CHARACTERIZING THE EPIDEMIOLOGY OF HISTORIC AND NOVEL PATHOGENS IN BLANDING'S TURTLES (EMYDOIDEA BLANDINGII).

Pathogens such as herpesviruses, Mycoplasma spp., and frog virus 3-like ranavirus have contributed to morbidity and mortality in many species of free-living and zoo-maintained chelonians. However, their prevalence is understudied in Blanding's turtles (Emydoidea blandingii) across North America. To assess the presence of these pathogens, Blanding's turtles were sampled in Lake County, Illinois, in 2017 (N = 213) and 2018 (N = 160). DNA from cloacal-oral swabs was assayed for four ranaviruses, three Mycoplasma spp., two Salmonella spp., Emydoidea herpesvirus 1 (EBHV1), and tortoise intranuclear coccidiosis (TINC) using a multiplex quantitative polymerase chain reaction (qPCR). Pathogens were most frequently detected in adult turtles (n = 25) and rarely in subadults (n = 2) or juveniles (n = 1). EBHV1 was detected in 22 individuals with no clinical signs of illness, most (n = 20) occurring in the month of May (P < 0.0001). EBHV1 cases at one study site significantly clustered within the same 0.64-km area from 17 to 22 May 2017 (P < 0.0001) and 14 to 15 May 2018 (P = 0.0006). Individuals were rarely positive for Salmonella typhimurium (n = 6). A novel Mycoplasma sp. sharing high homology with other emydid Mycoplasma spp. was detected in one turtle with nasal discharge. Neither TINC nor any ranaviruses were detected. Continued monitoring of this population and habitat may facilitate identification of risk factors for pathogen occurrence and clarify the impact of infectious diseases on Blanding's turtle conservation outcomes.

Serosurvey for Canine Influenza in Coyotes (Canis latrans) in Illinois, USA, 2000-23.

Coyotes (Canis latrans) share urban habitats with domestic dogs (Canis lupus familiaris), providing opportunities for pathogen transmission. In Chicago, Illinois, USA, canine influenza virus (CIV) is prevalent in dogs. Serologic investigation for exposure in 101 coyote samples collected 2000-23 did not detect any antibodies against CIV H3N2 and H3N8.

Efficacy of Edible and Leisure Reinforcers with Domestic Dogs.

Preference assessments are often used to identify stimuli that function as potential reinforcers for training or intervention purposes. Specifically, various preference assessment formats have been used to identify preferred stimuli for humans, cockroaches, cotton-top tamarins, tortoises, and wolves, to name a few. However, to date, no study has evaluated the differential efficacy between food and leisure stimuli within domestic dogs. The current study aimed to compare the reinforcing value and efficacy between food and leisure stimuli for domestic dogs by comparing rates of behavior when receiving access to either their top-preferred food or leisure items. Overall results suggest (1) domestic dogs prefer food over leisure items, and (2) food is more likely to function as a reinforcer than leisure items for domestic dog's behavior. These results suggest that dog owners and trainers should consider using food reinforcers over leisure items as reinforcers when attempting to train dogs.

A novel herpesvirus detected in 3 species of chelonians.

Herpesviruses are found in free-living and captive chelonian populations, often in association with morbidity and mortality. To date, all known chelonian herpesviruses fall within the subfamily Alphaherpesvirinae. We detected a novel herpesvirus in 3 species of chelonians: a captive leopard tortoise (Stigmochelys pardalis) in western TX, USA; a steppe tortoise (Testudo [Agrionemys] horsfieldii) found near Fort Irwin, CA, USA; and 2 free-living, three-toed box turtles (Terrapene mexicana triunguis) found in Forest Park, St. Louis, MO. The leopard tortoise was coinfected with the tortoise intranuclear coccidian and had clinical signs of upper respiratory tract disease. The steppe tortoise had mucopurulent nasal discharge and lethargy. One of the three-toed box turtles had no clinical signs; the other was found dead with signs of trauma after being observed with blepharedema, tympanic membrane swelling, cervical edema, and other clinical signs several weeks prior to death. Generally, the branching order of the turtle herpesviruses mirrors the divergence patterns of their hosts, consistent with codivergence. Based on phylogenetic analysis, this novel herpesvirus clusters with a clade of viruses that infect emydid hosts and is likely of box turtle origin. Therefore, we suggest the name terrapene alphaherpesvirus 3 (TerAHV3) for the novel virus. This virus also has the ability to host-jump to tortoises, and previously documented herpesviral morbidity tends to be more common in aberrant hosts. The relationship between clinical signs and infection with TerAHV3 in these animals is unclear, and further investigation is merited.

