Ten-year prognostic outcomes of molar survival using the Miller-Mcentire Periodontal Prognostic Index - A longitudinal prospective study.

Background: A 10-year survival analysis was performed to assess the predictive validity of the periodontal risk score (formerly known as Miller-McEntire Periodontal Prognostic Index [MMPPI]) to predict long-term survival of periodontally diseased molars in a longitudinally assessed cohort. Materials and Methods: The MMPPI scores were computed at baseline by summarizing scores allocated for individual factors. The cohort was treated, followed up, and placed under regular periodontal maintenance. Molar survival data collected up to 10 years of follow-up were analyzed. Cox proportional regression was performed, and hazards ratio (HR) were computed for each prognostic factor and the MMPPI score. To estimate the predictive value of MMPPI, a receiver operating curve (ROC) curve analysis was performed. Results: From 1032 molars, 155 molars were extracted over the 10-year follow-up duration. Cox proportional hazard analysis showed significant hazard ratios for tooth loss for the component variables significant HR was noted for age: 4.92 (3.34:7.27), smoking: 1.74 (1.38-2.22), diabetes: 1.66 (1.49-1.86), molar type: 1.39 (1.15-1.67), probing depth: 2.00 (1.63-2.46), furcation: 2.64 (2.30-3.03), mobility: 3.45 (2.98-4.01), and total MMPPI score: 1.98 (1.85-2.12). ROC curve analysis showed an area under the curve value of 0.94 for the MMPPI index as a predictor of molar loss at 8 years, and the Youden index was maximized at the optimal cutoff point score of 7. Conclusions: All component scores of MMPPI showed significant hazard ratios at 10 years. These findings support the previous results from the 5-year analysis of this university-based cohort and warrant validation in independent cohorts.

The Effect of Crystal Arthropathy on the Diagnostic Criteria of Native Septic Arthritis.

INTRODUCTION: Distinguishing between septic arthritis and crystal arthropathy flares can be challenging. The purpose of this study was to determine how the presence of synovial crystals affects the diagnostic criteria of septic arthritis. METHODS: A retrospective review identified patients undergoing joint aspirations to rule out native septic arthritis. Differences between septic arthritis presenting with and without synovial crystals were analyzed. A receiver-operating characteristic curve was plotted for laboratory markers to determine the area under the curve, or diagnostic accuracy, for septic arthritis and to evaluate thresholds that maximized sensitivity and specificity. RESULTS: There were 302 joint aspirations in 267 patients. Septic arthritis was diagnosed in 17.9% (54/302). Patients with synovial crystals were less likely to have septic arthritis (4.2% [5/119] vs. 26.8% [49/183], P < 0.0001). Septic arthritis in patients with no synovial crystals was associated with fever and a higher synovial white blood cell (WBC) count, synovial polymorphonuclear cell percentage (PMN%), serum WBC, and C-reactive protein (CRP) ( P < 0.05). Septic arthritis in patients with synovial crystals was only associated with inability to bear weight and a higher synovial WBC and CRP ( P < 0.05). Synovial PMN% was considered nondiagnostic of septic arthritis (area under the curve 0.56) in patients with crystals while synovial WBC and CRP had acceptable (0.76) and excellent (0.83) diagnostic utility, respectively. The WBC and CRP value thresholds that maximized sensitivity and specificity for septic arthritis were greater in patients with crystals (21,600 vs. 17,954 cells/µL and 125 vs. 69 mg/L, respectively). DISCUSSION: The presence of synovial crystals reduced the likelihood of septic arthritis and altered the laboratory diagnostic criteria. PMN% was nondiagnostic in the setting of synovial crystals.

Associations with unplanned repeat irrigation and debridement of native septic arthritis.

