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Objectives To determine which combinations of type 2 diabetes (T2D) and multiple chronic conditions (MCC) contribute to total spending and differences in spending between groups based on sex, race/ethnicity, and rural residency. Study design Retrospective cohort study using 2012 Medicare claims data from beneficiaries in Michigan with T2D. Methods Zero-inflated Poisson regression models to estimate relationships of demographic characteristics and MCC combinations on hospital outpatient, acute inpatient, skilled nursing, hospice, and Part D drug spending. Results Across most MCC combinations, there are lower odds of no spending, with a concurrent increase in the expected mean of actual spending when payments are made, except for hospital outpatient costs. For hospital outpatient services, we observed lower spending across all MCC combinations. When controlling for MCC, we generally found that compared with White beneficiaries, Black, Asian/Pacific Islander, and Hispanic beneficiaries experience increased odds of no spending, but when payments were made, payments generally increased. American Indian/Alaska Native beneficiaries are the exception; they experience decreased odds of no payments for hospital outpatient and acute inpatient services, with a concurrent decrease in mean expected payments. Conclusions When considering a range of MCC combinations, we observed differences in total payments between racial/ethnic minority groups and White beneficiaries. Our results highlight the ongoing need to make changes in the health care system to make the system more accessible to racial/ethnic minority groups.

Introduction Hip fractures remain one of the most prevalent and deadly conditions afflicting those 65 years and older. For other health conditions (e.g. myocardial infarction), hospital location is associated with poorer health outcomes. To our knowledge, no study has investigated the relationship between hip fracture morality rate in the United States between urban and rural hospital settings. Methods A retrospective cohort study was conducted to examine differences in in-hospital mortality between groups treated in rural, urban-teaching, and urban-non-teaching hospitals, as well as public and private hospitals. Mortality rates were also compared for variances between surgical treatment, sex, insurance, patient location, race, and income. Discharge data was collected for 256,240 inpatient stays from the 2012 National Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality. Results Odds of mortality were 14.6% greater in rural hospital hip fracture patients compared to Urban/Non-Teaching centers (p Conclusions Results from this study lend support to necessitate further research investigating prospective barriers to care of those in rural settings. This may point to limitations in resources and trained medical and surgical specialists in rural hospitals and need for continued research to mitigate such findings.

Background This study aimed to describe the prevalence of type 2 diabetes and combinations of multiple chronic conditions (MCCs) that are leading causes of death (LCD) and confirm that disparities exist between groups based on race and sex. Materials and Methods We conducted a retrospective cohort study using 2012 Medicare claims data from beneficiaries with type 2 diabetes over the age of 65 in the state of Michigan. Results Female beneficiaries have type 2 diabetes and 1 or more MCCs that are LCD more often than males. Most type 2 diabetes patients have diabetes alone without MCCs, while a large proportion have at least 1 additional chronic condition that is a LCD. One in 3 patients have 3 or more chronic conditions. The most prevalent type 2 diabetes coexisting MCCs are congestive heart failure (CHF), chronic obstructive pulmonary disease and chronic kidney disease. Asian/Pacific Islanders have the highest prevalence of type 2 diabetes without MCCs, and the highest prevalence of diabetes plus CHF. While fewer black beneficiaries have diabetes alone or 1 additional MCC, the prevalence of 3 or more MCCs in blacks generally exceeds the prevalence in other races. In beneficiaries with newly diagnosed type 2 diabetes, chronic obstructive pulmonary disease and CHF are the first new chronic conditions to be diagnosed after an initial type 2 diabetes diagnosis. Conclusions Race and sex disparities occur in the prevalence of type 2 diabetes and MCCs that are LCD in Medicare beneficiaries in the state of Michigan.

People with diabetes need routine health care to prevent potential exacerbations of diabetes and detect or prevent the development of additional chronic conditions that can worsen the course of diabetes. Using 2012 Medicare claims data from the State of Michigan for 443,932 beneficiaries with type 2 diabetes, we determined that there are differences between white and racial/ethnic minority people with diabetes in accessing any preventive care and in the amount of service used once they do access care, even after adjusting for the presence of multiple chronic conditions.

Background The early days of the coronavirus disease (COVID-19) pandemic in the United States brought uncertainty in the knowledge about COVID-19 and what to do about it. It is necessary to understand public knowledge and behaviors if we are to effectively address the pandemic. Objective The aim of this study is to test the hypothesis that knowledge about COVID-19 influences participation in different behaviors including self-reports of purchasing more goods than usual, attending large gatherings, and using medical masks. Methods This study was funded and approved by the Institutional Review Board on March 17, 2020. The cross-sectional online survey of 1034 US residents aged 18 years or older was conducted on March 17, 2020. Results For every point increase in knowledge, the odds of participation in purchasing more goods (odds ratio [OR] 0.88, 95% CI 0.81-0.95), attending large gatherings (OR 0.87, 95% CI 0.81-0.93), and using medical masks (OR 0.56, 95% CI 0.50-0.62) decreased by 12%, 13%, and 44%, respectively. Gen X and millennial participants had 56% and 76% higher odds, respectively, of increased purchasing behavior compared to baby boomers. The results suggest that there is a politicization of response recommendations. Democrats had 30% lower odds of attending large gatherings (OR 0.70, 95% CI 0.50-0.97) and 48% lower odds of using medical masks (OR 0.52, 95% CI 0.34-0.78) compared to Republicans. Conclusions This survey is one of the first attempts to study determinants of knowledge and behaviors in response to the COVID-19 pandemic in the United States. A national, coordinated effort toward a pandemic response may ensure better compliance with behavioral recommendations to address this public health emergency.

