A glimpse into the fungal metabolomic abyss: Novel network analysis reveals relationships between exogenous compounds and their outputs.

Fungal specialized metabolites are a major source of beneficial compounds that are routinely isolated, characterized, and manufactured as pharmaceuticals, agrochemical agents, and industrial chemicals. The production of these metabolites is encoded by biosynthetic gene clusters that are often silent under standard growth conditions. There are limited resources for characterizing the direct link between abiotic stimuli and metabolite production. Herein, we introduce a network analysis-based, data-driven algorithm comprising two routes to characterize the production of specialized fungal metabolites triggered by different exogenous compounds: the direct route and the auxiliary route. Both routes elucidate the influence of treatments on the production of specialized metabolites from experimental data. The direct route determines known and putative metabolites induced by treatments and provides additional insight over traditional comparison methods. The auxiliary route is specific for discovering unknown analytes, and further identification can be curated through online bioinformatic resources. We validated our algorithm by applying chitooligosaccharides and lipids at two different temperatures to the fungal pathogen Aspergillus fumigatus. After liquid chromatography-mass spectrometry quantification of significantly produced analytes, we used network centrality measures to rank the treatments' ability to elucidate these analytes and confirmed their identity through fragmentation patterns or in silico spiking with commercially available standards. Later, we examined the transcriptional regulation of these metabolites through real-time quantitative polymerase chain reaction. Our data-driven techniques can complement existing metabolomic network analysis by providing an approach to track the influence of any exogenous stimuli on metabolite production. Our experimental-based algorithm can overcome the bottlenecks in elucidating novel fungal compounds used in drug discovery.

Risk of Pancreatitis With Incretin Therapies Versus Thiazolidinediones in the Veterans Health Administration.

BACKGROUND: Incretin therapies, comprised of the dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have been increasingly utilized for the treatment of type 2 diabetes (T2DM). Previous studies have conflicting results regarding risk of pancreatitis associated with these agents-some suggest an increased risk and others find no correlation. Adverse event reporting systems indicate that incretin therapies are some of the most common drugs associated with reports of pancreatitis. OBJECTIVES: This study aimed to compare the odds of developing pancreatitis in veterans with T2DM prescribed an incretin therapy versus thiazolidinediones (TZDs: pioglitazone and rosiglitazone) within the Veterans Health Administration (VHA). METHODS: This was a retrospective cohort study analyzing veterans with T2DM first prescribed an incretin therapy or a TZD between January 1, 2011, and December 31, 2021. A diagnosis of pancreatitis within 365 days of being prescribed either therapy was counted as a positive case. Data was collected and analyzed utilizing VA's Informatics and Computing Infrastructure (VINCI) and an adjusted odds ratio was calculated. RESULTS: The TZD cohort consisted of 42 912 patients compared with the incretin cohort of 304 811 patients. The TZD cohort had a pancreatitis incidence rate of 1.94 cases per 1000 patients. The incretin cohort had a incidence rate of 2.06 cases per 1000 patients. An adjusted odds ratio found no statistical difference of pancreatitis cases between the TZD and incretin cohorts (adjusted odds ratio [AOR] = 0.94, 95% CI [0.75, 1.18]). CONCLUSION AND RELEVANCE: This retrospective cohort study of national VHA data found a relatively low incidence of pancreatitis in both cohorts, and an adjusted odds ratio found no statistical difference of pancreatitis in patients prescribed an incretin therapy compared with a control group. This data adds to growing evidence that incretin therapies do not seem to be associated with an increased risk of developing pancreatitis.

Exploring the role of plant lysin motif receptor-like kinases in regulating plant-microbe interactions in the bioenergy crop Populus.

