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1.
J Surg Educ ; 79(6): e173-e180, 2022.
Article in English | MEDLINE | ID: mdl-35842405

ABSTRACT

OBJECTIVE: To describe the first year of the Educational Quality Improvement Program (EQIP) DESIGN: The Educational Quality Improvement Program (EQIP) was formed by the Association of Program Directors in Surgery (APDS) in 2018 as a continuous educational quality improvement program. Over 18 months, thirteen discrete goals for the establishment of EQIP were refined and executed through a collaborative effort involving leaders in surgical education. Alpha and beta pilots were conducted to refine the data queries and collection processes. A highly-secure, doubly-deidentified database was created for the ingestion of resident and program data. SETTING & PARTICIPANTS: 36 surgical training programs with 1264 trainees and 1500 faculty members were included in the dataset. 51,516 ERAS applications to programs were also included. Uni- and multi-variable analysis was then conducted. RESULTS: EQIP was successfully deployed within the timeline described in 2020. Data from the ACGME, ABS, and ERAS were merged with manually entered data by programs and successfully ingested into the EQIP database. Interactive dashboards have been constructed for use by programs to compare to the national cohort. Risk-adjusted multivariable analysis suggests that increased time in a technical skills lab was associated with increased success on the ABS's Qualifying Examination, alone. Increased time in a technical skills lab and the presence of a formal teaching curriculum were associated with increased success on both the ABS's Qualifying and Certifying Examination. Program type may be of some consequence in predicting success on the Qualifying Examination. CONCLUSIONS: The APDS has proved the concept that a highly secure database for the purpose of continuous risk-adjusted quality improvement in surgical education can be successfully deployed. EQIP will continue to improve and hopes to include an increasing number of programs as the barriers to participation are overcome.


Subject(s)
General Surgery , Internship and Residency , Humans , United States , Curriculum , Education, Medical, Graduate , Quality Improvement , General Surgery/education
2.
J Surg Educ ; 79(4): 867-874, 2022.
Article in English | MEDLINE | ID: mdl-35365435

ABSTRACT

BACKGROUND: Although the ACGME has called for outcomes-based evaluation of residency programs, few metrics or benchmarks exist connecting educational processes with resident educational outcomes. To address this deficiency, a national Education Quality Improvement Program (EQIP) for General Surgery training is proposed. METHODS: We describe the initial efforts to create this platform. In addition, a national survey was administered to 330 Program Directors to assess their interest in and concerns about a continuous educational quality improvement project. RESULTS: We demonstrate that through a collaborative process and the support of the Association of Program Directors in Surgery (APDS), we were able to develop the groundwork for a national surgical educational improvement project, now called EQIP. The survey response rate was 45.8% (152 of 332 programs) representing a mix of university (55.3%), university-affiliated (18.4%), independent (24.3%), and military (2.0%) programs. Most respondents (66.2%) had not previously heard of EQIP. Most respondents (69.7%) believe that educational outcomes can be measured. The majority of respondents indicated they believed EQIP could be successful (57%). Only 2.3% thought EQIP would not be successful. Almost all programs (98.7%) expressed a willingness to participate, although 19.1% did not believe that they had adequate resources to participate. CONCLUSION: The APDS EQIP platform holds promise as a useful and achievable method to obtain educational outcomes data. These data can be used as a basis for continuous surgical educational quality improvement. General Surgery Program Directors have expressed enthusiasm for EQIP and are willing to participate in the program examining outcomes of General Surgery training programs, with an ultimate goal of improving overall residency training.


Subject(s)
General Surgery , Internship and Residency , Education, Medical, Graduate , General Surgery/education , Humans , Quality Improvement , Surveys and Questionnaires , United States
3.
Drug Alcohol Depend Rep ; 1: 100002, 2021 Dec.
Article in English | MEDLINE | ID: mdl-35156104