PURPOSE: To identify associations with unplanned repeat irrigation and debridement (I&D) after arthrotomy for native septic arthritis. METHODS: A retrospective review identified patients with native septic arthritis treated with open arthrotomies. The primary outcome was unplanned repeat I&D within 90 days. Associations evaluated for included comorbidities, ability to bear weight, fever, immunosuppressed status, purulence, C-reactive protein, erythrocyte sedimentation rate, white blood cell count (synovial fluid and serum levels), and synovial fluid polymorphonuclear cell percentage (PMN%). RESULTS: There were 59 arthrotomies in 53 patients involving the knee (n = 32), shoulder (n = 10), elbow (n = 8), ankle (n = 6), and hip (n = 3). The median patient age was 52, and a 71.2% were male. An unplanned repeat I&D was required in 40.7% (n = 24). The median time to the second I&D was 4 days (interquartile range 3 to 9). On univariate analysis, unplanned repeat I&Ds were associated with fever (p = 0.03), purulence (p = 0.01), bacteria growth on cultures (p = 0.02), and the use of deep drains (p = 0.05). On multivariate analysis, the only variables that remained associated with unplanned repeat I&Ds were fever (odds ratio (OR) 5.5, 95% confidence interval (CI) 1.3, 23.6, p = 0.02) and purulence (OR 5.3, CI 1.1, 24.4, p = 0.03). CONCLUSIONS: An unplanned repeat I&D was required in 40.7% of patients and was associated with fever and purulence. These findings highlight the difficulty of controlling these infections and support the need for future research into better methods of management. LEVEL OF EVIDENCE: Diagnostic, Level III.

Advanced practice providers in infectious disease: Enhancing the infectious disease team of the future.

As the infectious disease (ID) workforce encounters increasing demand for services with fewer physicians entering the field, advanced practice providers (APPs) in infectious disease offer a unique ability to enhance high-quality patient care. However, little is known about their incorporation into ID, their utilization in immunocompromised settings, or their future use. This article reviews currently known data on APPs in ID including how some groups have used APPs and provides a framework for thoughtful, deliberate steps to incorporate APPs into the ID medical team, including transplant infectious disease. Highlighted specifically are education and mentorship opportunities with ideas for curriculum development and onboarding approaches. Strategic steps must be taken for APP inclusion as the medical landscape continues to change, patient complexity increases, and the ID team of the future takes shape.

Key Issues in the First Year of Transition for a Large Medicaid-Funded Children's Service.

Behavioral Health Rehabilitation Service (BHRS) is a comprehensive service for Pennsylvania's Medicaid-enrolled youth and their families. In 2021, BHRS transitioned to Intensive Behavioral Health Service (IBHS) through state-wide policy change. To assess impact, the largest behavioral health managed care organization in the state compared service utilization in BHRS in 2019 versus IBHS in 2021. Results show that significantly more youth received non-Applied Behavior Analysis (non-ABA) services in BHRS (n = 13,795) than IBHS (n = 10,083) and more youth were discharged during the measurement period for BHRS versus IBHS (47% vs. 44%). Significantly more youth received ABA through IBHS versus BHRS (n = 4,385 vs. n = 2,690). The number of youth served in therapeutic service in IBHS did not indicate improved access during this first year of transition; however, more youth received evidence based treatments through IBHS indicating higher quality care for some youth and families.

Centering intersectional sustainability in leadership education: A case for the sustainable development goals.

Sustainability leadership has the transformative potential of helping to center an array of skills and mindsets needed for leaders and leaderful organizations and collectives to successfully address the many interrelated and connected challenges of the 21st century. This article makes the case that the United Nations Sustainable Development Goals (SDGs) are a useful framework for integrating sustainability into leadership education and development broadly and can advance these needed skill sets and learning orientations. Leadership educators should consider centering this in their work in order to effectively prepare learners for the challenges of today and tomorrow.

Risk Factors for Below-the-Knee Amputation in Diabetic Foot Osteomyelitis After Minor Amputation.