For plants, distinguishing between mutualistic and pathogenic microbes is a matter of survival. All microbes contain microbe-associated molecular patterns (MAMPs) that are perceived by plant pattern recognition receptors (PRRs). Lysin motif receptor-like kinases (LysM-RLKs) are PRRs attuned for binding and triggering a response to specific MAMPs, including chitin oligomers (COs) in fungi, lipo-chitooligosaccharides (LCOs), which are produced by mycorrhizal fungi and nitrogen-fixing rhizobial bacteria, and peptidoglycan in bacteria. The identification and characterization of LysM-RLKs in candidate bioenergy crops including Populus are limited compared to other model plant species, thus inhibiting our ability to both understand and engineer microbe-mediated gains in plant productivity. As such, we performed a sequence analysis of LysM-RLKs in the Populus genome and predicted their function based on phylogenetic analysis with known LysM-RLKs. Then, using predictive models, molecular dynamics simulations, and comparative structural analysis with previously characterized CO and LCO plant receptors, we identified probable ligand-binding sites in Populus LysM-RLKs. Using several machine learning models, we predicted remarkably consistent binding affinity rankings of Populus proteins to CO. In addition, we used a modified Random Walk with Restart network-topology based approach to identify a subset of Populus LysM-RLKs that are functionally related and propose a corresponding signal transduction cascade. Our findings provide the first look into the role of LysM-RLKs in Populus-microbe interactions and establish a crucial jumping-off point for future research efforts to understand specificity and redundancy in microbial perception mechanisms.

Lack of correlation between standardized antimicrobial administration ratios (SAARs) and healthcare-facility-onset Clostridioides difficile infection rates in Veterans Affairs medical facilities.

We detected no correlation between standardized antimicrobial administration ratios (SAARs) and healthcare facility-onset Clostridioides difficile infection (HO-CDI) rates in 102 acute-care Veterans Affairs medical centers over 16 months. SAARs may be useful for investigating trends in local antimicrobial use, but no ratio threshold demarcated HO-CDI risk.

Lipo-Chitooligosaccharides Induce Specialized Fungal Metabolite Profiles That Modulate Bacterial Growth.

Lipo-chitooligosaccharides (LCOs) are historically known for their role as microbial-derived signaling molecules that shape plant symbiosis with beneficial rhizobia or mycorrhizal fungi. Recent studies showing that LCOs are widespread across the fungal kingdom have raised questions about the ecological function of these compounds in organisms that do not form symbiotic relationships with plants. To elucidate the ecological function of these compounds, we investigate the metabolomic response of the ubiquitous human pathogen Aspergillus fumigatus to LCOs. Our metabolomics data revealed that exogenous application of various types of LCOs to A. fumigatus resulted in significant shifts in the fungal metabolic profile, with marked changes in the production of specialized metabolites known to mediate ecological interactions. Using network analyses, we identify specific types of LCOs with the most significant effect on the abundance of known metabolites. Extracts of several LCO-induced metabolic profiles significantly impact the growth rates of diverse bacterial species. These findings suggest that LCOs may play an important role in the competitive dynamics of non-plant-symbiotic fungi and bacteria. This study identifies specific metabolomic profiles induced by these ubiquitously produced chemicals and creates a foundation for future studies into the potential roles of LCOs as modulators of interkingdom competition. IMPORTANCE The activation of silent biosynthetic gene clusters (BGC) for the identification and characterization of novel fungal secondary metabolites is a perpetual motion in natural product discoveries. Here, we demonstrated that one of the best-studied symbiosis signaling compounds, lipo-chitooligosaccharides (LCOs), play a role in activating some of these BGCs, resulting in the production of known, putative, and unknown metabolites with biological activities. This collection of metabolites induced by LCOs differentially modulate bacterial growth, while the LCO standards do not convey the same effect. These findings create a paradigm shift showing that LCOs have a more prominent role outside of host recognition of symbiotic microbes. Importantly, our work demonstrates that fungi use LCOs to produce a variety of metabolites with biological activity, which can be a potential source of bio-stimulants, pesticides, or pharmaceuticals.

Antiviral Strategies Against SARS-CoV-2: A Systems Biology Approach.