ABSTRACT

BACKGROUND: People who use drugs have been particularly vulnerable during the COVID-19 pandemic because of their unique social, harm reduction, and treatment needs. These unique needs and challenges have significant influence on the severity of their substance use, mental health symptomatology, willingness to engage in treatment, and adherence to treatment options. This has included immense challenges related to the dissemination of COVID-19 messaging and the need for harm reduction and treatment service entities to adopt new formats to continue operation. METHODS: In-depth interview data were collected people who use drugs (N=24) residing in Oklahoma from November 2020 through February 2021 to assess perspectives on (1) their access to harm reduction, substance use prevention, and treatment programs during the COVID-19 pandemic, (2) the perceived quality of such services and programs during this time, and (3) the perceived availability of tailored COVID-19 information. RESULTS: Several factors emerged related to accessing and quality of substance use services during COVID-19, including poor accessibility (e.g., internet access), diminished quality (i.e., lack of social support), and lack of tailored COVID-19 prevention and treatment messaging. CONCLUSIONS: Upticks in COVID-19 cases and deaths are expected to continue as new SARS-CoV-2 variants are introduced. The present findings highlight the need for tailored COVID-19 messaging (e.g., minimizing the sharing of substance use supplies that can spread COVID-19, mask wearing, COVID-19 vaccination), which is responsive to unique needs of substance using populations. Similarly, as prevention and treatment programs are delivered online, efforts are necessary to ensure equitable access and enhanced quality of services.

4.
J Surg Educ ; 78(4): 1340-1344, 2021.
Article in English | MEDLINE | ID: mdl-33358934

ABSTRACT

OBJECTIVE: The COVID-19 pandemic has disrupted graduate medical education, impacting Accreditation Council for Graduate Medical Education (ACGME)-mandated didactics. We aimed to study the utility of 2 methods of virtual learning: the daily National Surgery Resident Lecture Series (NSRLS), and weekly "SCORE School" educational webinars designed around the Surgical Council on Resident Education (SCORE) curriculum. DESIGN AND SETTING: NSRLS: The National Surgery Resident Lecture Series was a daily virtual educational session initially led by faculty at an individual surgical residency program. Thirty-eight lectures were assessed for number of live viewings (March 23, 2020-May 15, 2020). SCORE SCHOOL: Attendance at eleven weekly SCORE educational webinars was characterized into live and asynchronous viewings (May 13, 2020-August 5, 2020). Each 1-hour live webinar was produced by SCORE on a Wednesday evening and featured nationally recognized surgeon educators using an online platform that allowed for audience interaction. RESULTS: NSRLS: There were a mean of 71 live viewers per NSRLS session (range 19-118). Participation began to decline in the final 2 weeks as elective case volumes increased, but sessions remained well-attended. SCORE SCHOOL: There were a range of 164-3889 live viewers per SCORE School session. Sessions have most commonly been viewed asynchronously (89.8% of viewings). Live viewership decreased as the academic year ended and then rebounded with the start of the new academic year (range 4.9%-27%). Overall, the eight webinars were viewed 11,135 times. Each webinar continues to be viewed a mean of 43 times a day (range 0-102). Overall, the eleven webinars have been viewed a total of 22,722 times. CONCLUSIONS: Virtual didactics aimed at surgical residents are feasible, well-attended (both live and recorded), and have high levels of viewer engagement. We have observed that careful coordination of timing and topics is ideal. The ability for asynchronous viewing is particularly important for attendance. As the COVID-19 pandemic continues to disrupt healthcare systems, training programs must continue to adapt to education via virtual platforms.


Subject(s)
COVID-19 , General Surgery , Internship and Residency , Curriculum , Education, Medical, Graduate , General Surgery/education , Humans , Pandemics , SARS-CoV-2
5.
N Engl J Med ; 381(19): 1820-1830, 2019 11 07.
Article in English | MEDLINE | ID: mdl-31562798

ABSTRACT

BACKGROUND: Long-term outcomes after percutaneous coronary intervention (PCI) with contemporary drug-eluting stents, as compared with coronary-artery bypass grafting (CABG), in patients with left main coronary artery disease are not clearly established. METHODS: We randomly assigned 1905 patients with left main coronary artery disease of low or intermediate anatomical complexity (according to assessment at the participating centers) to undergo either PCI with fluoropolymer-based cobalt-chromium everolimus-eluting stents (PCI group, 948 patients) or CABG (CABG group, 957 patients). The primary outcome was a composite of death, stroke, or myocardial infarction. RESULTS: At 5 years, a primary outcome event had occurred in 22.0% of the patients in the PCI group and in 19.2% of the patients in the CABG group (difference, 2.8 percentage points; 95% confidence interval [CI], -0.9 to 6.5; P = 0.13). Death from any cause occurred more frequently in the PCI group than in the CABG group (in 13.0% vs. 9.9%; difference, 3.1 percentage points; 95% CI, 0.2 to 6.1). In the PCI and CABG groups, the incidences of definite cardiovascular death (5.0% and 4.5%, respectively; difference, 0.5 percentage points; 95% CI, -1.4 to 2.5) and myocardial infarction (10.6% and 9.1%; difference, 1.4 percentage points; 95% CI, -1.3 to 4.2) were not significantly different. All cerebrovascular events were less frequent after PCI than after CABG (3.3% vs. 5.2%; difference, -1.9 percentage points; 95% CI, -3.8 to 0), although the incidence of stroke was not significantly different between the two groups (2.9% and 3.7%; difference, -0.8 percentage points; 95% CI, -2.4 to 0.9). Ischemia-driven revascularization was more frequent after PCI than after CABG (16.9% vs. 10.0%; difference, 6.9 percentage points; 95% CI, 3.7 to 10.0). CONCLUSIONS: In patients with left main coronary artery disease of low or intermediate anatomical complexity, there was no significant difference between PCI and CABG with respect to the rate of the composite outcome of death, stroke, or myocardial infarction at 5 years. (Funded by Abbott Vascular; EXCEL ClinicalTrials.gov number, NCT01205776.).