BACKGROUND: Below-the-knee amputation (BKA) can be a detrimental outcome of diabetic foot osteomyelitis (DFO). Ideal treatment of DFO is controversial, but studies suggest minor amputation reduces the risk of BKA. We evaluated risk factors for BKA after minor amputation for DFO. METHODS: This is a retrospective cohort of patients discharged from Denver Health Medical Center from February 1, 2012, through December 31, 2014. Patients who underwent minor amputation for diagnosis of DFO were eligible for inclusion. The outcome evaluated was BKA in the 6 months after minor amputation. RESULTS: Of 153 episodes with DFO that met the study criteria, 11 (7%) had BKA. Failure to heal surgical incision at 3 months (P < .001) and transmetatarsal amputation (P = .009) were associated with BKA in the 6 months after minor amputation. Peripheral vascular disease was associated with failure to heal but not with BKA (P = .009). Severe infection, bacteremia, hemoglobin A1c, and positive histopathologic margins of bone and soft tissue were not associated with BKA. The median antibiotic duration was 42 days for positive histopathologic bone resection margin (interquartile range, 32-47 days) and 16 days for negative margin (interquartile range, 8-29 days). Longer duration of antibiotics was not associated with lower risk of BKA. CONCLUSIONS: Patients who fail to heal amputation sites in 3 months or who have transmetatarsal amputation are at increased risk for BKA. Future studies should evaluate the impact of aggressive wound care or whether failure to heal is a marker of another variable.

Locomotor analysis identifies early compensatory changes during disease progression and subgroup classification in a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a motoneuron degenerative disease that is challenging to diagnose and presents with considerable variability in survival. Early identification and enhanced understanding of symptomatic patterns could aid in diagnosis and provide an avenue for monitoring disease progression. Use of the mSOD1G93A mouse model provides control of the confounding environmental factors and genetic heterogeneity seen in amyotrophic lateral sclerosis patients, while investigating underlying disease-induced changes. In the present study, we performed a longitudinal behavioral assessment paradigm and identified an early hindlimb symptom, resembling the common gait abnormality foot drop, along with an accompanying forelimb compensatory mechanism in the mSOD1G93A mouse. Following these initial changes, mSOD1 mice displayed a temporary hindlimb compensatory mechanism resembling an exaggerated steppage gait. As the disease progressed, these compensatory mechanisms were not sufficient to sustain fundamental locomotor parameters and more severe deficits appeared. We next applied these initial findings to investigate the inherent variability in B6SJL mSOD1G93A survival. We identified four behavioral variables that, when combined in a cluster analysis, identified two subpopulations with different disease progression rates: a fast progression group and a slow progression group. This behavioral assessment paradigm, with its analytical approaches, provides a method for monitoring disease progression and detecting mSOD1 subgroups with different disease severities. This affords researchers an opportunity to search for genetic modifiers or other factors that likely enhance or slow disease progression. Such factors are possible therapeutic targets with the potential to slow disease progression and provide insight into the underlying pathology and disease mechanisms.

How Do Preoperative Antibiotics Affect Culture Yield in Diabetic Foot Infections?

The impact of preoperative antibiotics on culture of diabetic foot infection samples has not been studied. We found that increasing exposure to preoperative antibiotics was associated with less frequent growth of streptococci and anaerobes and more culture-negative results. In contrast, the yield of Staphylococcus aureus and Gram-negative bacilli was unaffected.

Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen.