ObjectiveTo test the hypothesis that knowledge of COVID-19 influences participation in different behaviors including self-reports of purchasing more goods than usual, attending large gatherings, and using medical masks.MethodsCross-sectional online survey of 1,034 U.S. residents age 18+ conducted on March 17, 2020.ResultsFor every point increase in knowledge, the odds of participation in purchasing more goods (OR=0.88, 95% CI:0.81-0.95), attending large gatherings (OR=0.87, 95%CI: 0.81-0.93), and using medical masks (OR=0.56, 95% CI:0.50-0.62) decreased by 12%, 13%, and 44%, respectively. Gen X and Millennial participants had 56% to 76% higher odds, respectively, of increased purchasing behavior, compared to Baby Boomers. Results suggest politicization of response recommendations. Democrats had 30% lower odds of attending large gatherings (OR=0.70, 95% CI:0.50-0.97), and 48% lower odds of using medical masks (OR=0.52, 95% CI:0.34-0.78), compared to Republicans.ConclusionsThis survey is one of the first attempts to study determinants of knowledge and behaviors in response to the COVID-19 pandemic in the U.S. A national, coordinated effort at pandemic response may ensure better compliance with behavioral recommendations to address this public health emergency.

This study uses data from the 2012 National Inpatient Sample to determine if mortality, length of stay, and discharge disposition are different between rural and urban American Indians and Alaska Natives (AI/ANs) with alcohol abuse, depression, diabetes, and post-traumatic stress disorder. Results show no difference in mortality between groups. Alcohol abuse, depression, and diabetes are less prevalent in rural AI/ANs, and rural patients have shorter lengths of stay and fewer chronic conditions, diagnoses, and procedures. Finally, urban patients are discharged to short-term hospitals or skilled nursing facilities at higher rates. Rural diabetes patients exhibit increased mortality, but there is little evidence that rurality adversely affects the AI/AN population for the conditions we studied.

Aims The aims of this study are to confirm disparities in diabetes mortality rates based on race, determine if race predicts combinations of diabetes and multiple chronic conditions (MCC) that are leading causes of death (LCD), and determine if combinations of diabetes plus MCC mediate the relationship between race and mortality. Methods We performed a retrospective cohort study of 443,932 Medicare beneficiaries in the State of Michigan with type 2 diabetes mellitus and MCC. We applied Cox proportional hazards regression to determine predictors of mortality. We applied multinomial logistic regression to determine predictors of MCC combinations. Results We found that race influences mortality in Medicare beneficiaries with Type 2 diabetes mellitus and MCC. Prior to adjusting for MCC combinations, we observed that Blacks and American Indian/Alaska Natives have increased risk of mortality compared to Whites, while there is no difference in mortality between Hispanics and Whites. Regarding MCC combinations, Black/African American beneficiaries experience increased odds for most MCC combinations while Asian/Pacific Islanders and Hispanics experience lower odds for MCC combinations, compared to Whites. When adjusting for MCC, mortality disparities observed between Whites, Black/African Americans, and American Indians/Alaska Natives persist. Conclusions Compared to Whites, Black/African Americans in our cohort had increased odds of most MCC combinations, and an increased risk of mortality that persisted even after adjusting for MCC combinations.

Presently, disparities exist between race, sex, socioeconomic status, hospitals, income, comorbidities, and insurance profiles of patients undergoing DBS surgery. Here, we aim to highlight several variables and their predictive powers of DBS surgery outcomes as measured by dischargelocation, length of hospital stays, and total hospital charges. A retrospective cohort study using discharge data from NIS and HCUP for analyses and regression model statistics is performed. Comparative analyses demonstrate urban patients were more often non-routinely discharged, possessed private insurance, and accrued greater hospital costs compared to rural patients. Moreover, regression analyses predicts urban patients have 70% lower odds of routine discharge while those with a major loss of function prior to surgery also have 81% lower odds of routine discharge compared to those with minor loss of function. Ultimately, our study found urban patients or patients with major illnesses have higher hospital charges, longer hospitalization, and more often non-routinely discharged.

Background Rural communities experience significant barriers to quality healthcare, including disparities in medical care following acute myocardial infarctions (AMI). This study sought to determine if the population density of the county where Medicare patients were hospitalized following AMI predicted short-term outcomes and to quantify longitudinal changes in hospital performance on quality of care metrics. Methods Hospital-level data was queried from the 2012 and 2018 Centers for Medicare & Medicaid Services archives. Each hospital was classified based on residing county using the National Center for Health Statistics Rural-Urban Continuum Codes (RUCC). Variations and longitudinal changes in risk-adjusted outcomes and quality of care metrics were stratified by RUCC classification and analyzed. Results Among the 4798 hospitals identified, rural hospitals had significantly higher risk-adjusted 30-day mortality (rs = 0.095, p Conclusions In the United States, only modest variations currently exist between rural and urban hospitals in the medical care of AMI. Although the performance gap has narrowed, new strategies to improve timely and effective care are necessary to alleviate residual cardiovascular healthcare disparities in rural communities.

Background Training future healthcare profession students using interprofessional education (IPE) is critical to improve quality of health care and patient safety. Objective The objective of this study was to implement an IPE program and determine student satisfaction with each session, including a clinical case requiring teams with members from each profession addressing clinical scenarios. Subjects The subjects of this study were students from Athletic Training, Medicine, Nursing, Pharmacy, Physical Therapy, Physician Assistant, Social Work, and Speech-Language Pathology. Methods Evaluations, administered to all participating students, consisted of Likert-style responses, rating agreement with a series of questions, and space for descriptive comments. Score differences for each question were compared using independent group t-tests with a P-value of 0.05 to determine statistical significance. Results There were statistically higher satisfaction ratings for the problem-based learning case when compared to less interactive sessions ( P < 0.0001). Conclusion Students perceived benefits of the IPE program. Perceptions improved when various students had the opportunity to work together on clinically relevant problems.