Subject(s)
Coronary Artery Bypass , Coronary Artery Disease/therapy , Drug-Eluting Stents , Percutaneous Coronary Intervention , Aged , Coronary Artery Disease/mortality , Coronary Artery Disease/surgery , Everolimus/administration & dosage , Female , Humans , Male , Middle Aged , Myocardial Infarction/epidemiology , Myocardial Ischemia/therapy , Odds Ratio , Stroke/epidemiology
6.
J Surg Educ ; 76(6): e146-e151, 2019.
Article in English | MEDLINE | ID: mdl-31395521

ABSTRACT

OBJECTIVE: The Surgical Council on Resident Education (SCORE) web portal provides a uniform, comprehensive, competency-based curriculum for general surgery residents. One of SCORE's principal founding goals was to provide equal opportunity for access of educational resources at programs across the United States which reported having a range of resources. We aimed to determine if there was a difference in portal usage by trainees in independent versus university programs, and across geographic areas. METHODS: Using analytic software, we measured SCORE usage by trainees in 246 subscribing programs from August 2015 to March 2017. The primary outcome was the average duration of SCORE use per login. Secondary outcomes were the geographic region of each program, and university versus independent designation. Encounters lasting >8 hours (comprising 7% of the data set) were excluded to eliminate the likelihood of failure to log off the portal. RESULTS: Over the study period, there were 669,501 SCORE sessions with 22% of these lasting 1 to 5 minutes, 33% lasting 6 to 30 minutes, and 28% lasting 31 to 120 minutes. Between the university (64.4% of encounters) and independent (35.6% of encounters) program types, there was no significant difference in average visit length overall, or in the normally-distributed designated time categories (t test -1.0, p = 0.3). When mean encounter length per program was compared by geographic regions, there was also no difference in the three time categories (ANOVA p = 0.9, 0.2, and 0.5, respectively). CONCLUSIONS: Most (50%) of SCORE encounters lasted 30 minutes of less, confirming prior work that shows trainees use the portal in relatively short bursts of activity. While there were more encounters from university program trainees (proportional with their greater numbers), the mean duration of an individual encounter did not significantly differ by program type as a whole or by region. These results suggest that SCORE is an equally accessible educational resource and is used by surgical trainees, regardless of program type or geographic region.


Subject(s)
Curriculum , General Surgery/education , Internet/statistics & numerical data , United States
7.
J Surg Educ ; 75(6): e11-e16, 2018 Nov.
Article in English | MEDLINE | ID: mdl-29793808

ABSTRACT

INTRODUCTION: The Surgical Council on Resident Education (SCORE) has presented a workshop annually at the annual meeting of the Association of Program Directors (APDS) to discuss the evolution of the SCORE portal and best practices for implementation within residency training programs. METHODS/RESULTS: A review of the literature was undertaken, along with a summation of discussion at these several workshops. A history of the SCORE project and a summary of its organizational framework and content are presented. In addition, best practices for use of SCORE within programs are described. CONCLUSIONS: The SCORE portal is now a decade old, and is used ubiquitously in US surgical training programs. With this experience, there is data to show the utility of SCORE to support trainee learning and programmatic didactics.