Matrix metalloproteinase-12 is a therapeutic target for asthma in children and young adults.

BACKGROUND: Matrix metalloproteinase (MMP)-12-mediated pathologic degradation of the extracellular matrix and the subsequent repair cycles influence the airway changes in patients with asthma and chronic obstructive pulmonary disease (COPD). The common serine variant at codon 357 of the MMP12 gene (rs652438) is associated with clinical manifestations consistent with more aggressive matrix degradation in other tissues. OBJECTIVE: We sought to explore the hypothesis that MMP12 represents a novel therapeutic target in asthma. METHODS: The role of the rs652438 variant on clinical phenotype was explored in young asthmatic patients and patients with COPD. Candidate MMP-12 inhibitors were identified on the basis of potency and selectivity against a panel of other MMPs. The role of MMP-12-specific inhibition was tested in vitro, as well as in animal models of allergic airway inflammation. RESULTS: The odds ratio for having greater asthma severity was 2.00 (95% CI, 1.24-3.24; P = .004) when comparing asthmatic patients with at least 1 copy of the serine variant with those with none. The carrier frequency for the variant increased in line with asthma treatment step (P = .000). The presence of the variant nearly doubled the odds in favor of asthmatic exacerbations (odds ratio, 1.90; 95% CI, 1.19-3.04; P = .008) over the previous 6 months. The serine variant was also associated with increased disease severity in patients with COPD (P = .016). Prior administration of an MMP-12-specific inhibitor attenuated the early airway response and completely blocked the late airway response with subsequent Ascaris suum challenge in sheep. CONCLUSION: Studies on human participants with asthma and COPD show that the risk MMP12 gene variant is associated with disease severity. In allergen-sensitized sheep pharmacologic inhibition of MMP12 downregulates both early and late airway responses in response to allergic stimuli.

Plasma electrophoresis profiles of Blanding's turtles (Emydoidea blandingii) and influences of month, age, sex, health status, and location.

Baseline plasma electrophoresis profiles (EPH) are important components of overall health and may aid in the conservation and captive management of species. The aim of this study was to establish plasma protein fractions for free-ranging Blanding's turtles (Emydoidea blandingii) and evaluate differences due to age class (adult vs. sub-adult vs. juvenile), sex (male, female, or unknown), year (2018 vs. 2019), month (May vs. June vs. July), health status, and geographical location (managed vs. unmanaged sites). Blood samples were obtained from 156 Blanding's turtles in the summer of 2018 and 129 in 2019 at two adjacent sites in Illinois. Results of the multivariate analysis demonstrated that age class, sex, year, month, health status, and geographical location all contributed to the variation observed in free-ranging populations. Adult females had the highest concentration of many protein fractions, likely associated with reproductive activity. Juveniles had lower protein concentrations. Temperature and rainfall differences between years impacted concentrations between 2018 and 2019, while May and June of both years saw higher levels in some protein fractions likely due to peak breeding and nesting season. Individuals with evidence of trauma or disease also showed increased plasma protein fractions when compared to those that were considered healthy. The two sites showed a wide/large variation over the two years. All of these factors emphasize the importance of considering multiple demographic or environmental factors when interpreting the EPH fractions. Establishing ranges for these analytes will allow investigation into disease prevalence and other environmental factors impacting this endangered species.

Detection of a novel herpesvirus associated with squamous cell carcinoma in a free-ranging Blanding's turtle.

The spread of both infectious and noninfectious diseases through wildlife populations is of increasing concern. Neoplastic diseases are rarely associated with population-level impacts in wildlife; however, impacts on individual health can be severe and might reflect deteriorating environmental conditions. An adult male free-ranging Blanding's turtle (Emydoidea blandingii) originally captured in 2005 and deemed healthy, was recaptured in 2018 with a 1 × 1.5 cm intra-oral broad-based right mandibular mass. An excisional biopsy was performed, and histopathology revealed squamous cell carcinoma (SCC). Consensus herpesvirus PCR identified a novel herpesvirus (proposed name Emydoidea herpesvirus 2 [EBHV-2]) within the tumor. EBHV-2 shares 85% sequence homology with Terrapene herpesvirus 2 (TerHV-2), a herpesvirus linked to fibropapillomas in eastern box turtles (Terrapene carolina carolina). Virus-associated fibropapillomas have been identified in multiple marine turtle species and have had debilitating effects on their populations, but to date, virus-associated SCCs are rarely reported.