Objective The objectives of this pilot study were to compare the interexaminer reliability of 2 different methods of Cobb angle measurement and to determine whether the participants considered 1 of the 2 methods easier to learn, understand, and apply. Methods Entry-level anatomy students who have familiarity with vertebral column anatomy but have not had previous radiology training were instructed on how to measure a Cobb angle. Each student measured 2 curves (thoracic and lumbar) on a single radiograph, first with the traditional method of Cobb angle measurement and second with a novel method of Cobb angle measurement using a digital level. Results The variance of measurements decreased by using the novel method from thoracic to lumbar measurements and for the moderate and severe scoliosis films. All decreases in variance were statistically significant except for the lumbar measurement variance for the severe scoliosis film. The novel method of Cobb angle measurement with these same participants showed interexaminer reliability. More than 78% of naive participants considered the proposed method easier to learn, understand, and apply when compared with the traditional method. Conclusion In this group of naive students, there was improved interrater reliability, greater satisfaction, and reduced measurement variances in some cases, with a novel method using a digital level to measure the Cobb angle compared with the traditional method of measurement.

Objective The aim of the study was to determine whether routine left atrial appendage ligation in cardiac surgery would reduce the risk of postoperative atrial fibrillation–related cerebrovascular accident. Methods We performed an institutional review board–approved, case-control, retrospective chart review of adult patients who underwent cardiac surgery by a single surgeon between January 1, 2001, and December 31, 2010. Preoperative CHADS 2 score criteria were collected, and outcomes through postoperative day 30 were analyzed. Results A total of 2067 patients were reviewed. Propensity score matching was used to create matched groups based on left atrial appendage ligation, and 631 patients were matched in each group. Subjects with postoperative atrial fibrillation were 2.4 times (95% confidence interval, 1.51-2.82) more likely to undergo valve surgery, 2.11 times (95% confidence interval, 1.56-2.86) more likely to be aged more than 75 years, and 1.36 times (95% confidence interval, 1.03-1.80) more likely to have undergone left atrial appendage ligation. In the left atrial appendage ligation group with postoperative atrial fibrillation (n = 145), there were zero subjects (0%) with a postoperative cardiovascular accident. In the non–left atrial appendage ligation group with postoperative atrial fibrillation (n = 115), there were 7 subjects (6.1%) with a postoperative cardiovascular accident (0.0% vs 6.1%, P = .003). Conclusions Although postoperative atrial fibrillation remains a common complication of cardiac surgery, there was a significant decrease in the incidence of postoperative cerebrovascular accidents since routine ligation of the left atrial appendage was undertaken. This has been found to be a safe adjunct to a wide variety of cardiac procedures and therefore deserves further study by a larger randomized controlled trial.

Rishi Agarwal,1,2 Paramveer Saluja,1 Angela Pham,3 Karen Ledbetter,3 Sukhveer Bains,3 Seema Varghese,3 John Clements,1 Young H Kim41Synergy Medical Education Alliance, Michigan State University College of Human Medicine, Saginaw, Michigan, USA; 2MD Anderson Cancer Center, Houston, Texas, USA; 3Michigan State University, Saginaw, Michigan, USA; 4Seton Cancer Institute, Saginaw, Michigan, USAIntroduction: The current standard for treating operable early stage non-small cell lung cancer is surgical resection and for inoperable cases it is external beam radiotherapy. Lung functions are adversely affected with both the above treatments. CyberKnife treatment limits radiation damage by tracking targets moving with each breath. The effect of CyberKnife treatment on pulmonary function tests has not been well documented.Methods: Lung cancer patients who underwent CyberKnife treatment and had pre- and post-treatment pulmonary function tests were included. Paired t-tests were conducted. We also conducted subgroup analysis.Results : Thirty-seven patients were included. Median age was 73 years. No statistical difference between mean pre- and post-CyberKnife pulmonary function tests was found.Discussion: We observed that CyberKnife better preserves lung function status compared to current standards of care. It has shown to have very minimal side effects.Keywords: non-small cell lung cancer, radiation pneumonitis, radiotherapy, pulmonary function tests

Introduction: Use of advance directives is underutilized despite the Patient Self Determination Act of 1990. This study was undertaken to determine use and opinions of advance directives by patients at a multidisciplinary. Methods: Institutional Review Board—approved prospective survey of patients age 18 and over. Results: Of 306 participants, 77 (25.2%) had a durable power of attorney and 45 (14.7%) had living wills. Of these, 226 (73.9%) responded that it was important to make health care wishes known to their doctor. Only 36 (15.9%) had done so. A total of 266 (86.9%) felt it was important to discuss health care wishes with their family and only 160 (60.1%) had done so. Conclusions: While adequately describing use and attitudes toward advance directives, it is significant to note that patients believe their wishes for end-of-life care will be honored; however, they fail to take the necessary steps to guarantee this.

OBJECTIVE: BB-81384, a novel peptide deformylase (PDF) inhibitor, was characterized in terms of enzyme inhibition profile, antibacterial activity, rodent pharmacokinetics and oral efficacy in murine infection models. METHODS: MICs were determined by standard NCCLS broth microdilution. Selectivity of metalloenzyme inhibition was determined with a limited panel of enzymes via standard biochemical assays. Profiling of the pharmacokinetics and select tissue disposition in mice was determined and compared with that of the macrolide, azithromycin. In vivo murine efficacy studies using Streptococcus pneumoniae were conducted using a peritonitis model, as well as lung and thigh burden models of infection. RESULTS: BB-81384 selectively inhibited PDF with an IC(50) approximately 10 nM and with MICs < 0.5 mg/L against most S. pneumoniae pathogens. Pharmacokinetic analysis revealed good oral bioavailability and moderate clearance and volume of distribution. BB-81384 partitioning to lung tissue was similar in terms of magnitude and kinetics to that of the plasma compartment. Single-administration oral efficacy in a mouse peritonitis model was evident with an ED(50) of 30 mg/kg. BB-81384 reduced the bacterial load by approximately 5 and 3 log units in organ-burden models of lung and thigh infection, respectively. CONCLUSION: BB-81384, a novel PDF inhibitor with good activity against S. pneumoniae in vitro, was the first compound of this class to be profiled for oral pharmacokinetics and tissue disposition and to demonstrate oral anti-pneumococcal efficacy in mice.