Subject(s)
Curriculum , General Surgery/education , Internship and Residency/organization & administration , Benchmarking
8.
J Surg Educ ; 74(6): e133-e137, 2017.
Article in English | MEDLINE | ID: mdl-29079112

ABSTRACT

PURPOSE: The Surgical Council on Resident Education (SCORE) was established in 2004 with 2 goals: to develop a standardized, competency-based curriculum for general surgery residency training; and to develop a web portal to deliver this content. By 2012, 96% of general surgery residency programs subscribed to the SCORE web portal. Surgical educators have previously described the myriad ways they have incorporated SCORE into their curricula. The aim of this study was to analyze user data to describe how and when residents use SCORE. METHODS: Using analytic software, we measured SCORE usage from July, 2013 to June, 2016. Data such as IP addresses, geo-tagging coordinates, and operating system platforms were collected. The primary outcome was the median duration of SCORE use. Secondary outcomes were the time of day and the operating system used when accessing SCORE. Descriptive statistics were performed, and a p < 0.05 was deemed statistically significant. RESULTS: There were 42,743 total SCORE subscribers during the study period (75% resident and 25% faculty) with a mean of 14,248 subscribers per year. The overall median duration of SCORE use was 11.9minute/session (interquartile range [IQR]: 6.8). Additionally, there was a significant increase in session length over the 3 academic years; 10.1 (IQR: 6.4), 11.9 (IQR: 7.2), and 13.2minute/session (IQR: 5.4) in 2013 to 2014, 2014 to 2015, and 2015 to 2016, respectively (p < 0.001). SCORE usage was highest in November to February at 21.0minute/session (14.2) compared to July to October and March to June (12.3 [IQR: 3.2] and 9.6minute/session [IQR: 2.2]), respectively (p < 0.001). This seasonal trend continued for all 3 years. We observed an increased number of sessions per day over the 3 years: median of 1500 sessions/d (IQR: 1115) vs 1706 (IQR: 1334) vs 1728 (IQR: 1352), p < 0.001. (Fig.). Most SCORE sessions occurred at night: 38,011 (IQR: 4532) vs 17,529 (IQR: 19,850) during the day (p < 0.001). Windows was the most frequently used operating system at 48.9% (p < 0.001 vs others). CONCLUSIONS: SCORE usage has increased significantly over the last 3 years, when measured by number of sessions per day and length of time per session. There are predictable daily, diurnal, and seasonal variations in SCORE usage. The annual in-training examination is a prominent factor stimulating SCORE usage.


Subject(s)
Educational Measurement/methods , General Surgery/education , Internet/statistics & numerical data , Internship and Residency/methods , Software , Clinical Competence , Competency-Based Education/methods , Curriculum , Education, Medical, Graduate/methods , Female , Humans , Male , United States
9.
N Engl J Med ; 375(23): 2223-2235, 2016 12 08.
Article in English | MEDLINE | ID: mdl-27797291

ABSTRACT

BACKGROUND: Patients with obstructive left main coronary artery disease are usually treated with coronary-artery bypass grafting (CABG). Randomized trials have suggested that drug-eluting stents may be an acceptable alternative to CABG in selected patients with left main coronary disease. METHODS: We randomly assigned 1905 eligible patients with left main coronary artery disease of low or intermediate anatomical complexity to undergo either percutaneous coronary intervention (PCI) with fluoropolymer-based cobalt-chromium everolimus-eluting stents (PCI group, 948 patients) or CABG (CABG group, 957 patients). Anatomic complexity was assessed at the sites and defined by a Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score of 32 or lower (the SYNTAX score reflects a comprehensive angiographic assessment of the coronary vasculature, with 0 as the lowest score and higher scores [no upper limit] indicating more complex coronary anatomy). The primary end point was the rate of a composite of death from any cause, stroke, or myocardial infarction at 3 years, and the trial was powered for noninferiority testing of the primary end point (noninferiority margin, 4.2 percentage points). Major secondary end points included the rate of a composite of death from any cause, stroke, or myocardial infarction at 30 days and the rate of a composite of death, stroke, myocardial infarction, or ischemia-driven revascularization at 3 years. Event rates were based on Kaplan-Meier estimates in time-to-first-event analyses. RESULTS: At 3 years, a primary end-point event had occurred in 15.4% of the patients in the PCI group and in 14.7% of the patients in the CABG group (difference, 0.7 percentage points; upper 97.5% confidence limit, 4.0 percentage points; P=0.02 for noninferiority; hazard ratio, 1.00; 95% confidence interval, 0.79 to 1.26; P=0.98 for superiority). The secondary end-point event of death, stroke, or myocardial infarction at 30 days occurred in 4.9% of the patients in the PCI group and in 7.9% in the CABG group (P<0.001 for noninferiority, P=0.008 for superiority). The secondary end-point event of death, stroke, myocardial infarction, or ischemia-driven revascularization at 3 years occurred in 23.1% of the patients in the PCI group and in 19.1% in the CABG group (P=0.01 for noninferiority, P=0.10 for superiority). CONCLUSIONS: In patients with left main coronary artery disease and low or intermediate SYNTAX scores by site assessment, PCI with everolimus-eluting stents was noninferior to CABG with respect to the rate of the composite end point of death, stroke, or myocardial infarction at 3 years. (Funded by Abbott Vascular; EXCEL ClinicalTrials.gov number, NCT01205776 .).


