OBJECTIVE To develop consensus-based recommendations for measures to be taken
by medical and public health professionals if hemorrhagic fever viruses (HFVs)
are used as biological weapons against a ...civilian population. PARTICIPANTS The Working Group on Civilian Biodefense included 26 representatives
from academic medical centers, public health, military services, governmental
agencies, and other emergency management institutions. EVIDENCE MEDLINE was searched from January 1966 to January 2002. Retrieved references,
relevant material published prior to 1966, and additional sources identified
by participants were reviewed. CONSENSUS PROCESS Three formal drafts of the statement that synthesized information obtained
in the evidence-gathering process were reviewed by the working group. Each
draft incorporated comments and judgments of the members. All members approved
the final draft. CONCLUSIONS Weapons disseminating a number of HFVs could cause an outbreak of an
undifferentiated febrile illness 2 to 21 days later, associated with clinical
manifestations that could include rash, hemorrhagic diathesis, and shock.
The mode of transmission and clinical course would vary depending on the specific
pathogen. Diagnosis may be delayed given clinicians' unfamiliarity with these
diseases, heterogeneous clinical presentation within an infected cohort, and
lack of widely available diagnostic tests. Initiation of ribavirin therapy
in the early phases of illness may be useful in treatment of some of these
viruses, although extensive experience is lacking. There are no licensed vaccines
to treat the diseases caused by HFVs.
Atrial fibrillation (AF) wavefront dynamics are complex and difficult to interpret, contributing to uncertainty about the mechanisms that maintain AF. We aimed to investigate the interplay between ...rotors, wavelets, and focal sources during fibrillation.
Arrhythmia wavefront dynamics were analysed for four optically mapped canine cholinergic AF preparations. A bilayer computer model was tuned to experimental preparations, and varied to have (i) fibrosis in both layers or the epicardium only, (ii) different spatial acetylcholine distributions, (iii) different intrinsic action potential duration between layers, and (iv) varied interlayer connectivity. Phase singularities (PSs) were identified and tracked over time to identify rotational drivers. New focal wavefronts were identified using phase contours. Phase singularity density and new wavefront locations were calculated during AF. There was a single dominant mechanism for sustaining AF in each of the preparations, either a rotational driver or repetitive new focal wavefronts. High-density PS sites existed preferentially around the pulmonary vein junctions. Three of the four preparations exhibited stable preferential sites of new wavefronts. Computational simulations predict that only a small number of connections are functionally important in sustaining AF, with new wavefront locations determined by the interplay between fibrosis distribution, acetylcholine concentration, and heterogeneity in repolarization within layers.
We were able to identify preferential sites of new wavefront initiation and rotational activity, in order to determine the mechanisms sustaining AF. Electrical measurements should be interpreted differently according to whether they are endocardial or epicardial recordings.
Prostate cancer is the most common cancer among men in the UK. Prostate-specific antigen testing followed by biopsy leads to overdetection, overtreatment as well as undertreatment of the disease. ...Evidence of treatment effectiveness has lacked because of the paucity of randomised controlled trials comparing conventional treatments.
To evaluate the effectiveness of conventional treatments for localised prostate cancer (active monitoring, radical prostatectomy and radical radiotherapy) in men aged 50-69 years.
A prospective, multicentre prostate-specific antigen testing programme followed by a randomised trial of treatment, with a comprehensive cohort follow-up.
Prostate-specific antigen testing in primary care and treatment in nine urology departments in the UK.
Between 2001 and 2009, 228,966 men aged 50-69 years received an invitation to attend an appointment for information about the Prostate testing for cancer and Treatment (ProtecT) study and a prostate-specific antigen test; 82,429 men were tested, 2664 were diagnosed with localised prostate cancer, 1643 agreed to randomisation to active monitoring (
= 545), radical prostatectomy (
= 553) or radical radiotherapy (
= 545) and 997 chose a treatment.
The interventions were active monitoring, radical prostatectomy and radical radiotherapy.
Definite or probable disease-specific mortality at the 10-year median follow-up in randomised participants.
Overall mortality, metastases, disease progression, treatment complications, resource utilisation and patient-reported outcomes.
