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Background. US recommendations issued in 1999 for hepatitis A (HA) childhood immunization varied according to regional HA incidences prior to vaccination. Mathematical models of HA transmission, especially those accounting for herd protection, can be useful in formulating new, highly effective recommendations that could lead to disease elimination. Methods. A mathematical model of HA transmission was designed to assess the impact of different vaccination strategies on the evolution of HA infection over time in the United States. The model represents HA transmission dynamics and is stratified by age and regions defined in the Advisory Committee for Immunization Practices 1999 recommendations. The model accounts for herd protection and HA importation, using an age-dependent “force of infection” varying over time as a function of the prevalence of subjects with infectious HA. Results. The model predicts a clear benefit of vaccinating all US children at as young an age as possible. Nationwide routine immunization at 1 year of age with 70% coverage would prevent 57% of additional cases during the period 1995–2029, compared with the continuation of the regional strategy of vaccinating children at 2 years of age, as recommended by the Advisory Committee for Immunization Practices in 1999. In contrast, the model also predicts that nationwide routine immunization for children 12 years of age only would result in a 14% increase of HA cases during the period 1995–2029, compared with the number of cases predicted with the regional strategy of the immunization of 2-year-olds. Conclusions. These findings highlight the importance of accounting for herd protection induced by early childhood HA vaccination. They also support the very recent Advisory Committee for Immunization Practices recommendations for universal HA immunization of 1-year-olds.

[...]these experts promote prevention with their advice to consider the vaccination of some essential service personnel if and when increased production capacity could make vaccine available. [...]it is prudent to heed the prescient advice of the 1999 Working Group on Civilian Biodefense and embrace the 2010 Centers for Disease Control and Prevention Advisory Committee on Immunization Practices' final recommendation, which supports offering the anthrax vaccine, “for persons involved in emergency response activities including but not limited to, police departments, fire departments, hazardous material units, government responders, and the National Guard.” The manufacturer is consistently producing 8 to 9 million doses each year (K. Connolly, personal communication, March 2010). [...]500 000 doses of the anthrax vaccine in the SNS are being destroyed every month because their shelf life has expired.

In the study reported by Gorse et al. a unique, educational opportunity was lost. The vaccine and biodefense communities almost experienced the rare chance in a Phase I study to scientifically compare head-to-head an early-stage, investigational recombinant anthrax vaccine (rPA102) with the safe, effective and already FDA-licensed anthrax vaccine, AVA (BioThrax ®). The authors take a stab at making safety and immunogenicity comparisons between the candidate vaccine and AVA (BioThrax ®) but the study design and analytical approach makes this inappropriate. Inaccurate and poorly substantiated editorial comments in the paper's introduction compound these methodological problems. The reader is presented with a series of false and misleading statements about AVA (BioThrax ®). Out-of-date sources are relied upon and these references are offered to the reader as the best evidence available when more current papers with up-to-date information and data exist. Additionally, the conclusions in several original contributions are misrepresented in this paper by Gorse et al. Issues with protocol and bias notwithstanding, the single most compelling observation from this trial could be that the response of those subjects in this study population ( n = 19) who received AVA on the altered schedule and route of two doses of AVA (BioThrax ®) delivered intramuscularly (IM) in just 4 weeks mounted a robust immune response. Given the more than 30 year history of the safe and effective use of AVA (BioThrax ®) as well as the more current data on AVA (BioThrax ®) a strong case can be made for continued funding to investigate the feasibility of adding another route of delivery (IM) and optimizing the schedule for this already FDA-licensed vaccine.