Thrombin-mediated proteolysis is a major determinant of metastasis, but is not universally important for primary tumor growth. Here, we report that colorectal adenocarcinoma represents one important exception whereby thrombin-mediated functions support both primary tumor growth and metastasis. In contrast with studies of multiple nongastrointestinal cancers, we found that the growth of primary tumors formed by murine and human colon cancer cells was reduced in mice by genetic or pharmacologic reduction of circulating prothrombin. Reduced prothrombin expression was associated with lower mitotic indices and invasion of surrounding tissue. Mechanistic investigations revealed that thrombin-driven colonic adenocarcinoma growth relied upon at least two targets of thrombin-mediated proteolysis, protease-activated receptor-1 (PAR-1) expressed by stromal cells and the extracellular matrix protein, fibrinogen. Colonic adenocarcinoma growth was reduced in PAR-1-deficient mice, implicating stromal cell-associated PAR-1 as one thrombin target important for tumor outgrowth. Furthermore, tumor growth was dramatically impeded in fibrinogen-deficient mice, offering the first direct evidence of a critical functional role for fibrinogen in malignant tumor growth. Tumors harvested from fibrinogen-deficient mice displayed a relative reduction in cell proliferative indices, as well as increased tumor necrosis and decreased tumor vascular density. Collectively, our findings established a functional role for thrombin and its targets PAR-1 and fibrinogen in the pathogenesis of colonic adenocarcinoma, supporting tumor growth as well as local invasion and metastasis.

Parental Use of Electronic Cigarettes.

OBJECTIVE: To describe parental use of electronic cigarettes (e-cigs) to better understand the safety risks posed to children. METHODS: Between June 24 and November 6, 2014, parents completed a self-administered paper survey during an office visit to 15 pediatric practices in a Midwestern practice-based research network. Attitudes towards and use of e-cigs are reported for those aware of e-cigs before the survey. RESULTS: Ninety-five percent (628 of 658) of respondents were aware of e-cigs. Of these, 21.0% (130 of 622) had tried e-cigs at least once, and 12.3% (77) reported e-cig use by ≥1 person in their household (4.0% exclusive e-cig use, 8.3% dual use with regular cigarettes). An additional 17.3% (109) reported regular cigarette use. Most respondents from e-cig-using homes did not think e-cigs were addictive (36.9% minimally or not addictive, 25.0% did not know). While 73.7% believed that e-liquid was very dangerous for children if they ingested it, only 31.2% believed skin contact to be very dangerous. In 36.1% of e-cig-using homes, neither childproof caps nor locks were used to prevent children's access to e-liquid. Only 15.3% reported their child's pediatrician was aware of e-cig use in the home. CONCLUSIONS: E-cig use occurred in 1 in 8 homes, often concurrently with regular cigarettes. Many parents who used e-cigs were unaware of the potential health and safety hazards, including nicotine poisoning for children, and many did not store e-liquid safely. Pediatricians could provide education about e-cig associated safety hazards but are unaware of e-cig use in their patients' homes.

Factor XIII Transglutaminase Supports the Resolution of Mucosal Damage in Experimental Colitis.

The thrombin-activated transglutaminase factor XIII (FXIII) that covalently crosslinks and stablizes provisional fibrin matrices is also thought to support endothelial and epithelial barrier function and to control inflammatory processes. Here, gene-targeted mice lacking the FXIII catalytic A subunit were employed to directly test the hypothesis that FXIII limits colonic pathologies associated with experimental colitis. Wildtype (WT) and FXIII-/- mice were found to be comparable in their initial development of mucosal damage following exposure to dextran sulfate sodium (DSS) challenge. However, unlike FXIII-sufficient mice, FXIII-deficient cohorts failed to efficiently resolve colonic inflammatory pathologies and mucosal damage following withdrawal of DSS. Consistent with prior evidence of ongoing coagulation factor activation and consumption in individuals with active colitis, plasma FXIII levels were markedly decreased in colitis-challenged WT mice. Treatment of colitis-challenged mice with recombinant human FXIII-A zymogen significantly mitigated weight loss, intestinal bleeding, and diarrhea, regardless of whether cohorts were FXIII-sufficient or were genetically devoid of FXIII. Similarly, both qualitative and quantitative microscopic analyses of colonic tissues revealed that exogenous FXIII improved the resolution of multiple colitis disease parameters in both FXIII-/- and WT mice. The most striking differences were seen in the resolution of mucosal ulceration, the most severe histopathological manifestation of DSS-induced colitis. These findings directly demonstrate that FXIII is a significant determinant of mucosal healing and clinical outcome following inflammatory colitis induced mucosal injury and provide a proof-of-principle that clinical interventions supporting FXIII activity may be a means to limit colitis pathology and improve resolution of mucosal damage.

