Most COVID-19 vaccines require two doses, however with limited vaccine supply, policymakers are considering single-dose vaccination as an alternative strategy. Using a mathematical model combined ...with optimization algorithms, we determined optimal allocation strategies with one and two doses of vaccine under various degrees of viral transmission. Under low transmission, we show that the optimal allocation of vaccine vitally depends on the single-dose efficacy. With high single-dose efficacy, single-dose vaccination is optimal, preventing up to 22% more deaths than a strategy prioritizing two-dose vaccination for older adults. With low or moderate single-dose efficacy, mixed vaccination campaigns with complete coverage of older adults are optimal. However, with modest or high transmission, vaccinating older adults first with two doses is best, preventing up to 41% more deaths than a single-dose vaccination given across all adult populations. Our work suggests that it is imperative to determine the efficacy and durability of single-dose vaccines, as mixed or single-dose vaccination campaigns may have the potential to contain the pandemic much more quickly.
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy of childhood. This incurable disease is characterised by muscle wasting and loss of walking ability leading to complete ...wheelchair dependence by 13 years of age. Prolongation of walking is one of the major aims of treatment.
The aim of this review was to assess whether glucocorticoid corticosteroids stabilize or improve muscle strength and walking in boys with DMD.
This is an update of the Cochrane systematic review first published in 2004 (Manzur 2004). We searched the Cochrane Neuromuscular Disease Group Trials Register (August 2006) using the term 'Duchenne muscular dystrophy'. We also searched MEDLINE (January 1966 to July 2007), EMBASE (January 1980 to August 2006), CINAHL and LILACS (January 1982 to August 2006). We wrote to authors of published studies and other experts in this disease to help identify other trials, checked the references in the identified trials and hand searched the abstracts of relevant journals.
Types of studies: randomised or quasi-randomised trials.
all patients with a definite diagnosis of Duchenne muscular dystrophy. Types of interventions: glucocorticoids such as prednisone, prednisolone, deflazacort or others, with a minimum treatment period of three months.
prolongation of walking (independent walking without long leg calipers).
strength outcome measures, manual muscle strength testing using Medical Research Council strength scores, functional outcome measures and adverse events.
We identified six randomised controlled trials that met the inclusion criteria for our review, and one of these (Beenakker 2005) is a new addition to this update, as it was published subsequent to our first review (Manzur 2004). Two review authors independently selected the trials for the review and assessed methodological quality. Data extraction and inputting were double-checked.
data from one small study used prolongation of walking as an outcome measure and did not show significant benefit.
The meta-analysis of the results from four randomised controlled trials with altogether 249 participants showed that glucocorticoid corticosteroids improved muscle strength and function over six months. Improvements were seen in time taken to rise from the floor (Gowers' time), nine metres walking time, four-stair climbing time, ability to lift weights, leg function grade and forced vital capacity. One randomised controlled trial with altogether 28 participants showed that glucocorticoid corticosteroids stabilize muscle strength and function for up to two years. The most effective prednisolone regime appears to be 0.75 mg/kg/day, given in a daily dose regime. Not enough data were available to compare efficacy of prednisone with deflazacort. Adverse effects: Excessive weight gain, behavioural abnormalities, cushingoid appearance and excessive hair growth were all more common with glucocorticoid corticosteroids than placebo. Long-term adverse effects of glucocorticoid therapy could not be evaluated because of the short-term duration of the randomised studies.Non-randomised studies: A number of non-randomised studies with important efficacy and adverse effects data are tabulated and discussed.
There is evidence from randomised controlled studies that glucocorticoid corticosteroid therapy in Duchenne muscular dystrophy improves muscle strength and function in the short-term (six months to two years). The most effective prednisolone regime appears to be 0.75 mg/kg/day, given daily. In the short term, adverse effects were significantly more common but not clinically severe. Long-term benefits and hazards of glucocorticoid treatment cannot be evaluated from the currently published randomised studies. Non-randomised studies support the conclusions of functional benefits but also identify clinically significant adverse effects of long-term treatment. These benefits and adverse effects have implications for future research studies and clinical practice.
