Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance

Pneumocystis pneumonia (PCP) remains a major cause of illness and death in HIV-infected persons. Sulfa drugs, trimethoprim-sulfamethoxazole (TMP-SMX) and dapsone are mainstays of PCP treatment and prophylaxis. While prophylaxis has reduced the incidence of PCP, its use has raised concerns about development of resistant organisms. The inability to culture human Pneumocystis, Pneumocystis jirovecii, in a standardized culture system prevents routine susceptibility testing and detection of drug resistance. In other microorganisms, sulfa drug resistance has resulted from specific point mutations in the dihydropteroate synthase (DHPS) gene. Similar mutations have been observed in P. jirovecii. Studies have consistently demonstrated a significant association between the use of sulfa drugs for PCP prophylaxis and DHPS gene mutations. Whether these mutations confer resistance to TMP-SMX or dapsone plus trimethoprim for PCP treatment remains unclear. We review studies of DHPS mutations in P. jirovecii and summarize the evidence for resistance to sulfamethoxazole and dapsone

Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity

Virus infection of mammalian cells is sensed by pattern recognition receptors and leads to an innate immune response that restricts virus replication and induces adaptive immunity. In response, viruses have evolved many countermeasures that enable them to replicate and be transmitted to new hosts, despite the host innate immune response. Poxviruses, such as vaccinia virus (VACV), have large DNA genomes and encode many proteins that are dedicated to host immune evasion. Some of these proteins are secreted from the infected cell, where they bind and neutralize complement factors, interferons, cytokines and chemokines. Other VACV proteins function inside cells to inhibit apoptosis or signalling pathways that lead to the production of interferons and pro-inflammatory cytokines and chemokines. In this review, these VACV immunomodulatory proteins are described and the potential to create more immunogenic VACV strains by manipulation of the gene encoding these proteins is discussed

Pediatric Transplantation in the United States, 1997–2006

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73373/1/j.1600-6143.2008.02172.x.pd

Resection of multifocal non–small cell lung cancer when the bronchioloalveolar subtype is involved

AbstractObjectiveBronchioloalveolar lung cancer is commonly multifocal and can also present with other non–small cell types. The staging and treatment of multifocal non–small cell cancer are controversial. We evaluated the current staging of multifocal bronchioloalveolar carcinoma and the therapeutic effectiveness of resection when this tumor type is involved.MethodsWe reviewed our experience between 1992 and 2000 with complete pulmonary resections for bronchioloalveolar carcinoma. Kaplan-Meier survival curves were calculated from the dates of pulmonary resection.ResultsAmong 73 patients with bronchioloalveolar carcinoma, 14 patients, 7 male and 7 female with a mean age of 65 years (51-87 years), had multifocal lesions without lymph node metastases. Follow-up was 100% for a median of 5 years (range 2.6-8.5 years). Tumor distribution was unilateral in 9 patients and bilateral in 5 patients. The multifocal nature of the disease was discovered intraoperatively in 4 patients. Nine patients had 2 lesions, 4 patients had 3 lesions, and 1 patient had innumerable discrete foci in a single lobe. Operative mortality was 0. Postoperatively, 10 patients were staged pIIIB or pIV on the basis of multiple foci of similar morphology; 4 patients had some differences in histology (implying multiple stage 1 primaries). The median survival time to death from cancer was 14 months (141 days–5.6 years). The overall 5-year survival after resection of multifocal bronchioloalveolar carcinoma was 64%. Unilateral or bilateral distribution had no impact on survival.ConclusionsThe current staging system is not prognostic for multifocal bronchioloalveolar carcinoma without lymph node metastases. Complete resection of multifocal non–small cell lung cancer when bronchioloalveolar carcinoma is a component may achieve survivals similar to that of stage I and II unifocal non–small cell lung cancer. When bronchioloalveolar carcinoma is believed to be one of the cell types in multifocal disease without lymph node metastases, consideration should be given to surgical resection

Improved parametrization of Antarctic krill target strength models

Author Posting. © Acoustical Society of America, 2006. This article is posted here by permission of Acoustical Society of America for personal use, not for redistribution. The definitive version was published in Journal of the Acoustical Society of America 119 (2006): 232-242, doi:10.1121/1.2141229.There are historical discrepancies between empirical observations of Antarctic krill target strength and predictions using theoretical scattering models. These differences are addressed through improved understanding of key model parameters. The scattering process was modeled using the distorted-wave Born approximation, representing the shape of the animal as a bent and tapered cylinder. Recently published length-based regressions were used to constrain the sound speed and density contrasts between the animal and the surrounding seawater, rather than the earlier approach of using single values for all lengths. To constrain the parameter governing the orientation of the animal relative to the incident acoustic wave, direct measurements of the orientation of krill in situ were made with a video plankton recorder. In contrast to previous indirect and aquarium-based observations, krill were observed to orient themselves mostly horizontally. Averaging predicted scattering over the measured distribution of orientations resulted in predictions of target strength consistent with in situ measurements of target strength of large krill (mean length 40–43 mm) at four frequencies (43–420 kHz), but smaller than expected under the semi-empirical model traditionally used to estimate krill target strength.This project was supported by NSF U.S. Antarctic Program Grant No. OPP-9910307. G. Lawson was supported by an Office of Naval Research Graduate Traineeship Award in Ocean Acoustics (Grant No. N000 14-03-1-0212), a Fulbright Scholarship, a Natural Sciences and Engineering Research Council of Canada Post-Graduate Scholarship, and the Woods Hole Oceanographic Institution Academic Programs Office

The Global Health Security index and Joint External Evaluation score for health preparedness are not correlated with countries' COVID-19 detection response time and mortality outcome

Global Health Security Index (GHSI) and Joint External Evaluation (JEE) are two well-known health security and related capability indices. We hypothesised that countries with higher GHSI or JEE scores would have detected their first COVID-19 case earlier, and would experience lower mortality outcome compared to countries with lower scores. We evaluated the effectiveness of GHSI and JEE in predicting countries' COVID-19 detection response times and mortality outcome (deaths/million). We used two different outcomes for the evaluation: (i) detection response time, the duration of time to the first confirmed case detection (from 31st December 2019 to 20th February 2020 when every country's first case was linked to travel from China) and (ii) mortality outcome (deaths/million) until 11th March and 1st July 2020, respectively. We interpreted the detection response time alongside previously published relative risk of the importation of COVID-19 cases from China. We performed multiple linear regression and negative binomial regression analysis to evaluate how these indices predicted the actual outcome. The two indices, GHSI and JEE were strongly correlated (r = 0.82), indicating a good agreement between them. However, both GHSI (r = 0.31) and JEE (r = 0.37) had a poor correlation with countries' COVID-19–related mortality outcome. Higher risk of importation of COVID-19 from China for a given country was negatively correlated with the time taken to detect the first case in that country (adjusted R2 = 0.63–0.66), while the GHSI and JEE had minimal predictive value. In the negative binomial regression model, countries' mortality outcome was strongly predicted by the percentage of the population aged 65 and above (incidence rate ratio (IRR): 1.10 (95% confidence interval (CI): 1.01–1.21) while overall GHSI score (IRR: 1.01 (95% CI: 0.98–1.01)) and JEE (IRR: 0.99 (95% CI: 0.96–1.02)) were not significant predictors. GHSI and JEE had lower predictive value for detection response time and mortality outcome due to COVID-19. We suggest introduction of a population healthiness parameter, to address demographic and comorbidity vulnerabilities, and reappraisal of the ranking system and methods used to obtain the index based on experience gained from this pandemic