There were no statistically significant differences between the groups for 17 prostate cancer-specific (
= 0.48) and 169 all-cause (
= 0.87) deaths. Eight men died of prostate cancer in the active monitoring group (1.5 per 1000 person-years, 95% confidence interval 0.7 to 3.0); five died of prostate cancer in the radical prostatectomy group (0.9 per 1000 person-years, 95% confidence interval 0.4 to 2.2 per 1000 person years) and four died of prostate cancer in the radical radiotherapy group (0.7 per 1000 person-years, 95% confidence interval 0.3 to 2.0 per 1000 person years). More men developed metastases in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring,
= 33 (6.3 per 1000 person-years, 95% confidence interval 4.5 to 8.8); radical prostatectomy,
= 13 (2.4 per 1000 person-years, 95% confidence interval 1.4 to 4.2 per 1000 person years); and radical radiotherapy,
= 16 (3.0 per 1000 person-years, 95% confidence interval 1.9 to 4.9 per 1000 person-years;
= 0.004). There were higher rates of disease progression in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring (
= 112; 22.9 per 1000 person-years, 95% confidence interval 19.0 to 27.5 per 1000 person years); radical prostatectomy (
= 46; 8.9 per 1000 person-years, 95% confidence interval 6.7 to 11.9 per 1000 person-years); and radical radiotherapy (
= 46; 9.0 per 1000 person-years, 95% confidence interval 6.7 to 12.0 per 1000 person years;
< 0.001). Radical prostatectomy had the greatest impact on sexual function/urinary continence and remained worse than radical radiotherapy and active monitoring. Radical radiotherapy's impact on sexual function was greatest at 6 months, but recovered somewhat in the majority of participants. Sexual and urinary function gradually declined in the active monitoring group. Bowel function was worse with radical radiotherapy at 6 months, but it recovered with the exception of bloody stools. Urinary voiding and nocturia worsened in the radical radiotherapy group at 6 months but recovered. Condition-specific quality-of-life effects mirrored functional changes. No differences in anxiety/depression or generic or cancer-related quality of life were found. At the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year, the probabilities that each arm was the most cost-effective option were 58% (radical radiotherapy), 32% (active monitoring) and 10% (radical prostatectomy).
A single prostate-specific antigen test and transrectal ultrasound biopsies were used. There were very few non-white men in the trial. The majority of men had low- and intermediate-risk disease. Longer follow-up is needed.
At a median follow-up point of 10 years, prostate cancer-specific mortality was low, irrespective of the assigned treatment. Radical prostatectomy and radical radiotherapy reduced disease progression and metastases, but with side effects. Further work is needed to follow up participants at a median of 15 years.
Current Controlled Trials ISRCTN20141297.
This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in
; Vol. 24, No. 37. See the National Institute for Health Research Journals Library website for further project information.
The scattering of neutrons can be used to provide information on the structure and dynamics of biological systems on multiple length and time scales. Pursuant to a National Science Foundation‐funded ...workshop in February 2018, recent developments in this field are reviewed here, as well as future prospects that can be expected given recent advances in sources, instrumentation and computational power and methods. Crystallography, solution scattering, dynamics, membranes, labeling and imaging are examined. For the extraction of maximum information, the incorporation of judicious specific deuterium labeling, the integration of several types of experiment, and interpretation using high‐performance computer simulation models are often found to be particularly powerful.
A wide variety of neutron scattering techniques can be applied to obtain information on the structure and dynamics of biological systems on multiple scales. Recent progress is summarized, as are hoped‐for future developments in the context of the advent of next‐generation neutron sources on various continents.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