Proposed changes to management of lower respiratory tract infections in response to the Clostridium difficile epidemic.

Clostridium difficile infection (CDI) remains a major healthcare problem associated with antibiotic use in hospitals. Recent years have seen a dramatic increase in the incidence of CDI in the UK and internationally. Lower respiratory tract infections (LRTIs) are the leading indication for antibiotic prescription in hospitals and are therefore a critical battleground in the fight against inappropriate antibiotic use and healthcare-associated infections. This article reviews the evidence for interventions to reduce CDI in hospitalized patients with LRTIs. Reducing prescriptions of cephalosporins and fluoroquinolones in favour of penicillin-based regimens and increased use of tetracyclines have been proposed. Expanding outpatient management of LRTIs and reducing length of hospital stay will limit patient exposure to the healthcare environment in which C. difficile is most easily acquired. Intravenous (iv) broad-spectrum antibiotics are often prescribed when narrower spectrum, oral antimicrobials would be equally effective and, in a proportion of patients, antibiotic therapy is used unnecessarily. Shorter antibiotic regimes may be as effective as prolonged therapy and reduce antibiotic-related complications. Early switch from iv to oral therapy allows simpler antibiotic regimens and facilitates early discharge from hospital. Simple improvements in the management of LRTIs have the potential to reduce the incidence of healthcare-associated infections.

Tackling upper respiratory tract infections.

URTIs are the most common reason for general practice consultations. On average adults suffer two to three such infections per year. When assessing a patient with a URTI in general practice it is important to recognise which patients may require antibiotics, further investigations and/or hospital referral. NICE recommends immediate antibiotics or further investigation and/or management in the following patients who are at risk of complications: Systemically very unwell. Features suggestive of serious illness and complications. Pre-existing comorbidities Older than 65 years with acute cough and two or more of the following, or older than 80 years with acute cough and one or more of the following: hospitalisation in the previous year; diabetes; history of congestive heart failure; current use of oral glucocorticoids. Antibiotics should also be considered for patients with three or more Centor criteria. In other cases (acute otitis media, acute sore throat/pharyngitis/acute tonsillitis, common cold, acute rhinosinusitis or acute cough/acute bronchitis) NICE advocates a no prescribing or delayed prescribing strategy. Most URTIs are self-managed. Patients who do seek consultations often benefit from reassurance, education and instructions for symptomatic home treatment.

Erythrocyte sedimentation rate and hemoglobin-binding protein in free-living box turtles (Terrapene spp.).

The acute phase response is a highly conserved reaction to infection, inflammation, trauma, stress, and neoplasia. Acute phase assays are useful for wildlife health assessment, however, they are infrequently utilized in reptiles. This study evaluated erythrocyte sedimentation rate (ESR) in eastern (Terrapene carolina carolina) and ornate box turtles (Terrapene ornata ornata) and hemoglobin-binding protein (HBP) in T. ornata. Erythrocyte sedimentation rate in 90 T. carolina and 105 T. ornata was negatively associated with packed cell volume and was greater in unhealthy turtles (p < 0.05). Female T. ornata had higher ESR values than males (p < 0.05). Measurement of ESR with a microhematocrit tube proportionally overestimated values from a commercial kit (Winpette), though both methods may retain utility with separate reference intervals. Hemoglobin-binding protein concentration in 184 T. ornata was significantly increased in adults and unhealthy turtles (p < 0.05). Erythrocyte sedimentation rate values were similar between seasons and populations, and HBP values were consistent between years, indicating that these analytes may have more stable baseline values than traditional health metrics in reptiles. This study demonstrates that ESR and HBP are promising diagnostics for health assessment in wild box turtles. Incorporating these tests into wild herptile health assessment protocols may support conservation efforts and improve ecosystem health monitoring.

Managing LRTI in adults in the community.