A series of analogues of the peptide deformylase (PDF) inhibitor BB-3497 where the P3' amide bond was replaced with a ketone functionality is described. The in vitro antibacterial profiling of these compounds revealed that they demonstrate activity against pathogens associated with respiratory tract infections.

The family of matrix metalloproteinases (MMPs) comprises endopeptidases that are capable of degrading all extracellular matrix components. Given these actions, it is conceivable that MMPs may play a pathogenic role in inflammatory myopathies. These immune-mediated disorders are characterized by the invasion of mononuclear phagocytes and T lymphocytes and the loss of muscle fibres. We examined whether specific MMPs and their natural inhibitors (tissue inhibitors of metalloproteinases; TIMPs) are expressed in muscle during acute inflammatory attacks by studying muscle biopsies obtained from patients diagnosed as having polymyositis, dermatomyositis, sporadic inclusion body myositis and, for comparison, from cases of various muscular dystrophies. Quantitative polymerase chain reaction analysis revealed significantly elevated mRNA expression of interstitial collagenase (MMP-1) and gelatinase B (MMP-9) in polymyositis and dermatomyositis and to a lesser extent in inclusion body myositis, whereas the level of expression of TIMPs remained unchanged in comparison with controls. Increased mRNA levels were associated with enhanced enzyme expression, as determined by immunoblotting, gelatin zymography and in situ zymography. Immunohistochemically, MMP-1 could be localized around the sarcolemma of diseased muscle fibres and to cells resembling fibroblasts, whereas MMP-9 seemed to be expressed primarily by invading T lymphocytes. Raised levels of MMPs could not be detected in the sera of affected patients, emphasizing the crucial action of MMPs in the inflamed muscle. Our results imply a pathogenic role for specific MMPs in the genesis of inflammatory myopathies, and open new strategies for therapeutic intervention.

Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of various inflammatory diseases of the central nervous system. Evidence is accumulating that gelatinase B (MMP-9) might be involved in the pathogenesis of meningitis, but the spectrum of different MMPs involved in the inflammatory reaction of this disease has not been determined. We investigated the temporal and spatial mRNA expression pattern of gelatinase B in experimental meningococcal meningitis in rats. In contrast to controls, increased mRNA levels with peak values 6 h after injection with menigococci were found in brain specimens of the animals. Elevated MMP-9 mRNA expression was accompanied by enhanced proteolytic activity, as demonstrated by gelatin zymography, and positive immunoreactivity. The mRNA expression pattern of six other MMPs was investigated. Collagenase-3 and stromelysin-1 mRNAs were also found to be upregulated. In contrast, mRNA levels for gelatinase A, matrilysin, stromelysin-2 and stromelysin-3 remained unchanged. As evidenced by significantly increased intracranial pressure and by leakage of intravenously injected Evans blue through the blood vessel walls into the brain parenchyma, the animals injected with meningococci revealed signs of blood-brain barrier disruption. Augmented proteolytic activity of MMP-9 could also be demonstrated in CSF samples obtained from patients with bacterial meningitis, underlining the clinical relevance of our experimental findings. Our data indicate that gelatinase B, collagenase-3 and stromelysin-1 are selectively upregulated in bacterial meningitis and thus may contribute to the pathogenesis of this infectious disease of the central nervous system.

Matrix metalloproteinases (MMPs) are a family of enzymes that may be implicated in the pathogenesis of inflammatory demyelinating disorders such as multiple sclerosis. The present study investigated the expression of 92-kd gelatinase (MMP-9) and five other MMPs in sciatic nerve from Lewis rats with autoimmune experimental neuritis (EAN), an experimental model of the Guillain-Barre syndrome (GBS). Quantitative polymerase chain reaction analysis revealed an up-regulation of MMP-9 mRNA with peak levels concurrent with maximal disease severity. Increased mRNA expression was associated with enhanced enzyme activity, as detected by gelatin zymography. Immunohistochemically, MMP-9 could be localized primarily around blood vessels within the epineurium and endoneurium in diseased but not normal sciatic nerve. Among all other MMPs investigated, mRNA levels of matrilysin (MMP-7) were found to be up-regulated at the peak of the disorder, remaining at high levels throughout the clinical recovery phase of the disease. To apply these findings to human disease, sural nerve biopsies from GBS patients were examined. By using immunohistochemistry, positive immunoreactivity against MMP-9 and MMP-7 was noted and corroborated by demonstrating augmented mRNA expression in comparison with noninflammatory neuropathies. Furthermore, increased MMP-9 activity was detected by zymography. These findings indicate that 92-kd gelatinase and matrilysin are selectively up-regulated during EAN and expressed in nerves of GBS patients and thus may contribute to the pathogenesis of inflammatory demyelination of the peripheral nervous system.

Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barré syndrome. We have shown recently that BB-1101, a broad-spectrum matrix metalloproteinase (MMP) inhibitor, prevents development of EAN when given from the day of immunization and, more important clinically, reduces disease severity when given from symptom onset. This suggests the involvement of MMP activity in the pathogenesis of EAN. However, the exact function and expression patterns of MMPs in acute inflammation of the PNS have not been investigated. MMP-like enzymes are also involved in the processing of tumour necrosis factor-alpha (TNF-alpha), which has been implicated previously in the pathology associated with EAN. In the present study we investigated the profile of MMP and TNF-alpha expression and their localization in sciatic nerve tissue during EAN, using a semiquantitative competitive reverse transcriptase-coupled polymerase chain reaction and immunohistochemistry. In the normal rat PNS, four of the 10 MMPs studied were constitutively expressed and four MMPs were differentially regulated during EAN. Expression of TNF-alpha was elevated at peak disease severity and localized to Schwann cells, macrophages and endoneurial blood vessels. Expression levels of 92 kDa gelatinase and stromelysin-1 were significantly increased early in the development of EAN and continued to rise, peaking at day 15 coincident with maximum disease severity. Schwann cells and endothelial cells were the main cellular source of these enzymes. Prominent infiltration of inflammatory cells into the sciatic nerve was concordant with a significant increase in the expression levels of matrilysin and macrophage metalloelastase. Both matrilysin and macrophage metalloelastase were detected in invading macrophages, T lymphocytes and resident Schwann cells. The selective upregulation of specific MMPs during EAN and their varied cellular localization suggests that MMPs play a multifactorial role in the aetiology of EAN. Activity of MMPs could participate in the disruption of the blood-nerve barrier, breakdown of the myelin sheath, the release of TNF-alpha, and facilitate leukocyte invasion into the PNS. These observations highlight MMPs as potential targets for therapeutic intervention in acute peripheral neuropathies, such as Guillain-Barré syndrome.