Identification of B6SJL mSOD1(G93A) mouse subgroups with different disease progression rates.

Disease progression rates among patients with amyotrophic lateral sclerosis (ALS) vary greatly. Although the majority of affected individuals survive 3-5 years following diagnosis, some subgroups experience a more rapidly progressing form, surviving less than 1 year, and other subgroups experience slowly progressing forms, surviving nearly 50 years. Genetic heterogeneity and environmental factors pose significant barriers in investigating patient progression rates. Similar to the case for humans, variation in survival within the mSOD1 mouse has been well documented, but different progression rates have not been investigated. The present study identifies two subgroups of B6SJL mSOD1(G93A) mice with different disease progression rates, a fast progression group (FPG) and slow progression group, as evidenced by differences in the rate of motor function decline. In addition, increased disease-associated gene expression within the FPG facial motor nucleus confirmed the presence of a more severe phenotype. We hypothesize that a more severe disease phenotype could be the result of 1) an earlier onset of axonal disconnection with a consistent degeneration rate or 2) a more severe or accelerated degenerative process. We performed a facial nerve transection axotomy in both mSOD1 subgroups prior to disease onset as a method to standardize the axonal disconnection. Instead of leading to comparable gene expression in both subgroups, this standardization did not eliminate the severe phenotype in the FPG facial nucleus, suggesting that the FPG phenotype is the result of a more severe or accelerated degenerative process. We theorize that these mSOD1 subgroups are representative of the rapid and slow disease phenotypes often experienced in ALS.

Facial nerve axotomy in mice: a model to study motoneuron response to injury.

The goal of this surgical protocol is to expose the facial nerve, which innervates the facial musculature, at its exit from the stylomastoid foramen and either cut or crush it to induce peripheral nerve injury. Advantages of this surgery are its simplicity, high reproducibility, and the lack of effect on vital functions or mobility from the subsequent facial paralysis, thus resulting in a relatively mild surgical outcome compared to other nerve injury models. A major advantage of using a cranial nerve injury model is that the motoneurons reside in a relatively homogenous population in the facial motor nucleus in the pons, simplifying the study of the motoneuron cell bodies. Because of the symmetrical nature of facial nerve innervation and the lack of crosstalk between the facial motor nuclei, the operation can be performed unilaterally with the unaxotomized side serving as a paired internal control. A variety of analyses can be performed postoperatively to assess the physiologic response, details of which are beyond the scope of this article. For example, recovery of muscle function can serve as a behavioral marker for reinnervation, or the motoneurons can be quantified to measure cell survival. Additionally, the motoneurons can be accurately captured using laser microdissection for molecular analysis. Because the facial nerve axotomy is minimally invasive and well tolerated, it can be utilized on a wide variety of genetically modified mice. Also, this surgery model can be used to analyze the effectiveness of peripheral nerve injury treatments. Facial nerve injury provides a means for investigating not only motoneurons, but also the responses of the central and peripheral glial microenvironment, immune system, and target musculature. The facial nerve injury model is a widely accepted peripheral nerve injury model that serves as a powerful tool for studying nerve injury and regeneration.

Thrombin drives tumorigenesis in colitis-associated colon cancer.

