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

Anisotropy in high-frequency broadband acoustic backscattering in the presence of turbulent microstructure and zooplankton

Author Posting. © Acoustical Society of America, 2012. 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 132 (2012): 670-679, doi:10.1121/1.4730904.High-frequency broadband (120–600 kHz) acoustic backscattering measurements have been made in the vicinity of energetic internal waves. The transducers on the backscattering system could be adjusted so as to insonify the water-column either vertically or horizontally. The broadband capabilities of the system allowed spectral classification of the backscattering. The distribution of spectral shapes is significantly different for scattering measurements made with the transducers oriented horizontally versus vertically, indicating that scattering anisotropy is present. However, the scattering anisotropy could not be unequivocally explained by either turbulent microstructure or zooplankton, the two primary sources of scattering expected in internal waves. Daytime net samples indicate a predominance of short-aspect-ratio zooplankton. Using zooplankton acoustic scattering models, a preferential orientation of the observed zooplankton cannot explain the measured anisotropy. Yet model predictions of scattering from anisotropic turbulent microstructure, with inputs from coincident microstructure measurements, were not consistent with the observations. Possible explanations include bandwidth limitations that result in many spectra that cannot be unambiguously attributed to turbulence or zooplankton based on spectral shape. Extending the acoustic bandwidth to cover the range from 50 kHz to 2 MHz could help improve identification of the dominant sources of backscattering anisotropy

The Landscape of Videofluoroscopy in the UK: A Web-Based Survey

Videofluoroscopy (VFS) is considered one of the gold-standard assessments of swallowing. Whilst guidelines for the application and conduct of VFS exist, their translation into clinical practice remain challenging. To build a greater understanding on how VFS clinics operate in the UK. A web-based survey was shared with speech and language therapists (SLTs) working in VFS clinics via professional networks and social media from October 2018 to January 2019. 101 responses were received. Two thirds of clinics were SLT-led, with the majority of clinics being run by two SLTs (73.6%) and a radiographer (95.5%) also known as radiologic technologists, diagnostic radiographers and medical radiation technologists. Less than 50% of radiographers had received specialist training. Around half of the clinics used a standard assessment or analysis protocol and 88.1% a rating scale. Set recipes for a range of textures were used in 53.4% of VFS clinics. Barium and water soluble contrasts were used, but only 15.8% knew the concentration of contrast used. The most commonly reported VFS pulse and frame rate was 15 per second. There was evidence of a lack of SLT knowledge regarding technical operation of VFS. Screening times varied from 0.7–10 min (median 3 min, IQR 2.5–3.5). Around 50% of respondents reported quality issues affecting analysis. In a survey of UK SLTs, translation of VFS guidance into practice was found to be limited which may impact on the quality of assessment and analysis. Collaboration with radiology, strengthening of guidelines and greater uptake of specialist training is deemed essential

Bat IFITM3 restriction depends on S-palmitoylation and a polymorphic site within the CD225 domain

Host interferon-induced transmembrane proteins (IFITMs) are broad-spectrum antiviral restriction factors. Of these, IFITM3 potently inhibits viruses that enter cells through acidic endosomes, many of which are zoonotic and emerging viruses with bats (order Chiroptera) as their natural hosts. We previously demonstrated that microbat IFITM3 is antiviral. Here, we show that bat IFITMs are characterized by strong adaptive evolution and identify a highly variable and functionally important site-codon 70-within the conserved CD225 domain of IFITMs. Mutation of this residue in microbat IFITM3 impairs restriction of representatives of four different virus families that enter cells via endosomes. This mutant shows altered subcellular localization and reduced S-palmitoylation, a phenotype copied by mutation of conserved cysteine residues in microbat IFITM3. Furthermore, we show that microbat IFITM3 is S-palmitoylated on cysteine residues C71, C72, and C105, mutation of each cysteine individually impairs virus restriction, and a triple C71A-C72A-C105A mutant loses all restriction activity, concomitant with subcellular re-localization of microbat IFITM3 to Golgi-associated sites. Thus, we propose that S-palmitoylation is critical for Chiropteran IFITM3 function and identify a key molecular determinant of IFITM3 S-palmitoylation

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