Matrix metalloproteinases (MMPs) comprise a group of proteolytic enzymes that are implicated in the pathogenesis of inflammatory diseases of the nervous system such as multiple sclerosis. However, the exact function and expression pattern of MMPs in the inflamed nervous system are not known. In the present study we investigated the expression of 92-kDa gelatinase (MMP-9) in spinal cord from animals with adoptive transfer experimental autoimmune encephalomyelitis (AT-EAE), using a semiquantitative competitive reverse transcriptase-polymerase chain reaction assay. Increased levels of MMP-9 mRNA were found with peak values at times of maximum disease severity. Increased mRNA expression was associated with enhanced proteolytic activity of this enzyme, as demonstrated by gelatin zymography. Immunohistochemistry revealed immunoreactivity along the meninges, around blood vessels and within the parenchyma, in diseased but not in normal spinal cord. Furthermore, the expression pattern of five other MMPs was investigated. Matrilysin (MMP-7) was also found to be upregulated with maximum mRNA levels at the peak of the disease. In contrast, mRNAs for collagenase-3, 72-kDa gelatinase, and stromelysin-1 and -3 were not changed. Our findings indicate that 92-kDa gelatinase and matrilysin are selectively upregulated during AT-EAE and thus may contribute to the pathogenesis of inflammatory diseases of the CNS.

Matrix metalloproteinases (MMPs) are a large family of Zn2+ endopeptidases that are expressed in inflammatory conditions and are capable of degrading connective tissue macromolecules. MMP-like enzymes are also involved in the processing of a variety of cell surface molecules including the pro-inflammatory cytokine TNF-alpha. MMPs and TNF-alpha have both been implicated in the pathology associated with neuro-inflammatory diseases (NIDs), particularly multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). We have shown that BB-1101, a broad spectrum hydroxamic acid-based combined inhibitor of MMP activity and TNF processing, reduces the clinical signs and weight loss in an acute EAE model in Lewis rats. However, little is known about which MMPs are involved in the neuroinflammatory process. In order to determine the optimum inhibitory profile for an MMP inhibitor in the treatment of NID, we investigated the profile of MMP expression and activity during EAE. The development of disease symptoms was associated with a 3-fold increase in MMP activity in the cerebrospinal fluid (CSF), which could be inhibited by treatment with BB-1101, and an increase in 92 kDa gelatinase activity detected by gelatin substrate zymography. Quantitative PCR analysis of normal and EAE spinal cord revealed the expression of at least seven MMPs. Of these, matrilysin showed the most significant change, being elevated over 500 fold with onset of clinical symptoms and peaking at maximum disease severity. Of the other six MMPs detected, 92 kDa gelatinase showed a modest 5 fold increase which peaked at the onset of clinical signs and then declined during the most severe phase of the disease. Matrilysin was localised by immunohistochemistry to the invading macrophages within the inflammatory lesions of the spinal cord. Matrilysin's potent broad spectrum proteolytic activity and its localisation to inflammatory lesions in the CNS suggest this enzyme could be particularly involved in the pathological processes associated with neuro-inflammatory disease.

This review revealed a lack of statistical difference for staple line leak with or without staple line reinforcement in laparoscopic sleeve gastrectomy., Background and Objectives: Laparoscopic sleeve gastrectomy is gaining popularity as a bariatric procedure, with outcomes similar to gastric band and gastric bypass. Staple-line disruption is a significant source of morbidity and death. We aim to evaluate the effect of staple-line reinforcement on the gastric leak rate, morbidity, and mortality rate. Methods: A systematic review was performed using title key words “sleeve gastrectomy,” and articles were reviewed for description of operative technique and postoperative outcomes including staple-line leak. Rates of leak, bleeding, surgical-site infection, reintervention, readmission, and mortality were analyzed. We calculated pooled event rates and 95% confidence intervals using fixed-effects modeling to determine differences between the reinforcement group (group A) and non-reinforcement group (group B). Results: We identified 390 articles, and 30 met the inclusion criteria. Group A had 3293 patients, and group B had 1588 patients. After heterogeneity calculations, 9 variables met the criteria to be analyzed. The leak rate was 3.9% (95% confidence interval, 2.9%–5.5%) in group A and 3.2% (95% confidence interval, 2.8%–4.1%) in group B. The mortality rate was 0.8% (95% confidence interval, 0.4%–1.5%) in group A and 0.7% (95% confidence interval, 0.4%–1.1%) in group B. Our results also showed no statistical difference for any of our other 7 outcome variables. Conclusion: Our study shows a lack of statistical difference in leak rate, overall morbidity, or mortality rate in laparoscopic sleeve gastrectomy with or without staple-line reinforcement. Because of study limitations, we propose that prospective trials are needed to determine the effect of staple-line reinforcement on leak rates.