IMPORTANCE: Moyamoya disease (MMD), a progressive vasculopathy leading to narrowing and ultimate occlusion of the intracranial internal carotid arteries, is a cause of childhood stroke. The cause of ...MMD is poorly understood, but genetic factors play a role. Several familial forms of MMD have been identified, but the cause of most cases remains elusive, especially among non–East Asian individuals. OBJECTIVE: To assess whether ultrarare de novo and rare, damaging transmitted variants with large effect sizes are associated with MMD risk. DESIGN, SETTING, AND PARTICIPANTS: A genetic association study was conducted using whole-exome sequencing case-parent MMD trios in a small discovery cohort collected over 3.5 years (2016-2019); data were analyzed in 2020. Medical records from US hospitals spanning a range of 1 month to 1.5 years were reviewed for phenotyping. Exomes from a larger validation cohort were analyzed to identify additional rare, large-effect variants in the top candidate gene. Participants included patients with MMD and, when available, their parents. All participants who met criteria and were presented with the option to join the study agreed to do so; none were excluded. Twenty-four probands (22 trios and 2 singletons) composed the discovery cohort, and 84 probands (29 trios and 55 singletons) composed the validation cohort. MAIN OUTCOMES AND MEASURES: Gene variants were identified and filtered using stringent criteria. Enrichment and case-control tests assessed gene-level variant burden. In silico modeling estimated the probability of variant association with protein structure. Integrative genomics assessed expression patterns of MMD risk genes derived from single-cell RNA sequencing data of human and mouse brain tissue. RESULTS: Of the 24 patients in the discovery cohort, 14 (58.3%) were men and 18 (75.0%) were of European ancestry. Three of 24 discovery cohort probands contained 2 do novo (1-tailed Poisson P = 1.1 × 10−6) and 1 rare, transmitted damaging variant (12.5% of cases) in DIAPH1 (mammalian diaphanous-1), a key regulator of actin remodeling in vascular cells and platelets. Four additional ultrarare damaging heterozygous DIAPH1 variants (3 unphased) were identified in 3 other patients in an 84-proband validation cohort (73.8% female, 77.4% European). All 6 patients were non–East Asian. Compound heterozygous variants were identified in ena/vasodilator-stimulated phosphoproteinlike protein EVL, a mammalian diaphanous-1 interactor that regulates actin polymerization. DIAPH1 and EVL mutant probands had severe, bilateral MMD associated with transfusion-dependent thrombocytopenia. DIAPH1 and other MMD risk genes are enriched in mural cells of midgestational human brain. The DIAPH1 coexpression network converges in vascular cell actin cytoskeleton regulatory pathways. CONCLUSIONS AND RELEVANCE: These findings provide the largest collection to date of non–East Asian individuals with sporadic MMD harboring pathogenic variants in the same gene. The results suggest that DIAPH1 is a novel MMD risk gene and impaired vascular cell actin remodeling in MMD pathogenesis, with diagnostic and therapeutic ramifications.
Objective
To evaluate 8‐year weight losses achieved with intensive lifestyle intervention (ILI) in the Look AHEAD (Action for Health in Diabetes) study.
Design and Methods
Look AHEAD assessed the ...effects of intentional weight loss on cardiovascular morbidity and mortality in 5,145 overweight/obese adults with type 2 diabetes, randomly assigned to ILI or usual care (i.e., diabetes support and education DSE). The ILI provided comprehensive behavioral weight loss counseling over 8 years; DSE participants received periodic group education only.
Results
All participants had the opportunity to complete 8 years of intervention before Look AHEAD was halted in September 2012; ≥88% of both groups completed the 8‐year outcomes assessment. ILI and DSE participants lost (mean ± SE) 4.7% ± 0.2% and 2.1 ± 0.2% of initial weight, respectively (P < 0.001) at year 8; 50.3% and 35.7%, respectively, lost ≥5% (P < 0.001), and 26.9% and 17.2%, respectively, lost ≥10% (P < 0.001). Across the 8 years ILI participants, compared with DSE, reported greater practice of several key weight‐control behaviors. These behaviors also distinguished ILI participants who lost ≥10% and kept it off from those who lost but regained.
Conclusions
Look AHEAD's ILI produced clinically meaningful weight loss (≥5%) at year 8 in 50% of patients with type 2 diabetes and can be used to manage other obesity‐related co‐morbid conditions.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
An association was observed between an inflammation-related risk score (IRRS) and worse overall survival (OS) among a cohort of mostly White women with invasive epithelial ovarian cancer (EOC). ...Herein, we evaluated the association between the IRRS and OS among Black women with EOC, a population with higher frequencies of pro-inflammatory exposures and worse survival.
The analysis included 592 Black women diagnosed with EOC from the African American Cancer Epidemiology Study (AACES). Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of the IRRS and OS, adjusting for relevant covariates. Additional inflammation-related exposures, including the energy-adjusted Dietary Inflammatory Index (E-DII
), were evaluated.
A dose-response trend was observed showing higher IRRS was associated with worse OS (per quartile HR: 1.11, 95% CI: 1.01-1.22). Adding the E-DII to the model attenuated the association of IRRS with OS, and increasing E-DII, indicating a more pro-inflammatory diet, was associated with shorter OS (per quartile HR: 1.12, 95% CI: 1.02-1.24). Scoring high on both indices was associated with shorter OS (HR: 1.54, 95% CI: 1.16-2.06).