The unprecedented scientific achievements in combating the COVID-19 pandemic reflect a global response informed by unprecedented access to data. We now have the ability to rapidly generate a diversity of information on an emerging pathogen and, by using high-performance computing and a systems biology approach, we can mine this wealth of information to understand the complexities of viral pathogenesis and contagion like never before. These efforts will aid in the development of vaccines, antiviral medications, and inform policymakers and clinicians. Here we detail computational protocols developed as SARS-CoV-2 began to spread across the globe. They include pathogen detection, comparative structural proteomics, evolutionary adaptation analysis via network and artificial intelligence methodologies, and multiomic integration. These protocols constitute a core framework on which to build a systems-level infrastructure that can be quickly brought to bear on future pathogens before they evolve into pandemic proportions.

Ratio of Mixed Venous Oxygen Saturation-to-Pulmonary Capillary Wedge Pressure: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program.

BACKGROUND: Hemodynamic values from right heart catheterization aid diagnosis and clinical decision-making but may not predict outcomes. Mixed venous oxygen saturation percentage and pulmonary capillary wedge pressure relate to cardiac output and congestion, respectively. We theorized that a novel, simple ratio of these measurements could estimate cardiovascular prognosis. METHODS: We queried Veterans Affairs' databases for clinical, hemodynamic, and outcome data. Using the index right heart catheterization between 2010 and 2016, we calculated the ratio of mixed venous oxygen saturation-to-pulmonary capillary wedge pressure, termed ratio of saturation-to-wedge (RSW). The primary outcome was time to all-cause mortality; secondary outcome was 1-year urgent heart failure presentation. Patients were stratified into quartiles of RSW, Fick cardiac index (CI), thermodilution CI, and pulmonary capillary wedge pressure alone. Kaplan-Meier curves and Cox proportional hazards models related comparators with outcomes. RESULTS: Of 12 019 patients meeting inclusion criteria, 9826 had values to calculate RSW (median 4.00, interquartile range, 2.67-6.05). Kaplan-Meier curves showed early, sustained separation by RSW strata. Cox modeling estimated that increasing RSW by 50% decreases mortality hazard by 19% (estimated hazard ratio, 0.81 [95% CI, 0.79-0.83], P<0.001) and secondary outcome hazard by 28% (hazard ratio, 0.72 [95% CI, 0.70-0.74], P<0.001). Among the 3793 patients with data for all comparators, Cox models showed RSW best associated with outcomes (by both C statistics and Bayes factors). Furthermore, pulmonary capillary wedge pressure was superior to thermodilution CI and Fick CI. Multivariable adjustment attenuated without eliminating the association of RSW with outcomes. CONCLUSIONS: In a large national database, RSW was superior to conventional right heart catheterization indices at assessing risk of mortality and urgent heart failure presentation. This simple calculation with routine data may contribute to clinical decision-making in this population.

What next for local government climate emergency declarations? The gap between rhetoric and action.

The UK, like other countries, has seen a proliferation of declarations of local climate emergencies. While these declarations have been interpreted as a demonstration of ambition, little is known about how and why they actually came about when they did and the implications this will have for what happens next. Focusing on London, UK, we present evidence collected via semi-structured interviews with experts and practitioners involved in the propagation of climate emergency declarations to critically explore how and why these declarations emerged, and the various different roles they are perceived to play for different local actors. Our findings reveal four journeys to local government declaration of a climate emergency (made actively from above, passively from above, actively from below, and passively from across) and three interwoven purposes (statements of intent, acting as a political gesture, and stimulating local action). We argue that these three purposes combine and coalesce to correlate the declaration of climate emergency with a local responsibility for emissions reduction, leaving little analytical space to question the scalar disconnect between the immediacy of the narrative at local scales and the slow-burning (and) global nature of the threat in question. If these emergency declarations are to be an opportunity for change in the governance of climate change, then the question of 'what next?' requires more in-depth, thorough and constructive engagement with the type of climate action the declarations are expected to induce while considering how this aligns with existing responsibilities and resource bases of local government.

