Five-Year Outcomes after PCI or CABG for Left Main Coronary Disease.

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.).

Everolimus-Eluting Stents or Bypass Surgery for Left Main Coronary Artery Disease.

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 .).

The Mycobacterium tuberculosis regulatory network and hypoxia.

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.

Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics.

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.

Surface activation of CNT Webs towards layer by layer assembly of biosensors.

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.

Mycobacterium tuberculosis strains lacking surface lipid phthiocerol dimycocerosate are susceptible to killing by an early innate host response.

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.

The APDS General Surgery Education Quality Improvement Program (EQIP).

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.

EQIP's First Year: A Step Closer to Higher Quality in Surgical Education.

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.

Client perspectives on the accessibility and quality of substance use treatment during the COVID-19 pandemic.

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.

Multi-institutional Collaborative Surgery Education Didactics: Virtual Adaptations During a Global Pandemic.

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.

SCORE - Leveling the Playing Field for Surgical Training Programs.

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.

Role of contrast-enhanced magnetic resonance imaging in detecting early adverse remodeling and subacute ventricular wall rupture complicating myocardial infarction.

Ventricular free wall rupture is a catastrophic complication of acute myocardial infarction accounting for a significant proportion of in-patient deaths. Various imaging modalities including two-dimensional and contrast echocardiography have been applied for the early diagnosis of free wall rupture. Cardiac magnetic resonance imaging has recently gained favor as a tool providing accurate diagnosis and visualization of the site of rupture to enable planned surgery. We present a case of subacute free wall rupture where contrast enhanced myocardial resonance imaging helped to delineate the location and extent of the myocardial tear, thereby prompting appropriate surgical intervention.

Best Practice for Implementation of the SCORE Portal in General Surgery Residency Training Programs.

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.

"Idiopathic" rapid-eye-movement (REM) sleep behavior disorder is associated with future development of neurodegenerative diseases.

OBJECTIVE: To determine whether a diagnosis of idiopathic rapid-eye-movement sleep behavior disorder (RBD) is associated with a future risk of development of neurodegenerative diseases. METHODS: We addressed the objective through development of a structured critically appraised topic that included a clinical scenario, structured question, search strategy, critical appraisal, results, summary of best evidence, commentary, and bottom-line conclusions. Participants included consultant and resident neurologists, clinical epidemiologists, medical librarians, and clinical content experts. RESULTS: A retrospective study of 44 consecutive patients diagnosed with idiopathic RBD demonstrated that 20 patients (45%) developed a neurologic disorder, most commonly Parkinson disease or Lewy body dementia, after a mean of 11.5 years from reported symptom onset and 5.1 years after RBD diagnosis. CONCLUSION: Currently available evidence is limited to cross-sectional and retrospective analyses of patients with RBD. Although ascertainment biases and the retrospective nature of the available evidence limits quantitative analyses, the diagnosis of idiopathic RBD portends a risk of greater than 45% for future development of a clinically defined neurodegenerative disease. This finding has significant implications for clinical neurologic and sleep disorder practice and neurodegenerative disease research.

What Can SCORE Web Portal Usage Analytics Tell Us About How Surgical Residents Learn?

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.

Direct complications of repeat median sternotomy in adults.

Whilst the potential risk to underlying vital structures from redo-sternotomy is well recognized, the actual risk is poorly quantified. Our aim was to determine the incidence of complications directly attributable to redo-sternotomy and to ascertain whether the use of femoro-femoral CPB (FF) prior to redo-sternotomy alters operative morbidity and mortality. Case notes of 185 patients undergoing cardiac surgery necessitating redo-sternotomy between May 1998 and November 2002 were reviewed. Of 121 males and 64 females, the median age was 65.5 years (range 60.1-75 years). Elective FF was performed in 71 (38.3%) of cases and 114 (60%) were performed without the aid of prior femoro-femoral CPB (WFF). Three (1.6%) patients initially planned for WFF were converted to emergency FF due to serious complications. Complications directly attributable to redo-sternotomy occurred in 21 (11.3%) cases; 12 (16.9%) in the FF group and 9 (5.3%) in the WFF group. Overall mortality was 1.6%. In summary, our results suggest that morbidity risk for the operation increases significantly with redo-sternotomy alone. Three deaths in our series from direct complications attributable to redo-sternotomy signify an added risk. Hence the necessity for careful surgical technique and judicious use of elective FF-CPB is emphasized.