Circadian rhythms enable cells and organisms to coordinate their physiology with the cyclic environmental changes that come as a result of Earth's light/dark cycles. Cyanobacteria make use of a ...post-translational oscillator to maintain circadian rhythms, and this elegant system has become an important model for circadian timekeeping mechanisms. Composed of three proteins, the KaiABC system undergoes an oscillatory biochemical cycle that provides timing cues to achieve a 24-h molecular clock. Together with the input/output proteins SasA, CikA, and RpaA, these six gene products account for the timekeeping, entrainment, and output signaling functions in cyanobacterial circadian rhythms. This Minireview summarizes the current structural, functional and mechanistic insights into the cyanobacterial circadian clock.
Trial results for two COVID-19 vaccines suggest at least 90% efficacy against symptomatic disease (VE
). It remains unknown whether this efficacy is mediated by lowering SARS-CoV-2 infection ...susceptibility (VE
) or development of symptoms after infection (VE
). We aim to assess and compare the population impact of vaccines with different efficacy profiles (VE
and VE
) satisfying licensure criteria. We developed a mathematical model of SARS-CoV-2 transmission, calibrated to data from King County, Washington. Rollout scenarios starting December 2020 were simulated with combinations of VE
and VE
resulting in up to 100% VE
. We assumed no reduction of infectivity upon infection conditional on presence of symptoms. Proportions of cumulative infections, hospitalizations and deaths prevented over 1 year from vaccination start are reported. Rollouts of 1 M vaccinations (5000 daily) using vaccines with 50% VE
are projected to prevent 23-46% of infections and 31-46% of deaths over 1 year. In comparison, vaccines with 90% VE
are projected to prevent 37-64% of infections and 46-64% of deaths over 1 year. In both cases, there is a greater reduction if VE
is mediated mostly by VE
. The use of a "symptom reducing" vaccine will require twice as many people vaccinated than a "susceptibility reducing" vaccine with the same 90% VE
to prevent 50% of the infections and death over 1 year. Delaying the start of the vaccination by 3 months decreases the expected population impact by more than 50%. Vaccines which prevent COVID-19 disease but not SARS-CoV-2 infection, and thereby shift symptomatic infections to asymptomatic infections, will prevent fewer infections and require larger and faster vaccination rollouts to have population impact, compared to vaccines that reduce susceptibility to infection. If uncontrolled transmission across the U.S. continues, then expected vaccination in Spring 2021 will provide only limited benefit.
Circadian clocks control gene expression to provide an internal representation of local time. We report reconstitution of a complete cyanobacterial circadian clock in vitro, including the central ...oscillator, signal transduction pathways, downstream transcription factor, and promoter DNA. The entire system oscillates autonomously and remains phase coherent for many days with a fluorescence-based readout that enables real-time observation of each component simultaneously without user intervention. We identified the molecular basis for loss of cycling in an arrhythmic mutant and explored fundamental mechanisms of timekeeping in the cyanobacterial clock. We find that SasA, a circadian sensor histidine kinase associated with clock output, engages directly with KaiB on the KaiC hexamer to regulate period and amplitude of the central oscillator. SasA uses structural mimicry to cooperatively recruit the rare, fold-switched conformation of KaiB to the KaiC hexamer to form the nighttime repressive complex and enhance rhythmicity of the oscillator, particularly under limiting concentrations of KaiB. Thus, the expanded in vitro clock reveals previously unknown mechanisms by which the circadian system of cyanobacteria maintains the pace and rhythmicity under variable protein concentrations.