Continuous Blood Glucose Monitoring Outcomes in Veterans With Type 2 Diabetes.

BACKGROUND: Nearly 25% of patients served in the US Department of Veterans Affairs have been diagnosed with type 2 diabetes mellitus (T2DM). Patients with DM typically monitor their blood glucose using intermittent fingerstick self-testing. Continuous glucose monitoring (CGM) might offer improved disease management. METHODS: We conducted a retrospective of VA patient records using a pre-post model. Average hemoglobin A1c (HbA1c) values were calculated for the year before and the year after CGM initiation. Our primary objective was to determine change in HbA1c from the year before CGM initiation to the year after. Secondary objectives included changes in blood pressure, weight, and DM-related hospital and clinic visits during the same time frame. RESULTS: Both the total population and the adherent subgroup showed reduction in HbA1c. The complete population showed a HbA1c change of -0.3, and the adherent subgroup had a change of -1.3. The total population had a mean change in weight of -1.9 lb (-0.9 kg), and the adherent subgroup had an average change of -8.0 lb. Average systolic blood pressure changes were -0.1 mm Hg in the total population and +3.3 mm Hg in the adherent subgroup. A decrease in total encounters for DM complications was observed in the total population (-0.3 total encounters per patient) and the adherent subgroup (-0.6 total encounters per patient). CONCLUSIONS: CGM did not correspond with clinically significant reductions in HbA1c. However, veterans with increased health care engagement were likely to achieve clinically significant HbA1c improvements. Adherent patients also had more reduction in weight and hospital or clinic visits with CGM compared with the total population.

Exploring the Impacts of Living in a "Green" City on Individual BMI: A Study of Lingang New Town in Shanghai, China.

Urban planning and design in the 21st century is increasingly focusing on sustainability, illustrated by the proliferation of greener cities. While operational definitions and the actual planning of these cities can vary considerably (e.g., eco cities and low carbon cities), conceptually, at least, these terms overlap, particularly with regard to how they attempt to achieve both greener infrastructural design and healthier human lifestyles. This paper presents the findings of survey-based research carried out within Lingang New Town in Shanghai in 2019. In the cities of the Global North, the interplay between green infrastructural provision and public health has been of interest, especially in the context of social inequalities; however, there is little research from rapidly urbanizing countries where green urbanism is being increasingly promoted. Using this newly constructed example, we identified a clear positive correlation between moving to a green city and the adoption of healthier lifestyles. The structural equation modelling results suggest that behaviors around the use of green space as well as perceptions of different green space have notable impacts on residents' physical health, measured by body mass index (BMI). The findings further illustrate systemic inequalities among private housing, rental housing and public housing typologies with regard to the distribution of health benefits.

Erectile Dysfunction Medications and Skin Cancer: An Analysis in US Veterans.

OBJECTIVE: To examine the relationship between phosphodiesterase 5 inhibitor drugs (PDE5i) and skin cancers in a large-scale study of Veterans. METHODS: This was a retrospective database review using the Department of Veterans Affairs Informatics and Computing Infrastructure database. Veterans Affairs Informatics and Computing Infrastructure was searched 19 years for Veterans who received PDE5i treatment of erectile dysfunction. A non-PDE5i group of Veterans was selected for comparison analysis. Follow-up time, outpatient clinic visits and incidence of malignant melanoma (MM), and basal cell carcinoma (BCC) were measured in both groups. RESULTS: A total of 2.55 million Veterans were included in this study (1.27 million in each group). Mean age of the PDE5i group and non-PDE5i group was 59.2 years (standard deviation [SD] ± 10.8) and 58.7 (SD ± 10.8), respectively. Mean follow-up time for the PDE5i group was 8.9 years (SD ± 4.2) and 8.5 years (SD ± 4.3) for non-PDE5i group. Odds ratio for malignant melanoma and BCC in the PDE5i group was 1.25 (confidence interval 95%, 1.22-1.28, P <.0001) and 1.49 (confidence interval 95%, 1.46-1.51, P <.0001), respectively. PDE5i users showed more mean outpatient visits/year (8.9 SD ± 9.50) compared to non-PDE5i users (5.9 SD ± 10.0; P <.0001). CONCLUSION: Veterans prescribed PDE5is to treat erectile show a minimal increased risk of MM and a greater risk of BCC compared to non-PDE5i users. PDE5i users visited outpatient VA clinics at a higher rate than non-PDE5i users in this study. These findings suggest confounding variables are likely involved in the relationship between skin cancers and PDE5i use. PDE5i drugs remain a safe treatment for erectile dysfunction.