Aims. Preoperative diabetic and glycemic screening may or may not be cost effective. Although hyperglycemia is known to compromise surgical outcomes, the effect of a diabetic diagnosis on outcomes is poorly known. We examine the effect of diabetes on outcomes for general and vascular surgery patients. Methods. Data were collected from the Michigan Surgical Quality Collaborative for general or vascular surgery patients who had diabetes. Primary and secondary outcomes were 30-day mortality and 30-day overall morbidity, respectively. Binary logistic regression analysis was used to identify risk factors. Results. We identified 177,430 (89.9%) general surgery and 34,006 (16.1%) vascular surgery patients. Insulin and noninsulin diabetics accounted for 7.1% and 9.8%, respectively. Insulin and noninsulin dependent diabetics were not at increased risk for mortality. Diabetics are at a slight increased odds than non-diabetics for overall morbidity, and insulin dependent diabetics more so than non-insulin dependent. Ventilator dependence, 10% weight loss, emergent case, and ASA class were most predictive. Conclusions. Diabetics were not at increased risk for postoperative mortality. Insulin-dependent diabetics undergoing general or vascular surgery were at increased risk of overall 30-day morbidity. These data provide insight towards mitigating poor surgical outcomes in diabetic patients and the cost effectiveness of preoperative diabetic screening.

Matrix metalloproteinases (MMPs) are a family of Zn2+ endopeptidases that are expressed in many inflammatory conditions and that contribute to connective tissue breakdown and the release of the pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha). There is emerging evidence that MMPs have a role in inflammatory disorders of the central nervous system (CNS) such as multiple sclerosis. However, little is known about the expression of MMPs by inflamed tissue within the CNS or by the glia, neurones, and leucocytes which participate in the inflammatory response. To address this issue we have developed a polymerase chain reaction (PCR)-based method for the quantitation of rat MMP mRNA levels, which we have applied to astrocyte cultures with and without inflammatory stimulation. The technique relies on a competition reaction in which a synthetic standard cDNA is co-amplified with the target cDNA in the same PCR reaction. Standard multi-competitor cDNAs, containing priming sites for nine MMPs, and two housekeeping genes were constructed. We have shown that MMP activity is increased over three-fold in neonatal rat astrocyte cultures following stimulation with lipopolysaccharide (LPS). At the mRNA level, MT-MMP-1, 72 kDa gelatinase, and stromelysin-3 were constitutively expressed and unaffected by LPS treatment, whereas 92 kDa gelatinase, and stromelysin-1 were strongly induced (1,000-fold). Stromelysin-2, rat collagenase, and macrophage metalloelastase were modestly upregulated by LPS treatment. Matrilysin was not expressed. This technique is suitable for quantifying MMP expression in the cells which contribute to inflammation in the CNS and could also be applied directly to tissue samples from animal models of disease.

Background The elderly population (aged 65 y and older) is expected to be the dominant age group in the United States by 2030. In addition, the prevalence of obesity in the United States is growing exponentially. Obese elderly patients are increasingly undergoing elective or emergent general surgery. There are few, if any, studies highlighting the combined effect of age and body mass index (BMI) on surgical outcomes. We hypothesize that increasing age and BMI synergistically impact morbidity and mortality in general surgery. Materials and methods We collected individual-level, de-identified patient data from the Michigan Surgical Quality Collaborative. Subjects underwent general surgery with general anesthetic, were >18 y, and had a BMI between 19 and 60. Primary and secondary outcomes were 30-d “Any morbidity” and mortality (from wound, respiratory, genitourinary, central nervous system, and cardiac systems), respectively. Preoperative risk variables included diabetes, dialysis, steroid use, cardiac risk, wound classification, American Society of Anesthesiology class, emergent cases, and 13 other variables. We conducted binary logistic regression models for 30-d morbidity and mortality to determine independent effects of age, BMI, interaction between both age and BMI, and a saturated model for all independent variables. Results We identified 149,853 patients. The average age was 54.6 y, and the average BMI was 30.9. Overall 30-d mortality was 2%, and morbidity was 6.7%. Age was a positive predictor for mortality and morbidity, and BMI was negatively associated with mortality and not significantly associated with morbidity. Age combined with higher BMI was positively associated with morbidity and mortality when the higher age groups were analyzed. Saturated models revealed age and American Society of Anesthesiology class as highest predictors of poor outcomes. Conclusions Although BMI itself was not a major independent factor predicting 30-d major morbidity or mortality, the morbidly obese, elderly (>50 and 70 y, respectively) subgroup may have an increased morbidity and mortality after general surgery. This information, along with patient-specific factors and their comorbidities, may allow us to better take care of our patients perioperatively and better inform our patients about their risk of surgical procedures.

Research question. This paper was done to answer the question on whether patients with IBS require higher analgesic or anxiolytic doses during colonoscopy. Setting. Gastroenterology practice in Michigan, USA. Methods. We reviewed the charts of patients following up with a US based gastroenterology practice. We collected data on whether or not they had IBS, and collected data on analgesic and anxiolytic requirement during colonoscopy. Results. 336 patients were included in the trial. 206 did not have IBS while 130 had a previous diagnosis of IBS. 234 were female (67.2%). When comparing patients who have IBS to those without IBS, we identified no statistically significant difference in midazolam dose (5.5 mg versus 5.5 mg), fentanyl dose ( 117 mg versus 112 mg) or meperidine dose (69 mg versus 69 mg). The lack of differences in medication doses used remained when we controlled for sex, prior analgesic use, and prior abdominal surgery. Conclusion. Dose of analgesic or anxiolytic used during colonoscopy cannot be used to identify patients with IBS.