When considering a diagnosis of LRTI the main differentiation to make is between pneumonia and non-pneumonic LRTI. It is more difficult to make this distinction in the community because of access constraints to chest radiography and the lack of a quick, simple marker to identify patients with true pneumonia accurately. The diagnosis of pneumonia in the community, without a chest radiograph, is suggested by symptoms that include: cough; (purulent) sputum production; breathlessness; pleurisy; occasional haemoptysis along with new focal signs on chest examination (e.g. crepitations, bronchial breathing, and dullness to percussion); at least one systemic feature (e.g. sweating, fevers, shivers, aches and pains and/or temperature >38 degrees C); and no other explanation for the symptoms. A recent observational study of around 150,000 patients with LRTI in the UK found that the following factors were associated with increased respiratory infection-related mortality: increasing age; smoking; increasing Charlson co-morbidity index; prior antibiotic prescribing; frequent consultation and prior specialist referral or admission. Acute adult LRTI presenting to GPs is a predominantly viral illness most commonly caused by rhinoviruses and influenza viruses. The most common bacterial cause of pneumonia is Streptococcus pneumoniae but frequently no organism is identified. In patients where you suspect non-pneumonic LRTI, the evidence suggests that chest radiography and blood tests for CRP are not helpful in their management in the community. The BTS guidelines recommend that GPs, particularly those working in out-of-hours and emergency assessment centres, should consider using pulse oximeters. The CRB-65 is a helpful tool in the community. Patients scoring 0 or 1 have the lowest mortality risk, however, a score of 2 or more should be a cause for concern and the patient may need to be admitted to hospital for assessment.

Investigating the Analytical Variability and Agreement of Manual Leukocyte Quantification Methods in Eastern Box Turtles (Terrapene carolina carolina).

Leukogram evaluation provides valuable information about inflammation, infection, and stress in free-living and zoo-maintained wildlife. While multiple protocols for quantifying leukocytes are available in reptiles, agreement between methods is infrequently described and analytical variability (including repeatability and reproducibility) has not been critically evaluated. This study addresses these knowledge gaps for two hematological methods in eastern box turtles (Terrapene carolina carolina): Avian Leukopet™ (LO) and total white blood cell (WBC) estimates from blood films (EST). The objectives of this study were (1) to evaluate agreement in total WBC and individual leukocyte counts between the LO and EST methods, (2) to document repeatability (intra-assay variability) and reproducibility (inter-assay variability) for the LO method, and (3) to investigate whether biological drivers of WBC counts differ between quantification methods. Box turtles (n = 120) were sampled from five study sites in Illinois during the 2018 active season. The LO method produced significantly higher WBC counts than the EST method, and constant and proportional error was variable for each leukocyte type. The LO method demonstrated an intra-assay variability of 8.2% and an inter-assay variability of 12%, independent of biological variation. WBC counts were significantly affected by age class using both LO and EST methods, but WBC differences between locations and sexes were only observed using the LO method. These findings emphasize the importance of considering leukocyte determination method when analyzing reptilian hematology results. The inherent variability in currently available methods creates uncertainty in resulting data and highlights the need of a gold standard for reptilian WBC quantification.

Hematology and plasma biochemistries in the Blanding's turtle (Emydoidea blandingii) in Lake County, Illinois.

Chelonians are one of the most imperiled vertebrate taxa on the planet due to changes in the environment, anthropogenic influences, and disease. Over the last two decades, conservation strategies including nest protection, head-starting and meso-predator control have been successfully adopted by the Lake County Forest Preserve District for a population of state-endangered Blanding's turtles (Emydoidea blandingii) in Illinois. Only recently have efforts expanded to assess the effects of management action on turtle health. The objectives of this study were to 1) establish reference intervals for 16 hematologic and plasma biochemical analytes in free-ranging Blanding's turtles, 2) characterize demographic and temporal drivers of clinical pathology values including age class, sex, month, and year, and 3) describe bloodwork differences between a managed (SBCP) and unmanaged (IBSP) study site. Hematology and plasma biochemistries were performed for 393 turtles from 2017-18 at two sites in the Lake Plain region. Subject or population-based reference intervals were established based on the index of individuality per American Society for Veterinary Clinical Pathology guidelines. Analytes differed by age class [packed cell volume (PCV), total solids (TS), total white blood cell counts (WBC), heterophils, lymphocytes, heterophil:lymphocyte ratio (H:L), total calcium (Ca), calcium:phosphorous (Ca:P), bile acids (BA), aspartate aminotransferase (AST)], sex [H:L, Ca, phosphorus (P), Ca:P, creatine kinase (CK)], month [eosinophils, H:L, Ca, P, uric acid (UA), AST], and year [PCV, WBC, lymphocytes, basophils, H:L, Ca, P, UA]. Several analytes also varied by site [PCV, TS, monocytes, eosinophils, P, UA, AST], suggesting that health status may be affected by habitat management or lack thereof. The results of this study provide a baseline for ongoing health assessments in this region as well as across the Blanding's turtle range.