Effect of High-Dose Ergocalciferol on Rate of Falls in a Community-Dwelling, Home-Based Primary Care Veteran Population: A Case-Crossover Study.

There was no difference identified in the rate of falls immediately prior to and following initiation of ergocalciferol 50,000 IU self-administered once weekly.

Usability Testing of the iPhone App to Improve Pain Assessment for Older Adults with Cognitive Impairment (Prehospital Setting): A Qualitative Study.

Objectives: Pain assessment in older adults with cognitive impairment is often challenging, and paramedics are not given sufficient tools/training to assess pain. The development of a mobile app may improve pain assessment and management in this vulnerable population. We conducted usability testing of a newly developed iPhone pain assessment application with potential users, in this case as a tool for clinical paramedic practice to improve pain assessment of older adults with cognitive impairment. Methods: We conducted usability testing with paramedic students and a Delphi panel of qualified paramedics. Participants studied the app and paper-based algorithm from which the app was developed. The potential use for the app was discussed. Usability testing focus groups were recorded, transcribed verbatim, and analyzed using a thematic approach. Proposed recommendations were disseminated to the Delphi panel that reviewed and confirmed them. Results: Twenty-four paramedic students from two UK ambulance services participated in the focus groups. Usability of the app and its potential were viewed positively. Four major themes were identified: 1) overall opinion of the app for use in paramedic services; 2) incorporating technological applications into the health care setting; 3) improving knowledge and governance; and 4) alternative uses for the app. Subthemes were identified and are presented. Discussion: Our results indicate that the pain assessment app constitutes a potentially useful tool in the prehospital setting. By providing access to a tool specifically developed to help identify/assess pain in a user-friendly format, paramedics are likely to have increased knowledge and confidence in assessing pain in patients with dementia.

FRAX Prediction With and Without Bone Mineral Density Testing.

The use of a fracture risk assessment tool with and without bone mineral density testing effectively predicted the risk of osteoporotic fractures in male veteran patients.

Crowdsourcing the Measurement of Interstate Conflict.

Much of the data used to measure conflict is extracted from news reports. This is typically accomplished using either expert coders to quantify the relevant information or machine coders to automatically extract data from documents. Although expert coding is costly, it produces quality data. Machine coding is fast and inexpensive, but the data are noisy. To diminish the severity of this tradeoff, we introduce a method for analyzing news documents that uses crowdsourcing, supplemented with computational approaches. The new method is tested on documents about Militarized Interstate Disputes, and its accuracy ranges between about 68 and 76 percent. This is shown to be a considerable improvement over automated coding, and to cost less and be much faster than expert coding.

Intensive insulin protocol implementation and outcomes in the medical and surgical wards at a Veterans Affairs Medical Center.