Subject(s)
Coronary Artery Bypass , Coronary Artery Disease/therapy , Drug-Eluting Stents , Everolimus/administration & dosage , Aged , Coronary Artery Bypass/adverse effects , Coronary Artery Disease/mortality , Coronary Artery Disease/surgery , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Percutaneous Coronary Intervention/adverse effects
10.
Analyst ; 141(9): 2748-55, 2016 04 25.
Article in English | MEDLINE | ID: mdl-26818435

ABSTRACT

Several surface activation methods such as chemical, electrochemical and plasma have been used for enhancing the electrochemical performance of carbon based electrodes for various applications. However, some of these surface activation methods may not be useful depending on the chemical and physical properties of the activated surface. Herein we investigate the surface activation of carbon nanotube (CNT) webs by electrochemical and plasma techniques to enhance their electrochemical performance and enable the fabrication of a biosensor using the layer-by-layer (LBL) approach. The pretreated CNT webs were characterized by SEM, TEM, Raman, XPS and electrochemical methods. TEM images and Raman analysis showed an increase in the level of surface defects upon pretreatment with higher number of defects after electrochemical pretreatment. XPS analysis showed an increase in the level of oxygen functional groups after pretreatment (4 to 5 times increase) which resulted in enhanced water wettability especially for plasma pretreated CNT webs. The pretreated CNT web electrodes also showed an enhanced electrochemical activity towards the oxidation and reduction of different redox probes with higher sensitivity for the electrochemically pretreated CNT web electrode that was accompanied by a higher level of noise in amperometric measurements. A highly linear response was obtained for the untreated and the electrochemically pretreated CNT web electrodes towards the amperometric detection of NADH (R(2) of 0.9996 and 0.9986 respectively) while a non-linear response was observed for the plasma pretreated CNT web electrode (R(2) of 0.8538). The pretreated CNT web electrodes enabled the fabrication of a LBL biosensor for alcohol detection with highest operational stability obtained for the plasma pretreated CNT web surface.


Subject(s)
Biosensing Techniques/methods , Electrochemical Techniques/methods , Nanotubes, Carbon/chemistry , Electrodes , Surface Properties
11.
Nat Chem Biol ; 12(2): 102-8, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26656089

ABSTRACT

High cancer death rates indicate the need for new anticancer therapeutic agents. Approaches to discovering new cancer drugs include target-based drug discovery and phenotypic screening. Here, we identified phosphodiesterase 3A modulators as cell-selective cancer cytotoxic compounds through phenotypic compound library screening and target deconvolution by predictive chemogenomics. We found that sensitivity to 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP, across 766 cancer cell lines correlates with expression of the gene PDE3A, encoding phosphodiesterase 3A. Like DNMDP, a subset of known PDE3A inhibitors kill selected cancer cells, whereas others do not. Furthermore, PDE3A depletion leads to DNMDP resistance. We demonstrated that DNMDP binding to PDE3A promotes an interaction between PDE3A and Schlafen 12 (SLFN12), suggestive of a neomorphic activity. Coexpression of SLFN12 with PDE3A correlates with DNMDP sensitivity, whereas depletion of SLFN12 results in decreased DNMDP sensitivity. Our results implicate PDE3A modulators as candidate cancer therapeutic agents and demonstrate the power of predictive chemogenomics in small-molecule discovery.


Subject(s)
Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism , Cytotoxins/pharmacology , Neoplasms/therapy , Pyridazines/chemistry , Pyridazines/pharmacology , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Cytotoxins/chemistry , Cytotoxins/isolation & purification , Drug Delivery Systems , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Genomics , Humans , Immunoblotting
12.
Nat Commun ; 6: 5829, 2015 Jan 12.
Article in English | MEDLINE | ID: mdl-25581030

ABSTRACT

Mycobacterium tuberculosis (MTB) infects 30% of all humans and kills someone every 20-30 s. Here we report genome-wide binding for ~80% of all predicted MTB transcription factors (TFs), and assayed global expression following induction of each TF. The MTB DNA-binding network consists of ~16,000 binding events from 154 TFs. We identify >50 TF-DNA consensus motifs and >1,150 promoter-binding events directly associated with proximal gene regulation. An additional ~4,200 binding events are in promoter windows and represent strong candidates for direct transcriptional regulation under appropriate environmental conditions. However, we also identify >10,000 'dormant' DNA-binding events that cannot be linked directly with proximal transcriptional control, suggesting that widespread DNA binding may be a common feature that should be considered when developing global models of coordinated gene expression.