In the study reported by Gorse et al. a unique, educational opportunity was lost. The vaccine and biodefense communities almost experienced the rare chance in a Phase I study to scientifically compare head-to-head an early-stage, investigational recombinant anthrax vaccine (rPA102) with the safe, effective and already FDA-licensed anthrax vaccine, AVA (BioThrax). The authors take a stab at making safety and immunogenicity comparisons between the candidate vaccine and AVA (BioThrax) but the study design and analytical approach makes this inappropriate. Inaccurate and poorly substantiated editorial comments in the paper's introduction compound these methodological problems. The reader is presented with a series of false and misleading statements about AVA (BioThrax). Out-of-date sources are relied upon and these references are offered to the reader as the best evidence available when more current papers with up-to-date information and data exist. Additionally, the conclusions in several original contributions are misrepresented in this paper by Gorse et al. Issues with protocol and bias notwithstanding, the single most compelling observation from this trial could be that the response of those subjects in this study population (n=19) who received AVA on the altered schedule and route of two doses of AVA (BioThrax) delivered intramuscularly (IM) in just 4 weeks mounted a robust immune response. Given the more than 30 year history of the safe and effective use of AVA (BioThrax) as well as the more current data on AVA (BioThrax) a strong case can be made for continued funding to investigate the feasibility of adding another route of delivery (IM) and optimizing the schedule for this already FDA-licensed vaccine.In the study reported by Gorse et al. a unique, educational opportunity was lost. The vaccine and biodefense communities almost experienced the rare chance in a Phase I study to scientifically compare head-to-head an early-stage, investigational recombinant anthrax vaccine (rPA102) with the safe, effective and already FDA-licensed anthrax vaccine, AVA (BioThrax). The authors take a stab at making safety and immunogenicity comparisons between the candidate vaccine and AVA (BioThrax) but the study design and analytical approach makes this inappropriate. Inaccurate and poorly substantiated editorial comments in the paper's introduction compound these methodological problems. The reader is presented with a series of false and misleading statements about AVA (BioThrax). Out-of-date sources are relied upon and these references are offered to the reader as the best evidence available when more current papers with up-to-date information and data exist. Additionally, the conclusions in several original contributions are misrepresented in this paper by Gorse et al. Issues with protocol and bias notwithstanding, the single most compelling observation from this trial could be that the response of those subjects in this study population (n=19) who received AVA on the altered schedule and route of two doses of AVA (BioThrax) delivered intramuscularly (IM) in just 4 weeks mounted a robust immune response. Given the more than 30 year history of the safe and effective use of AVA (BioThrax) as well as the more current data on AVA (BioThrax) a strong case can be made for continued funding to investigate the feasibility of adding another route of delivery (IM) and optimizing the schedule for this already FDA-licensed vaccine.

To the Editor: In your recent editorial “Access to Specialty Care” (Oct. 27 issue), 1 you mention informal, unofficial “sidewalk” or telephone consultations. Many physicians refer to such consultations as “curbsides.” 1 These consultations save health maintenance organizations (HMOs) money, because the specialists consulted at curbside are not reimbursed for their time and expertise. Although lawyers customarily bill for telephone calls and verbal advice, doctors generally do not charge for these services. In specialties such as cardiology and gastroenterology, there will always be a base-line number of consultations: these specialists perform procedures such as cardiac catheterization and endoscopy that generalists cannot perform. . . .

ObjectivesThe aim of the DiaFu study was to evaluate effectiveness and safety of negative pressure wound therapy (NPWT) in patients with diabetic foot wounds in clinical practice.DesignIn this controlled clinical superiority trial with blinded outcome assessment patients were randomised in a 1:1 ratio stratified by study site and ulcer severity grade using a web-based-tool.SettingThis German national study was conducted in 40 surgical and internal medicine inpatient and outpatient facilities specialised in diabetes foot care.Participants368 patients were randomised and 345 participants were included in the modified intention-to-treat (ITT) population. Adult patients suffering from a diabetic foot ulcer at least for 4 weeks and without contraindication for NPWT were allowed to be included.InterventionsNPWT was compared with standard moist wound care (SMWC) according to local standards and guidelines.Primary and secondary outcome measuresPrimary outcome was wound closure within 16 weeks. Secondary outcomes were wound-related and treatment-related adverse events (AEs), amputations, time until optimal wound bed preparation, wound size and wound tissue composition, pain and quality of life (QoL) within 16 weeks, and recurrences and wound closure within 6 months.ResultsIn the ITT population, neither the wound closure rate (difference: n=4 (2.5% (95% CI−4.7% – 9.7%); p=0.53)) nor the time to wound closure (p=0.244) was significantly different between the treatment arms. 191 participants (NPWT 127; SMWC 64) had missing endpoint documentations, premature therapy ends or unauthorised treatment changes. 96 participants in the NPWT arm and 72 participants in the SMWC arm had at least one AE (p=0.007), but only 16 AEs were related to NPWT.ConclusionsNPWT was not superior to SMWC in diabetic foot wounds in German clinical practice. Overall, wound closure rate was low. Documentation deficits and deviations from treatment guidelines negatively impacted the outcome wound closure.Trial registration numbersNCT01480362 and DRKS00003347.