BACKGROUND: Hyperglycemia is an important marker for clinical outcomes and mortality in hospitalized patients. New national standards have been established emphasizing the importance of improving inpatient glycemic control in individuals with diabetes or new-onset hyperglycemia. Implementation of these new standards is complex and requires a multidisciplinary team approach. A basal-bolus insulin regimen approach has been shown to improve inpatient glycemic control. Few studies have been published regarding basal-bolus insulin protocol outcomes in the non-intensive care unit (ICU) setting. OBJECTIVE: To evaluate the efficacy of a basal-bolus insulin protocol on inpatient glycemic control in a non-ICU setting, as measured by mean blood glucose and number of hypoglycemic episodes per patient admission. METHODS: A retrospective, observational, single-center study was conducted to compare blood glucose control pre- (October 2006-March 2007) and postprotocol (November 2007-January 2008) implementation. Inclusion criteria consisted of patient admission to a medical or surgical ward for at least 72 hours, with a diagnosis of diabetes, or presentation with 2 blood glucose readings greater than 180 mg/dL. Patients admitted to the ICU or those not admitted to a medical or surgical ward were excluded. RESULTS: Following protocol implementation, the mean +/- SD blood glucose level increased from 174 +/- 88 mg/dL to 188 +/- 95 mg/dL (p < 0.001) and the hypoglycemic incidents significantly decreased, from 1.11 to 0.51 events per patient admission (p < 0.0025). CONCLUSIONS: In this pilot study, implementation of a basal-bolus insulin protocol significantly reduced hypoglycemic events; however, mean blood glucose values increased. These results suggest that a basal-bolus insulin protocol can reduce hypoglycemia; however, factors such as protocol compliance, barriers in overcoming the use of the traditional sliding scale insulin regimens, staff education, and change of work-flow habits can influence the overall efficacy and impact of a basal-bolus insulin protocol on inpatient glycemic control.

Decreased risk of bladder cancer in men treated with quinazoline-based α1-adrenoceptor antagonists.

Previous studies documented that human bladder cancer cells are sensitive to the apoptotic effects of quinazoline-derived α1-adrenoreceptor antagonists and bladder tumors exhibit reduced tissue vascularity in response to terazosin. More recent evidence suggests that exposure to quinazoline α1-adrenorecptor antagonists leads to a significant reduction in prostate cancer incidence. This retrospective observational cohort study was conducted to determine whether male patients treated with quinazoline α1-adrenoceptor antagonists for either benign prostate hyperplasia (BPH) or hypertension have a decreased risk of developing bladder cancer. Review of the medical records of all male patients enrolled at the Lexington Veterans Administration (VA) Medical Center identified men exposed to quinazoline-based α1-adrenoceptor antagonists (Jan 1, 1998-Dec 31, 2002) for either hypertension and/or benign prostate obstructive symptoms. The whole group of 27,138 male patients was linked to the Markey Cancer Center's Kentucky Cancer Registry (KCR), part of the NCI's Surveillance, Epidemiology, and End Results (SEER) Program, to identify all incident bladder cancer cases diagnosed in this population. Measures of disease incidence, relative risk, and attributable risk were calculated to compare the risk of developing bladder cancer for α1-blocker-exposed versus unexposed men. A two-by-two contingency table of α1-antagonist exposure versus bladder cancer diagnoses was constructed and the relative risk was calculated. Our analysis revealed a cumulative bladder cancer incidence of 0.24% among the α1-blocker-exposed men compared to 0.42% in the unexposed group. Thus, there was a risk difference of -0.0018, which indicates that 1.8 fewer bladder cancer cases developed per 1000 exposed men. Alternatively stated, 556 men would need to be treated with quinazoline α1-blockers to prevent one case of bladder cancer. Exposure to quinazoline α1-blockers thus may have prevented 7 to 8 bladder cancer cases among the 4173 treated men during the study period. The data yield an unadjusted risk ratio of 0.57 (95% CI: 0.30, 1.08) and therefore, men treated with α1-adrenoreceptor antagonists have a 43% lower relative risk of developing bladder cancer than unexposed men (p=0.083). Our inability to determine person-years at risk of developing bladder cancer for each unexposed control patient, was a limitation for calculating an incidence ratio and rate difference. These results offer an initial indication that exposure to doxazosin and terazosin decreases the incidence of bladder cancer. This is the first epidemiological evidence that the anti-tumor action of quinazoline-based α1-antagonists may potentially translate into a protective effect from bladder cancer development.