Subject(s)
Bacterial Proteins/chemistry , DNA, Bacterial/chemistry , DNA-Binding Proteins/chemistry , Gene Expression Regulation, Bacterial , Mycobacterium tuberculosis/chemistry , Amino Acid Motifs , Bacterial Proteins/genetics , Binding Sites , Chromatin Immunoprecipitation , Computational Biology , DNA, Bacterial/genetics , DNA-Binding Proteins/genetics , Gene Expression Profiling , Genetic Vectors , Genome-Wide Association Study , Mycobacterium tuberculosis/genetics , Nucleotide Motifs , Promoter Regions, Genetic , Protein Binding , ROC Curve , Recombinant Proteins/chemistry , Transcription Factors/chemistry , Transcription, Genetic
13.
Genome Biol ; 15(11): 502, 2014.
Article in English | MEDLINE | ID: mdl-25380655

ABSTRACT

BACKGROUND: Mycobacterium tuberculosis senses and responds to the shifting and hostile landscape of the host. To characterize the underlying intertwined gene regulatory network governed by approximately 200 transcription factors of M. tuberculosis, we have assayed the global transcriptional consequences of overexpressing each transcription factor from an inducible promoter. RESULTS: We cloned and overexpressed 206 transcription factors in M. tuberculosis to identify the regulatory signature of each. We identified 9,335 regulatory consequences of overexpressing each of 183 transcription factors, providing evidence of regulation for 70% of the M. tuberculosis genome. These transcriptional signatures agree well with previously described M. tuberculosis regulons. The number of genes differentially regulated by transcription factor overexpression varied from hundreds of genes to none, with the majority of expression changes repressing basal transcription. Exploring the global transcriptional maps of transcription factor overexpressing (TFOE) strains, we predicted and validated the phenotype of a regulator that reduces susceptibility to a first line anti-tubercular drug, isoniazid. We also combined the TFOE data with an existing model of M. tuberculosis metabolism to predict the growth rates of individual TFOE strains with high fidelity. CONCLUSION: This work has led to a systems-level framework describing the transcriptome of a devastating bacterial pathogen, characterized the transcriptional influence of nearly all individual transcription factors in M. tuberculosis, and demonstrated the utility of this resource. These results will stimulate additional systems-level and hypothesis-driven efforts to understand M. tuberculosis adaptations that promote disease.


Subject(s)
Gene Regulatory Networks , Mycobacterium tuberculosis/genetics , Transcription Factors/genetics , Tuberculosis/genetics , Cloning, Molecular , Gene Expression Regulation, Bacterial/drug effects , Humans , Isoniazid/administration & dosage , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/pathogenicity , Promoter Regions, Genetic , Regulon/drug effects , Transcription Factors/biosynthesis , Transcription, Genetic/drug effects , Transcriptome/genetics , Tuberculosis/microbiology
14.
Infect Immun ; 82(12): 5214-22, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25287926

ABSTRACT

The innate immune response plays an important but unknown role in host defense against Mycobacterium tuberculosis. To define the function of innate immunity during tuberculosis, we evaluated M. tuberculosis replication dynamics during murine infection. Our data show that the early pulmonary innate immune response limits M. tuberculosis replication in a MyD88-dependent manner. Strikingly, we found that little M. tuberculosis cell death occurs during the first 2 weeks of infection. In contrast, M. tuberculosis cells deficient in the surface lipid phthiocerol dimycocerosate (PDIM) exhibited significant death rates, and consequently, total bacterial numbers were reduced. Host restriction of PDIM-deficient M. tuberculosis was not alleviated by the absence of interferon gamma (IFN-γ), inducible nitric oxide synthase (iNOS), or the phagocyte oxidase subunit p47. Taken together, these data indicate that PDIM protects M. tuberculosis from an early innate host response that is independent of IFN-γ, reactive nitrogen intermediates, and reactive oxygen species. By employing a pathogen replication tracking tool to evaluate M. tuberculosis replication and death during infection, we identify both host and pathogen factors affecting the outcome of infection.