Moxifloxacin monotherapy is effective in hospitalized patients with community-acquired pneumonia: the MOTIV study--a randomized clinical trial.

BACKGROUND: The aim of this study was to show that sequential intravenous and oral moxifloxacin monotherapy (400 mg once per day) is as efficacious and safe as a combination regimen (intravenous ceftriaxone, 2 g once per day, plus sequential intravenous and oral levofloxacin, 500 mg twice per day) in patients hospitalized with community-acquired pneumonia. METHODS: We conducted a prospective, multicenter, randomized, double-blind noninferiority trial. Patients with a Pneumonia Severity Index (PSI) of III-V were stratified on the basis of PSI risk class before randomization. The primary efficacy end point was clinical response at test of cure (4-14 days after the completion of treatment). Secondary efficacy end points were clinical and bacteriological response at end of treatment (days 7-14) and at follow-up assessment (21-28 days after the end of treatment), overall mortality, and mortality attributable to pneumonia. RESULTS: Seven hundred thirty-three patients were enrolled in the study (368 in the moxifloxacin arm and 365 in the comparator arm); 49% had a PSI of IV, and 10% had a PSI of V. Of 569 patients (291 in the moxifloxacin arm and 278 in the comparator arm) valid for per-protocol analysis, the overall clinical cure rates at test of cure were 86.9% for moxifloxacin and 89.9% for the comparator regimen (95% confidence interval, -8.1% to 2.2%). Bacteriological success at test of cure was 83.3% for moxifloxacin and 85.1% for the comparator regimen (95% confidence interval, -15.4% to 11.8%). There were no significant differences between moxifloxacin and comparator treatments in the incidence of treatment-emergent adverse events or in mortality. CONCLUSIONS: Monotherapy with sequential intravenous/oral moxifloxacin was noninferior to treatment with ceftriaxone plus levofloxacin combination therapy in patients with community-acquired pneumonia who required hospitalization.

Follow-Up Survey on Functionality of Nutrition Documentation and Ordering Nutrition Therapy in Currently Available Electronic Health Record Systems.

BACKGROUND: This is a follow-up survey to reassess the safety and efficacy of nutrition content in the available electronic health record (EHR) systems. MATERIALS AND METHODS: Members of the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.), American Society for Nutrition, and the Academy for Nutrition and Dietetics were asked to participate in an online survey. The survey included questions from a 2012 EHR survey on the safety and efficacy in 5 nutrition content areas as well as questions from previous 2003 and 2011 A.S.P.E.N. parenteral nutrition (PN) surveys. RESULTS: Percent of respondents using an EHR and using the EHR for less than 1 year increased between 2012 and 2014 (86%-94%, P < .05; 11%-16%, P < .05, respectively). However, there was no improvement in the safety and efficacy of the 5 nutrition content areas, with a significant decrease in 2 of these areas, ordering oral nutrition supplements and ordering PN. The top-rated EHR vendors had a higher average favorable response rate in regards to safety and efficacy in the nutrition content areas but even the top-rated EHR vendor had only a 60% average in favorable responses. Reported use of electronic PN ordering and a direct interface between the EHR and the automated compounding device (ACD) significantly increased from 2003 to 2011 to 2014 (29% to 33% to 63% and 16% to 19% to 28%, respectively, P < .05). CONCLUSIONS: This is a call to action to nutrition support clinicians, societies, and organizations to proactively be involved in initiatives to educate clinicians and collaborate with EHR vendors to enhance the EHR systems to improve the safety and efficacy of providing nutrition therapy in hospitalized patients.

Use of indicators to evaluate the quality of community-acquired pneumonia management.

Quality-assessment indicators for community-acquired pneumonia (CAP) founded on health care structure, process, and outcome have been recommended as a potential audit tool to evaluate the delivery of care. We prospectively audited the treatment of 205 patients admitted with CAP to 2 hospitals in Dundee against some of these key standards. Patients with severe CAP were more likely to die (mortality rate, 42% versus 7%) and to receive antibiotics by the intravenous route (relative risk [RR], 1.81; 95% confidence interval [CI], 1.38-2.37) and within 4 hours of admission to the hospital (RR, 1.22; 95% CI, 0.92-1.62). There was a lack of uniformity regarding the amount of oxygen prescribed, with evidence of poor case record and drug prescription chart documentation related to oxygen therapy. Adherence to the recommended antibiotic policy was associated with reduced risk of death or readmission to the hospital (RR, 0.58; 95% CI, 0.34-1.00). However, in a multivariate analysis, severity of pneumonia was the strongest predictor of death or readmission (P=.004), and adherence to the antibiotic policy was not statistically significant (P=.154). Our study has confirmed the value of quality indicators in evaluating our CAP management and has stimulated the development and implementation of a local hospital-based integrated care pathway.