An important step in the cascade leading to neuronal cell death is degradation of laminin and other components of the brain extracellular matrix by microglia-derived proteases. Excitotoxic cell death of murine hippocampal neurones in vivo can be prevented by inhibitors of tissue plasminogen activator (tPA) or by inhibitors of plasmin. Plasmin is a potent activator of the matrix metalloproteinases (MMPs), which are made by resident and recruited leukocytes following CNS injury. In this study, we show, using Taqman RT-PCR, that MMP mRNAs, but not other calcium-dependent proteases such as calpain mRNAs, are acutely up-regulated after an excitotoxic challenge in vivo. alpha(2)-antiplasmin or BB-3103, a broad-spectrum inhibitor of the MMPs, co-injected with kainic acid into the striatum, inhibits excitotoxic cell death in the rat striatum, and reduces both the number of recruited macrophages and the size of the lesion. We also show that leukocyte populations differentially express MMPs, which may account, in part, for the expression profile we observe in the challenged brain. Our results show that inhibition of the MMPs in the rat will prevent kainic acid-induced cell death in the brain. These studies suggest that MMP inhibitors have therapeutic potential for use in stroke, and support the increasing evidence that microglial activation may contribute to neuronal cell death.

Objectives: BB-83698 is a peptide deformylase inhibitor currently in clinical trials in Europe. The purpose of this study was to provide additional susceptibility data from clinical isolates, including drug-resistant strains. Methods: The in vitro activities of BB-83698 and comparators were determined against 281 streptococci, 154 Staphylococcus aureus, 110 Haemophilus influenzae and 50 Moraxella catarrhalis strains selected for their resistance phenotypes. Broth microdilution MICs and MBCs were determined according to NCCLS guidelines. Results: The MIC90s were 0.25-0.5 mg/L for S. pneumoniae, including penicillin-, erythromycin-, levo- floxacin- and multidrug-resistant strains. The MIC90s for Streptococcus pyogenes and Streptococcus agalactiae were 0.12 mg/L and for viridans streptococci, the MIC 90 was 0.5 mg/L. Against S. aureus, including oxacillin- and levofloxacin-resistant strains, and vancomycin-intermediate strains, the MIC90 was 8 mg/L. Against β-lactamase-negative and -positive H. influenzae, the MIC90s were 32 and 64 mg/L, respectively, and against both β-lactamase-negative and -positive M. catarrhalis the MIC 90 was 0.12 mg/L. In MBC studies, the ratio of MBC/MIC was 1:1 or 2:1 against 31% of S. pneumoniae, 33% of S. aureus, 63% of H. influenzae and 9% of M. catarrhalis. Conclusions: Although BB-83698 has reduced in vitro activity against H. influenzae, it is a potent antimicrobial with excellent activity against streptococci and Moraxella.

A series of analogues of the potent peptide deformylase (PDF) inhibitor BB-3497 containing alternative metal binding groups was synthesised. Enzyme inhibition and antibacterial activity data for these compounds revealed that the bidentate hydroxamic acid and N-formyl hydroxylamine structural motifs represent the optimum chelating groups on the pseudopeptidic BB-3497 backbone.

Lipid A is the hydrophobic anchor of lipopolysaccharide (LPS) and forms the major lipid component of the outer monolayer of the outer membrane of gram-negative bacteria. Lipid A is required for bacterial growth and virulence, and inhibition of its biosynthesis is lethal to bacteria. UDP-3- O -( R -3-hydroxymyristoyl)- N -acetylglucosamine deacetylase (LpxC) is a metalloenzyme that catalyzes the second step in the biosynthesis of lipid A. Inhibitors of LpxC have previously been shown to have antibiotic activities. We have screened a metalloenzyme inhibitor library for antibacterial activities against an Escherichia coli strain with reduced LpxC activity. From this screen, a series of sulfonamide derivatives of the α-( R )-amino hydroxamic acids, exemplified by BB-78484 and BB-78485, have been identified as having potent inhibitory activities against LpxC in an in vitro assay. Leads from this series showed gram-negative selective activities against members of the Enterobacteriaceae , Serratia marcescens , Morganella morganii , Haemophilus influenzae , Moraxella catarrhalis , and Burkholderia cepacia . BB-78484 was bactericidal against E. coli , achieving 3-log killing in 4 h at a concentration 4 times above the MIC, as would be predicted for an inhibitor of lipid A biosynthesis. E. coli mutants with decreased susceptibility to BB-78484 were selected. Analysis of these mutants revealed that resistance arose as a consequence of mutations in the fabZ or lpxC genes. These data confirm the antibacterial target of BB-78484 and BB-78485 and validate LpxC as a target for gram-negative selective antibacterials.

Background — Atherosclerosis is implicated in the pathogenesis of abdominal aortic aneurysm (AAA) but more often causes aortic occlusive disease (AOD). The matrix metalloproteinases (MMPs) degrade extracellular matrix and may play a central role in the pathogenesis of AAA. The aim of this study was to examine differences in the patterns of MMP and MMP inhibitor expression between AAA and AOD. Methods and Results — The expression of mRNA for 14 MMPs and 4 tissue inhibitors of metalloproteinases (TIMPs) was estimated in samples of aortic wall from 8 patients with AAA and 8 with AOD using the reverse-transcriptase polymerase chain reaction with a synthetic multicompetitor standard. AAA wall expressed significantly more stromelysin-1 (MMP-3) (mean log 10 ratio [copy enzyme cDNA/copy GAPDH cDNA], −1.9; range, −3.3 to −0.7) than the AOD wall (mean, 4; range, −5.7 to −2.4), P P Conclusions — Both AAA and AOD walls express similar levels of a wide range of MMPs, including cell membrane–bound MT-MMPs. Stromelysin-1 (MMP-3) and TIMP-3 were, however, over expressed in the AAA samples and may be involved aneurysm pathogenesis. Stromelysin-1 could provide a target for pharmacological inhibition.