Subject(s)
Lipids/deficiency , Lipids/immunology , Mycobacterium tuberculosis/chemistry , Mycobacterium tuberculosis/immunology , Tuberculosis/immunology , Tuberculosis/microbiology , Animals , Bacterial Load , Immunity, Innate , Interferon-gamma/metabolism , Lung/immunology , Lung/microbiology , Mice, Inbred C57BL , Reactive Nitrogen Species/metabolism
15.
PLoS One ; 8(9): e75245, 2013.
Article in English | MEDLINE | ID: mdl-24086479

ABSTRACT

Identification of new drug targets is vital for the advancement of drug discovery against Mycobacterium tuberculosis, especially given the increase of resistance worldwide to first- and second-line drugs. Because traditional target-based screening has largely proven unsuccessful for antibiotic discovery, we have developed a scalable platform for target identification in M. tuberculosis that is based on whole-cell screening, coupled with whole-genome sequencing of resistant mutants and recombineering to confirm. The method yields targets paired with whole-cell active compounds, which can serve as novel scaffolds for drug development, molecular tools for validation, and/or as ligands for co-crystallization. It may also reveal other information about mechanisms of action, such as activation or efflux. Using this method, we identified resistance-linked genes for eight compounds with anti-tubercular activity. Four of the genes have previously been shown to be essential: AspS, aspartyl-tRNA synthetase, Pks13, a polyketide synthase involved in mycolic acid biosynthesis, MmpL3, a membrane transporter, and EccB3, a component of the ESX-3 type VII secretion system. AspS and Pks13 represent novel targets in protein translation and cell-wall biosynthesis. Both MmpL3 and EccB3 are involved in membrane transport. Pks13, AspS, and EccB3 represent novel candidates not targeted by existing TB drugs, and the availability of whole-cell active inhibitors greatly increases their potential for drug discovery.


Subject(s)
Antitubercular Agents/pharmacology , Bacterial Proteins/metabolism , Drug Discovery/methods , Drug Evaluation, Preclinical/methods , Drug Resistance, Bacterial/genetics , Mycobacterium tuberculosis/genetics , Aspartic Acid Endopeptidases/genetics , Aspartic Acid Endopeptidases/metabolism , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , Drug Resistance, Bacterial/physiology , Models, Molecular , Molecular Structure , Mycobacterium tuberculosis/drug effects , Polyketide Synthases/chemistry , Polyketide Synthases/genetics , Sequence Analysis, DNA/methods
16.
Nature ; 499(7457): 178-83, 2013 Jul 11.
Article in English | MEDLINE | ID: mdl-23823726

ABSTRACT

We have taken the first steps towards a complete reconstruction of the Mycobacterium tuberculosis regulatory network based on ChIP-Seq and combined this reconstruction with system-wide profiling of messenger RNAs, proteins, metabolites and lipids during hypoxia and re-aeration. Adaptations to hypoxia are thought to have a prominent role in M. tuberculosis pathogenesis. Using ChIP-Seq combined with expression data from the induction of the same factors, we have reconstructed a draft regulatory network based on 50 transcription factors. This network model revealed a direct interconnection between the hypoxic response, lipid catabolism, lipid anabolism and the production of cell wall lipids. As a validation of this model, in response to oxygen availability we observe substantial alterations in lipid content and changes in gene expression and metabolites in corresponding metabolic pathways. The regulatory network reveals transcription factors underlying these changes, allows us to computationally predict expression changes, and indicates that Rv0081 is a regulatory hub.


Subject(s)
Gene Regulatory Networks , Hypoxia/genetics , Metabolic Networks and Pathways/genetics , Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/metabolism , Adaptation, Physiological , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Binding Sites , Chromatin Immunoprecipitation , Gene Expression Profiling , Gene Regulatory Networks/genetics , Genomics , Hypoxia/metabolism , Lipid Metabolism/genetics , Models, Biological , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/physiology , Oxygen/pharmacology , Proteolysis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reproducibility of Results , Sequence Analysis, DNA , Transcription Factors/genetics , Transcription Factors/metabolism , Tuberculosis/metabolism , Tuberculosis/microbiology
17.
Neurologist ; 17(5): 289-91, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21881475

ABSTRACT

Obstructive sleep apnea (OSA) is associated with hypertension (HTN) and cardiovascular disease. Transient episodes of hypoxia, hypercapnia, and blood pressure elevation during OSA may lead to neural damage and subsequently white matter disease (WMD). As WMD is usually the result of chronic small vessel ischemia, a relationship between OSA and cerebrovascular disease may exist. This case series aimed to establish a relationship between OSA and WMD. Sixty-two patients without cerebrovascular disease who had both a polysomnogram and brain magnetic resonance imaging were identified. All patients carried the diagnosis of HTN. WMD was evaluated using the age-related white matter changes scale. Although half of the study population had WMD on magnetic resonance imaging, no association was found between WMD with severity of OSA (P=0.9). Our results are limited by the small sample size and by coexistent HTN in all patients. Further studies are needed to elucidate the relationship between OSA and WMD, especially among nonhypertensive patients. Future research should also address if OSA treatment has any effect on WMD.