The established association between inflammatory bowel disease and colorectal cancer underscores the importance of inflammation in colon cancer development. On the basis of evidence that hemostatic proteases are powerful modifiers of both inflammatory pathologies and tumor biology, gene-targeted mice carrying low levels of prothrombin were used to directly test the hypothesis that prothrombin contributes to tumor development in colitis-associated colon cancer (CAC). Remarkably, imposing a modest 50% reduction in circulating prothrombin in fII+/- mice, a level that carries no significant bleeding risk, dramatically decreased adenoma formation following an azoxymethane/dextran sodium sulfate challenge. Similar results were obtained with pharmacologic inhibition of prothrombin expression or inhibition of thrombin proteolytic activity. Detailed longitudinal analyses showed that the role of thrombin in tumor development in CAC was temporally associated with the antecedent inflammatory colitis. However, direct studies of the antecedent colitis showed that mice carrying half-normal prothrombin levels were comparable to control mice in mucosal damage, inflammatory cell infiltration, and associated local cytokine levels. These results suggest that thrombin supports early events coupled to inflammation-mediated tumorigenesis in CAC that are distinct from overall inflammation-induced tissue damage and inflammatory cell trafficking. That prothrombin is linked to early events in CAC was strongly inferred by the observation that prothrombin deficiency dramatically reduced the formation of very early, precancerous aberrant crypt foci. Given the importance of inflammation in the development of colon cancer, these studies suggest that therapeutic interventions at the level of hemostatic factors may be an effective means to prevent and/or impede colitis-associated colon cancer progression.

Thrombomodulin is a determinant of metastasis through a mechanism linked to the thrombin binding domain but not the lectin-like domain.

Thrombomodulin (TM) is a predominantly endothelial transmembrane glycoprotein that modulates hemostatic function through a domain that controls thrombin-mediated proteolysis and an N-terminal lectin-like domain that controls inflammatory processes. To test the hypothesis that TM is a determinant of malignancy and dissect the importance of these functional domains in cancer biology, metastatic potential was evaluated in TM(Pro) mice expressing a mutant form of TM with reduced thrombin affinity and TM(LeD) mice lacking the N-terminal lectin-like domain. Studies of TM(Pro) mice revealed that TM is a powerful determinant of hematogenous metastasis. TM(Pro) mice exhibited a strongly prometastatic phenotype relative to control mice that was found to result from increased survival of tumor cells newly localized to the lung rather than any alteration in tumor growth. The impact of the TM(Pro) mutation on metastasis was dependent on both tumor cell-associated tissue factor and thrombin procoagulant function. In contrast, expression of a mutant form of TM lacking the lectin-like domain had no significant impact on metastasis. These studies directly demonstrate for the first time that TM-mediated regulation of tumor cell-driven procoagulant function strongly influences metastatic potential and suggest that endothelial cell-associated modulators of hemostasis may represent novel therapeutic targets in limiting tumor dissemination.

The development of inflammatory joint disease is attenuated in mice expressing the anticoagulant prothrombin mutant W215A/E217A.

Thrombin is a positive mediator of thrombus formation through the proteolytic activation of protease-activated receptors (PARs), fibrinogen, factor XI (fXI), and other substrates, and a negative regulator through activation of protein C, a natural anticoagulant with anti-inflammatory/cytoprotective properties. Protease-engineering studies have established that 2 active-site substitutions, W215A and E217A (fII(WE)), result in dramatically reduced catalytic efficiency with procoagulant substrates while largely preserving thrombomodulin (TM)-dependent protein C activation. To explore the hypothesis that a prothrombin variant favoring antithrombotic pathways would be compatible with development but limit inflammatory processes in vivo, we generated mice carrying the fII(WE) mutations within the endogenous prothrombin gene. Unlike fII-null embryos, fII(WE/WE) mice uniformly developed to term. Nevertheless, these mice ultimately succumbed to spontaneous bleeding events shortly after birth. Heterozygous fII(WT/WE) mice were viable and fertile despite a shift toward an antithrombotic phenotype exemplified by prolonged tail-bleeding times and times-to-occlusion after FeCl3 vessel injury. More interestingly, prothrombin(WE) expression significantly ameliorated the development of inflammatory joint disease in mice challenged with collagen-induced arthritis (CIA). The administration of active recombinant thrombin(WE) also suppressed the development of CIA in wild-type mice. These studies provide a proof-of-principle that pro/thrombin variants engineered with altered substrate specificity may offer therapeutic opportunities for limiting inflammatory disease processes.