Matrix metalloproteinases (MMPs) and tumour necrosis factor alpha (TNF-alpha) converting enzyme (TACE) contribute synergistically to the pathophysiology of bacterial meningitis. TACE proteolytically releases several cell-surface proteins, including the proinflammatory cytokine TNF-alpha and its receptors. TNF-alpha in turn stimulates cells to produce active MMPs, which facilitate leucocyte extravasation and brain oedema by degradation of extracellular matrix components. In the present time-course studies of pneumococcal meningitis in infant rats, MMP-8 and -9 were 100- to 1000-fold transcriptionally upregulated, both in CSF cells and in brain tissue. Concentrations of TNF-alpha and MMP-9 in CSF peaked 12 h after infection and were closely correlated. Treatment with BB-1101 (15 mg/kg subcutaneously, twice daily), a hydroxamic acid-based inhibitor of MMP and TACE, downregulated the CSF concentration of TNF-alpha and decreased the incidences of seizures and mortality. Therapy with BB-1101, together with antibiotics, attenuated neuronal necrosis in the cortex and apoptosis in the hippocampus when given as a pretreatment at the time of infection and also when administration was started 18 h after infection. Functionally, the neuroprotective effect of BB-1101 preserved learning performance of rats assessed 3 weeks after the disease had been cured. Thus, combined inhibition of MMP and TACE offers a novel therapeutic strategy to prevent brain injury and neurological sequelae in bacterial meningitis.

The proinflammatory Th1 cytokine, tumor necrosis factor-alpha (TNF alpha), the cell death signaling molecule FasL, and several extracellular matrix degrading metalloproteinases have been implicated in the pathogenesis of multiple sclerosis (MS). The latter enzymes, as well as TNF alpha-converting enzyme and FasL-converting enzyme, can be blocked by matrix metalloproteinase inhibitors (MMPIs). In this study, we show that a potent MMPI was clinically effective in an animal model for MS, experimental autoimmune encephalomyelitis (EAE) in the SJL/J mouse. Efficacy was remarkable, as indicated by blocking and reversal of acute disease and reduced number of relapses and diminished mean cumulative disease score in chronic relapsing animals. Also, demyelination and glial scarring were significantly decreased in MMPI-treated mice with chronic relapsing EAE, as was central nervous system gene expression for TNF alpha and fasL. It is interesting that expression of the beneficial cytokine interleukin-4 (IL-4) was increased, and IL-4 was expressed on glial cells. The relevance of these compounds for MS was underscored by their ability to specifically inhibit TNF alpha shedding and cytotoxicity of myelin-autoreactive human cytotoxic CD4+ T-cell clones. This is the first report to show a positive effect by MMPIs on chronic relapsing EAE, its central nervous system cytokine profile, and on TNF alpha shedding by human myelin-autoreactive T cells.

The pathology of multiple sclerosis (MS) is characterised by breakdown of the blood-brain barrier accompanied by infiltration of macrophages and T cells into the central nervous system (CNS). Myelin is degraded and engulfed by the macrophages, producing lesions of demyelination. Some or all of these mechanisms might involve proteinases, and here we have studied the cellular localisation and distribution of two matrix metalloproteinases (MMPs), MMP-7 (matrilysin) and MMP-9 (92-kDa gelatinase), in the normal human CNS and active demyelinating MS lesions. Cryostat sections of CNS samples were immunostained with antisera to MMP-7 and MMP-9. In addition, non-radioactive in situ hybridisation (ISH) was performed using a digoxygenin-labelled riboprobe to detect the expression of MMP-7. MMP-7 immunoreactivity was weakly detected in microglial-like cells in normal brain tissue sections, and was very strong in parenchymal macrophages in active demyelinating MS lesions. This pattern of expression was confirmed using ISH. MMP-7 immunoreactivity was not detected in macrophages in spleen or tonsil, indicating that it is specifically induced in infiltrating macrophages in active demyelinating MS lesions. MMP-9 immunoreactivity was detected in a few small blood vessels in normal brain tissue sections, whereas many blood vessels stained positive in CNS tissue sections of active demyelinating MS lesions. The up-regulation of MMPs in MS may contribute to the pathology of the disease.

Tumour necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory and immunomodulatory cytokine implicated in inflammatory conditions such as rheumatoid arthritis, Crohn's disease, multiple sclerosis and the cachexia associated with cancer or human immunodeficiency virus infection. TNF-alpha is initially expressed as a 233-amino-acid membrane-anchored precursor which is proteolytically processed to yield the mature, 157-amino-acid cytokine. The processing enzyme(s) which cleave TNF-alpha are unknown. Here we show that the release of mature TNF-alpha from leukocytes cultured in vitro is specifically prevented by synthetic hydroxamic acid-based metalloproteinase inhibitors, which also prevent the release of TNF-alpha into the circulation of endotoxin challenged rats. A recombinant, truncated TNF-alpha precursor is cleaved to biologically active, mature TNF-alpha by several matrix metalloproteinase enzymes. These results indicate that processing of the TNF-alpha precursor is dependent on at least one matrix metalloproteinase-like enzyme, inhibition of which represents a novel therapeutic mechanism for interfering with TNF-alpha production.

Children are at greater risk than adults of permanent brain damage and mortality following head injury or infection [1-5]. Rodent models have demonstrated a 'window of susceptibility' in young animals during which the brain parenchyma is at greater risk of acute neutrophil-mediated breakdown of the blood-brain barrier [6-7]. The exact mechanism of this age-related susceptibility to brain inflammation has yet to be defined, but animal models have revealed that the potent pro-inflammatory cytokine interleukin-1beta (IL-1beta) initiates an intense acute neutrophil-mediated inflammatory response in the brains of young rats and mice that is not seen in adults [6]. Here, we demonstrate the rapid induction of CXC chemokines (which contain a Cys-X-Cys motif), in particular the cytokine-induced neutrophil chemoattractant CINC-1, following the intracerebral administration of IL-1beta. The CXC chemokines produced a more intense neutrophil response in young rats than in adults. The IL-1beta-induced blood-brain barrier breakdown in young rats could be attenuated by an anti-CINC-1 neutralising antibody. These results show that the immature central nervous system (CNS) is dramatically more susceptible to the chemotactic effects of CXC chemokines. Blocking the CXC chemokine activity associated with brain inflammation inhibits neutrophil-mediated blood-brain barrier damage and represents a significant therapeutic possibility.