Subject(s)
Hypertension/complications , Leukoencephalopathies/etiology , Sleep Apnea Syndromes/etiology , Adult , Aged , Aged, 80 and over , Body Mass Index , Brain/pathology , Brain/physiopathology , Chi-Square Distribution , Female , Humans , Hypertension/epidemiology , Leukoencephalopathies/complications , Magnetic Resonance Imaging , Male , Middle Aged , Polysomnography , Sleep Apnea Syndromes/complications , Statistics, Nonparametric
18.
Ned Tijdschr Geneeskd ; 155(18): A3034, 2011.
Article in Dutch | MEDLINE | ID: mdl-21466729

ABSTRACT

OBJECTIVE: To assess the effectiveness of the Australian Medical Sheepskin (AMS) on the prevention of sacral pressure ulcers based on combined data from 3 previously published trials. DESIGN: Meta-analysis of randomised clinical trials (RCTs). METHOD: The effectiveness of these specially treated sheepskins from the Merino sheep was studied in three RCT's (2 involving Australian hospital patients and 1 involving Dutch nursing-home patients). In all 3 trials patients were randomized to 1 of 2 groups: a control group, who received standard care, and an intervention group, who, in addition to standard care, had at least one AMS placed under the sacral area when in bed. The total research population consisted of 1,281 patients from 11 institutions with 45 nursing wards. Data from the 3 RCT's were pooled and analysed: (a) with conventional meta-analysis based on the published effect sizes and (b) with multilevel logistic regression analysis based on the combined individual patient data for each trial separately and for the combined dataset. The primary outcome measure was the incidence of sacral pressure ulcers. RESULTS: The incidence of sacral pressure ulcers was 12.2% in the control group versus 5.4% in the intervention group. The odds-ratio was 0.37 (95% CI: 0.17-0.77) with conventional meta-analysis, and 0.35 (95% CI: 0.23-0.55) with multilevel logistic regression analysis on the combined individual patient data. CONCLUSION: Both analysis methods confirm that the AMS is effective in preventing sacral pressure ulcers. The confidence interval in the multilevel logistic regression analysis on individual patient data was almost 50% smaller than in the conventional meta-analysis, and gave a more reliable picture of the actual effect.


Subject(s)
Bedding and Linens , Pressure Ulcer/prevention & control , Animals , Australia , Ethnicity , Hospitals , Humans , Nursing Homes , Sheep , Treatment Outcome
20.
Med J Aust ; 193(11-12): 638-41, 2010.
Article in English | MEDLINE | ID: mdl-21143048

ABSTRACT

OBJECTIVE: To assess the effectiveness of the Australian Medical Sheepskin in preventing sacral pressure ulcers (PUs), based on combined data from existing published trials. DESIGN AND SETTING: Data from two randomised controlled trials (RCTs) among Australian hospital patients and one RCT among Dutch nursing home patients were pooled, comprising a total population of 1281 patients from 45 nursing wards in 11 institutions. These data were analysed in two ways: with conventional meta-analysis based on the published effect sizes; and with multilevel binary logistic regression based on the combined individual patient data. In the multilevel analysis, patient, nursing ward and institution were used as levels and we controlled for sex, age, PU risk and number of days of observation. MAIN OUTCOME MEASURE: Incidence of sacral PUs. RESULTS: Overall, the incidence of sacral PUs was 12.2% in the control group versus 5.4% in the intervention group with an Australian Medical Sheepskin. Conventional meta-analysis showed significantly reduced odds of developing a PU while using the sheepskin (odds ratio [OR], 0.37 [95% CI, 0.17-0.77]). Multilevel analysis gave an OR of 0.35 and narrowed the confidence interval by almost 50% (95% CI, 0.23-0.55). CONCLUSIONS: These analyses of pooled data confirm that the Australian Medical Sheepskin is effective in preventing sacral PUs. Multilevel analysis of individual patient data gives a more precise effect estimate than conventional meta-analysis.


Subject(s)
Bedding and Linens , Pressure Ulcer/prevention & control , Wool , Animals , Humans , Multilevel Analysis , Pressure Ulcer/epidemiology , Randomized Controlled Trials as Topic , Sacrococcygeal Region , Sheep
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