.To validate this algorithm,we compared the results obtained independently using OsteoMeasureTM and Visiopharm image analysis systems.The intraclass correlation coefficient between Visiopharm and OsteoMeasure was very close to one for all tissue elements tested,indicating nearly perfect reproducibility across methods.This new algorithm represents an accurate and labor-efficient method to quantify bone,cartilage,and fibrous tissue in healing mouse allografts.
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