Lung immaturity is a major cause of morbidity and mortality in premature infants. Understanding the molecular mechanisms driving normal lung development could provide insights on how to ameliorate disrupted development. While transcriptomic and proteomic analyses of normal lung development have been previously reported, characterization of changes in the lipidome is lacking. Lipids play significant roles in the lung, such as dipalmitoylphosphatidylcholine in pulmonary surfactant; however, many of the roles of specific lipid species in normal lung development, as well as in disease states, are not well defined. In this study, we used liquid chromatography-mass spectrometry (LC-MS/MS) to investigate the murine lipidome during normal postnatal lung development. Lipidomics analysis of lungs from post-natal day 7, day 14 and 6–8 week mice (adult) identified 924 unique lipids across 21 lipid subclasses, with dramatic alterations in the lipidome across developmental stages. Our data confirmed previously recognized aspects of post-natal lung development and revealed several insights, including in sphingolipid-mediated apoptosis, inflammation and energy storage/usage. Complementary proteomics, metabolomics and chemical imaging corroborated these observations. This multi-omic view provides a unique resource and deeper insight into normal pulmonary development.

Cell type-resolved proteome analyses of the brain, heart and liver have been reported, however a similar effort on the lipidome is currently lacking. Here we applied liquid chromatography-tandem mass spectrometry to characterize the lipidome of major lung cell types isolated from human donors, representing the first lipidome map of any organ. We coupled this with cell type-resolved proteomics of the same samples (available at Lungmap.net). Complementary proteomics analyses substantiated the functional identity of the isolated cells. Lipidomics analyses showed significant variations in the lipidome across major human lung cell types, with differences most evident at the subclass and intra-subclass (i.e. total carbon length of the fatty acid chains) level. Further, lipidomic signatures revealed an overarching posture of high cellular cooperation within the human lung to support critical functions. Our complementary cell type-resolved lipid and protein datasets serve as a rich resource for analyses of human lung function.

IntroductionPulmonary arterial hypertension (PAH) is a devastating disease characterised by remodelling of the pulmonary arteries, leading to right heart failure and death. The most common cause is a mutation in the bone morphogenetic protein receptor 2 (BMPR2), which plays a key role in disrupting the BMP/TGF-B pathway. The BMP pathway is negatively regulated by the HECT E3 ubiquitin ligase SMURF1. However, its lack of druggable binding site makes it difficult to target therapeutically.HypothesisWe hypothesised that increased SMURF1 expression contributes to the pathogenesis of PAH by negatively regulating BMP signalling, and that inhibiting SMURF1 will augment BMP signalling and reverse PAH-associated phenotype.AimThis study aims to: (1) Investigate the SMURF1 expression level in the pulmonary vasculature; (2) discover SMURF1 inhibitors using a large-scale screen; (3) determine their mechanism of action; and (4) assess their therapeutic potential in experimental models of PAH by examining effects on BMP signalling and cell phenotype.MethodsPulmonary tissue samples from patients undergoing transplantation (both PAH and controls) were examined to determine SMURF1 expression level. A time resolved fluorescence energy transfer (TR-FRET) assay designed to measure SMURF1 self-ubiquitylation and screen of 1.1 million compounds. Primary hits were then subjected to rationalisation and further analysis to identify specific inhibitors of SMURF1. Crystal structures of SMURF1 and SMURF2 in both ligand bound and ligand unbound, were determined at resolution from 2.05 to 2.75 Å. The interaction between identified inhibitors and their targets was validated using a split-CAT system. Finally, the effect of SMURF1 inhibition on signaling pathways and cellular phenotype was investigated in pulmonary endothelial cells and smooth muscle cells. In vivo studies were conducted using rat models of PAH induced by monocrotailne and sugan hypoxia.ResultsIncreased SMURF1 expression was observed in the pulmonary vessel in patients with PAH compared to controls. Selective SMURF1 inhibitors were identified through compound screening. Structural studies showed that inhibitor binding induced α-helix elongation over a glycine hing, restricting catalytic activity. This mechanism was validated using a resistant mutant. SMURF1 inhibitor prevents BMPR2 degradation, restores BMP signalling and cell homeostasis in patients with PAH. SMURF1 inhibition reversed pathological changes in experimental PAH models.ConclusionsThese findings demonstrate that SMURF1 inhibition reverse PAH pathology by restoring BMP signaling. This establishes SMURF1 as a promising therapeutic target and provides structural insights for developing inhibitors against HECT and other glycine-hing proteins.

Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.