Effect of alpha1-adrenoceptor antagonist exposure on prostate cancer incidence: an observational cohort study.

PURPOSE: The quinazoline based alpha1-adrenoceptor antagonists doxazosin and terazosin suppress prostate tumor growth via the induction of apoptosis and decrease in tissue vascularity. To assess the effect of alpha1-blocker exposure on the incidence of prostate cancer we performed an exploratory, observational cohort study. MATERIALS AND METHODS: The medical records of all male patients enrolled at Lexington Veterans Affairs Medical Center were searched to identify men treated with quinazoline based alpha1-adrenoreceptor antagonists between January 1, 1998 and December 31, 2002 for hypertension and/or benign prostatic enlargement. Medical records were subsequently linked to the Markey Cancer Center Kentucky Cancer Registry, a statewide population based central cancer registry that is part of the National Cancer Institute Surveillance, Epidemiology and End Results Program, to identify all incident prostate cancer cases diagnosed. All newly diagnosed prostate cancer cases unexposed to alpha1-adrenoreceptor antagonists in the total male Veterans Affairs population during this period were also identified from the Kentucky Cancer Registry database. Measures of disease incidence, relative risk and attributable risk were calculated to compare the risk of prostate cancer in alpha1-blocker exposed vs unexposed men. Kaplan-Meier curves and Cox regression models were used to compare overall survival between alpha1-blocker exposed and unexposed prostate cancer cases. RESULTS: Our analysis revealed a cumulative incidence of 1.65% in alpha1-blocker exposed men compared to 2.41% in the unexposed group. These data yielded an unadjusted RR of 0.683 (95% CI 0.532, 0.876) and a risk difference of -0.0076, indicating that 7.6 fewer prostate cancer cases developed per 1,000 exposed men. Thus, exposure to quinazoline alpha1-blockers may have prevented 32 prostate cancer cases among the 4,070 treated men during the study period. Therefore, men exposed to quinazoline alpha1-adrenoceptor antagonists were at 1.46 times lower RR and 31.7% lower attributable risk for prostate cancer than unexposed men. There was no association between alpha1-adrenoceptor antagonist exposure and overall survival. CONCLUSIONS: These data suggest that exposure to quinazoline based alpha1-adrenoceptor antagonists significantly decreases the incidence of prostate cancer. This evidence suggests that the apoptotic and anti-angiogenic effects of these drugs may prevent the development of prostate cancer.

Use of macrolides and tetracyclines for chronic inflammatory diseases.

OBJECTIVE: To review the efficacy of macrolides and tetracyclines in several chronic inflammatory conditions. DATA SOURCES: Searches of MEDLINE (1966-March 2004) and an extensive bibliography search were undertaken. Key terms included acne, blepharitis, cardiovascular disease, cystic fibrosis, periodontitis, rosacea, and rheumatoid arthritis. STUDY SELECTION AND DATA EXTRACTION: Data were obtained primarily from randomized placebo-controlled trials upon which key recommendations are based. DATA SYNTHESIS: Antibiotics are often prescribed for months or even years for treatment of chronic inflammatory conditions such as acne, blepharitis, cardiovascular disease, cystic fibrosis, periodontitis, rosacea, and rheumatoid arthritis. Randomized controlled trials have shown that azithromycin is useful in the management of cystic fibrosis and the tetracyclines are beneficial in the management of rheumatoid arthritis, acne, blepharitis, and periodontitis. Several large, randomized controlled trials have failed to show any benefit of macrolides in the secondary prevention of cardiovascular disease. No randomized placebo-controlled clinical trials have been performed to assess the efficacy of macrolides or tetracyclines in patients with rosacea. CONCLUSIONS: The use of tetracyclines and macrolides for rosacea is based primarily on anecdotal reports or open-label trials. Limited clinical trials support the use of tetracyclines or macrolides in acne, blepharitis, periodontitis, rheumatoid arthritis, and cystic fibrosis. Trials to date do not support the use of antibiotics for secondary prevention of cardiovascular disease.