Caesium(137) implant as sole radiation therapy for operable breast cancer: a phase II trial.

BACKGROUND AND PURPOSE: Clinical trials have indicated the need for irradiation of the tumour-bearing quadrant in patients with operable breast cancer treated by conservation therapy even under circumstances where there has been complete pathologic clearance. The aim of this phase II trial was to replace whole breast irradiation with brachytherapy to the tumour bed. PATIENTS AND METHODS: A series of 50 patients with operable breast cancers measuring <==4 cm diameter were treated by combination therapy comprising tumour excision axillary clearance and synoperative insertion of a rigid implant to the tumour bed. The implant was after-loaded with medium dose rate Cs(137) sources giving a dose of 45 Gy in daily four fractions of about 6 h duration. No external beam radiotherapy was given. RESULTS: After a median follow-up of 6.3 years, of the 49 evaluable patients, 80% were alive without relapse. Of the 9 patients (18%) who developed a breast relapse, the site of recurrence was in the index quadrant in 7 cases (78%). Of the series, 26 (81%) gave a subjective rating of cosmetic outcome which was excellent or good. Objectively the treated breast was deemed to be normal in 11 (42%) and abnormal in 15 (58%). CONCLUSIONS: This phase II study suggests that in a selected group of patients with early breast cancer, external whole breast radiotherapy can be replaced by interstitial irradiation to the tumour bed without compromising local disease control and giving an excellent or good cosmetic outcome in the majority of cases.

Pneumococcal bacteraemia: clinical and microbiological epidemiology in Dundee, Scotland.

OBJECTIVE: To report the incidence of drug resistant Streptococcus pneumoniae isolated from blood culture in Dundee, Scotland. We shall also review the clinical and laboratory findings in these cases. METHODS: A retrospective review was undertaken of all cases of S. pneumoniae bacteraemia identified in our local area during a three year period from August 1st, 1997 to July 31st, 2000 (107 cases.) Data was obtained from patient medical records, blood culture reports and results of Stoke's disk testing. Many organisms were also sent to the Scottish Meningococcus and Pneumococcus Reference Laboratory for serogrouping and determination of the minimum inhibitory concentration of common antibiotics. RESULTS: Annual incidence of bacteraemia was approximately 15.9-17.8 per 100000 population. Mortality was 33% (34 and 30% for those with pneumonia or meningitis, respectively). No relationship was seen between patient age and overall mortality. Factors relating to increased mortality were a high respiratory rate (p=0.01), high blood urea level (p=0.05) and the presence of confusion (p<0.01) on admission to hospital. The incidence of penicillin resistant S. pneumoniae was 7%, all of these isolates having low level resistance. Macrolide resistance was 8%. Neither were found to be increasing over the three year period. The most common serogroups were 23 (18%) and 14 (12%). CONCLUSIONS: The incidence of penicillin resistant S. pneumoniae isolated from blood culture in Dundee, Scotland, is similar to the UK average and did not appear to be rising between 1997 and 2000.

An observational study of matrix metalloproteinase (MMP)-9 in cystic fibrosis.

BACKGROUND: In cystic fibrosis (CF), cross-sectional studies have reported sputum matrix metalloproteinase (MMP)-9 to be elevated and negatively correlated with FEV1. This longitudinal study examined the association between MMP-9 and tissue inhibitors of metalloproteinases (TIMPs) to prognostic parameters in CF. METHOD: A cross-sectional survey of CF and control subjects; CF patients were followed up for a median of 49 months. MMP-9 and TIMP-1 and TIMP-2 were quantified in sputum and plasma. RESULTS: Seventy-three patients with CF, median age 22 years, and 40 controls were recruited. Fifty-three of these CF patients were followed up. Prospectively, in CF subjects, plasma MMP-9 activity was adversely associated with FEV1 (ß -1.15 (95% CI -2.10, -0.20), p = 0.019) and rate of FEV1 decline, and plasma TIMP-1 was adversely associated with mortality: hazard ratio 3.66 (1.91-7.04), p < 0.001. CONCLUSIONS: These associations further justify investigation of MMP-9 and TIMP-1 as biomarkers for short- to medium-term FEV1 decline and mortality in patients with CF.