Higher levels of inflammation-related exposures were associated with decreased EOC OS among Black women.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
North American pollution outflow is ubiquitous over the western North
Atlantic Ocean, especially in winter, making this location a suitable
natural laboratory for investigating the impact of ...precipitation on aerosol
particles along air mass trajectories. We take advantage of observational
data collected at Bermuda to seasonally assess the sensitivity of aerosol
mass concentrations and volume size distributions to accumulated
precipitation along trajectories (APT). The mass concentration of
particulate matter with aerodynamic diameter less than 2.5 µm
normalized by the enhancement of carbon monoxide above background
(PM2.5/ΔCO) at Bermuda was used to estimate the degree of
aerosol loss during transport to Bermuda. Results for December–February
(DJF) show that most trajectories come from North America and have the highest
APTs, resulting in a significant reduction (by 53 %) in PM2.5/ΔCO under high-APT conditions (> 13.5 mm) relative to low-APT
conditions (< 0.9 mm). Moreover, PM2.5/ΔCO was most
sensitive to increases in APT up to 5 mm (−0.044 µg m−3 ppbv−1 mm−1) and less sensitive to increases in APT over 5 mm.
While anthropogenic PM2.5 constituents (e.g., black carbon, sulfate,
organic carbon) decrease with high APT, sea salt, in contrast, was comparable
between high- and low-APT conditions owing to enhanced local wind and sea
salt emissions in high-APT conditions. The greater sensitivity of the fine-mode volume concentrations (versus coarse mode) to wet scavenging is evident
from AErosol RObotic NETwork
(AERONET) volume size distribution data. A combination of GEOS-Chem model
simulations of the 210Pb submicron aerosol tracer and its gaseous precursor
222Rn reveals that (i) surface aerosol particles at Bermuda are most
impacted by wet scavenging in winter and spring (due to large-scale
precipitation) with a maximum in March, whereas convective scavenging plays
a substantial role in summer; and (ii) North American 222Rn tracer
emissions contribute most to surface 210Pb concentrations at Bermuda in
winter (∼ 75 %–80 %), indicating that air masses arriving at
Bermuda experience large-scale precipitation scavenging while traveling from
North America. A case study flight from the ACTIVATE field campaign on 22 February 2020 reveals a significant reduction in aerosol number and volume
concentrations during air mass transport off the US East Coast associated
with increased cloud fraction and precipitation. These results highlight the
sensitivity of remote marine boundary layer aerosol characteristics to
precipitation along trajectories, especially when the air mass source is
continental outflow from polluted regions like the US East Coast.
In the wake of the Deepwater Horizon (DWH) oil spill, a number of government agencies, academic institutions, consultants, and nonprofit organizations conducted lab- and field-based research to ...understand the toxic effects of the oil. Lab testing was performed with a variety of fish, birds, turtles, and vertebrate cell lines (as well as invertebrates); field biologists conducted observations on fish, birds, turtles, and marine mammals; and epidemiologists carried out observational studies in humans. Eight years after the spill, scientists and resource managers held a workshop to summarize the similarities and differences in the effects of DWH oil on vertebrate taxa and to identify remaining gaps in our understanding of oil toxicity in wildlife and humans, building upon the cross-taxonomic synthesis initiated during the Natural Resource Damage Assessment. Across the studies, consistency was found in the types of toxic response observed in the different organisms. Impairment of stress responses and adrenal gland function, cardiotoxicity, immune system dysfunction, disruption of blood cells and their function, effects on locomotion, and oxidative damage were observed across taxa. This consistency suggests conservation in the mechanisms of action and disease pathogenesis. From a toxicological perspective, a logical progression of impacts was noted: from molecular and cellular effects that manifest as organ dysfunction, to systemic effects that compromise fitness, growth, reproductive potential, and survival. From a clinical perspective, adverse health effects from DWH oil spill exposure formed a suite of signs/symptomatic responses that at the highest doses/concentrations resulted in multi-organ system failure.
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Abstract Introduction Bleeding remains a leading cause of death in trauma patients. The iTClamp is a temporary wound closure device designed to control external bleeding within seconds of injury. We ...describe our experience using this device on 10 patients in the prehospital environment. Methods We have implemented the iTClamp for prehospital use through our physician-staffed helicopter emergency medical service (HEMS). Indications were massive bleeding that could not be controlled with an ordinary compressive bandage or a haemostatic bandage. Results Ten patients were treated with the iTClamp. Seven patients had a severe head injury due to various traumas, one patient had a neck injury from a disk cutter, one patient had an open chest wound and one patient had an open femur fracture. After applying the iTClamp, bleeding was controlled in 90% of these patients ( n = 9), with complete cessation reported in 60% ( n = 6), partial cessation with adequate control reported in 30% ( n = 3); in one patient, the bleeding could not be controlled with the iTClamp alone. It took an average of 10 s to apply the iTClamp, and the average usage satisfaction score was 7.7. Conclusion We conclude that the iTClamp is a safe, fast and useful tool for stopping or controlling external blood loss in our series of prehospital patients. Further studies of the iTClamp are needed to determine which patients might benefit from this device.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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