The DNA-binding network of Mycobacterium tuberculosis.

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.

Is open thoracotomy still a good treatment option for the management of empyema in children?

BACKGROUND: The incidence of pediatric postpneumonic empyema increases, and there is little consensus on its management. Open thoracotomy has been linked with high morbidity and prolonged hospitalization. Our aim was to review the outcome after open thoracotomy and to provide a set of data for comparison with other treatment modalities. METHODS: Forty-four children (median age, 8 years, 2 months to 16 years) undergoing surgery for postpneumonic empyema between 1993 and 2002 in our unit were studied. RESULTS: The median time from onset of symptoms to admission in a pediatric unit was 8 days (range, 2 to 63 days), the median time from pediatric admission to surgical referral was 3 days (range, 0 to 19 days), and the median time from surgical admission to thoracotomy was 1 day (range, 0 to 2 days). Eight children had a chest drain before surgical admission. Six patients, who were referred late (19 to 69 days), had lung abscesses. A limited muscle sparing thoracotomy (44 patients), formal decortication (36 patients), lung debridement (5 patients), and lobectomy (1 patient) were performed. After thoracotomy, median time to apyrexia was 1 day (range, 0 to 27 days) and drain removal was 3 days (range, 1 to 16 days). A pathogen was isolated in 21 patients. There were no deaths. Four children with abscesses remained septic and had lobectomies (2 patients) and debridements (2 patients). The median postoperative hospital stay was 5 to 53 days. One child had postpneumonic empyema develop and had decortication 3 months postoperatively. At follow-up, all children were doing well and had satisfactory radiographs. The Kaplan-Meier 5-year and 10-year survival rate, freedom from any reoperation, and freedom from hospital readmission were 100%, 87%, and 98%, respectively. CONCLUSIONS: Open thoracotomy remains an excellent option for management of stage II-III empyema in children. When open thoracotomy is performed in a timely manner there is low morbidity and it provides rapid resolution of symptoms with a short hospital stay. However, delayed referrals may result in advanced pulmonary sepsis and a protracted clinical course. The late results are encouraging. Use of thoracoscopy or fibrinolysis should be considered on the basis of their own merit, not on the assumption of probable adverse outcomes after thoracotomy.

Identification of compounds that inhibit late steps of peptidoglycan synthesis in bacteria.

A screening system is described that can detect and confirm inhibitors of the late steps of cell wall biosynthesis. The primary high through-put screen monitors induction of beta-lactamase following exposure to samples, in an Escherichia coli envA- strain that carries the beta-lactamase gene from Citrobacter freundii on a plasmid. Positive samples were detected from compound libraries, from natural products libraries, and from fractions of natural products crude preparations. These samples were then subjected to in vitro assays that could detect the incorporation of soluble cell wall precursor into Lipid I, Lipid II, and polymerized cell wall, using a TLC system that was very accurate and unambiguous in detecting known cell wall inhibitors. One partially purified sample containing a novel antibacterial agent derived from natural products was found to inhibit the formation of Lipid I (50% inhibition at < or = 62.5 ng/ml), whereas another partially purified sample also derived from natural products inhibited transglycosylation into cell wall polymer (50% inhibition at < or = 10 microg/ml). This screening system proved to be especially useful because it was sufficiently sensitive and robust to detect inhibitors among samples of crude preparations or varying states of purity.

Mapping and manipulating the Mycobacterium tuberculosis transcriptome using a transcription factor overexpression-derived regulatory network.

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.