Mild traumatic brain injury in the Veteran population is frequently comorbid with pain, post-traumatic stress disorder, and/or depression. However, not everyone exposed to mild traumatic brain injury ...experiences these comorbidities and it is unclear what factors contribute to this variability. The objective of this study was to identify comorbidity phenotypes among Post-9/11 deployed Veterans with no or mild traumatic brain injury and examine the association of comorbidity phenotypes with adverse outcomes. We found that Veterans with mild traumatic brain injury (n = 93,003) and no brain injury (n = 434,378) were mean age of 32.0 (SD 9.21) on entering Department of Veterans Health Administration care, were predominantly Caucasian non-Hispanic (64.69%), and served in the Army (61.31%). Latent class analysis revealed five phenotypes in each subcohort; Moderately Healthy and Mental Health phenotypes were common to both. The Healthy phenotype was found only in no brain injury. Unique phenotypes in mild traumatic brain injury included Moderately Healthy+Decline, Polytrauma, and Polytrauma+Improvement. There was substantial variation in adverse outcomes. The Polytrauma+Improvement phenotype had the lowest likelihood of adverse outcomes. There were no differences between Moderately Healthy+Decline and Polytrauma phenotypes. Phenotypes of comorbidity vary significantly by traumatic brain injury status including divergence in phenotypes (and outcomes) over time in the mild traumatic brain injury subcohort. Understanding risk factors for the divergence between Polytrauma vs. Polytrauma+Improvement and Moderately Healthy vs. Moderately Healthy+Decline, will improve our ability to proactively mitigate risk, better understand the early patterns of comorbidity that are associated with neurodegenerative sequelae following mild traumatic brain injury, and plan more patient-centered care.
Recent theories posit that adult neurogenesis supports dentate gyrus pattern separation and hence is necessary for some types of discrimination learning. Using an inducible transgenic mouse model, we ...investigated the contribution of adult-born neurons to spatial and nonspatial touch-screen discriminations of varying levels of difficulty. Arresting neurogenesis caused a modest but statistically significant impairment in a position discrimination task. However, the effect was present only on trials after a learned discrimination was reversed, suggesting that neurogenesis supports cognitive flexibility rather than spatial discrimination per se. The deficit was present 4-10 weeks after the arrest of neurogenesis but not immediately after, consistent with previous evidence that the behavioral effects of arresting neurogenesis arise because of the depletion of adult-born neurons at least 1 month old. The arrest of neurogenesis failed to affect a nonspatial brightness discrimination task that was equal in difficulty to the spatial task. The data suggest that adult neurogenesis is not strictly necessary for spatial or perceptual discrimination learning and instead implicate adult neurogenesis in factors related to reversal learning, such as cognitive flexibility or proactive interference.
Summary Background Prognosis for women with abdominal aortic aneurysm might be worse than the prognosis for men. We aimed to systematically quantify the differences in outcomes between men and women ...being assessed for repair of intact abdominal aortic aneurysm using data from study periods after the year 2000. Methods In these systematic reviews and meta-analysis, we identified studies (randomised, cohort, or cross-sectional) by searching MEDLINE, Embase, CENTRAL, and grey literature published between Jan 1, 2005, and Sept 2, 2016, for two systematic reviews and Jan 1, 2009, and Sept 2, 2016, for one systematic review. Studies were included if they were of both men and women, with data presented for each sex separately, with abdominal aortic aneurysms being assessed for aneurysm repair by either endovascular repair (EVAR) or open repair. We conducted three reviews based on whether studies reported the proportion morphologically suitable (within manufacturers' instructions for use) for EVAR (EVAR suitability review), non-intervention rates (non-intervention review), and 30-day mortality (operative mortality review) after intact aneurysm repair. Studies had to include at least 20 women (for the EVAR suitability review), 20 women (for the non-intervention review), and 50 women (for the operative mortality review). Studies were excluded if they were review articles, editorials, letters, or case reports. For the operative review, studies were also excluded if they only provided hazard ratios or only reported in-hospital mortality. We assessed the quality of the studies using the Newcastle–Ottawa scoring system, and contacted authors for the provision of additional data if needed. We combined results across studies by random-effects meta-analysis. This study is registered with PROSPERO, number CRD42016043227. Findings Five studies assessed the morphological eligibility for EVAR (1507 men, 400 women). The overall pooled proportion of women eligible (34%) for EVAR was lower than it was in men (54%; odds ratio OR 0·44, 95% CI 0·32–0·62). Four single-centre studies reported non-intervention rates (1365 men, 247 women). The overall pooled non-intervention rates were higher in women (34%) than men (19%; OR 2·27, 95% CI 1·21–4·23). The review of 30-day mortality included nine studies (52 018 men, 11 076 women). The overall pooled estimate for EVAR was higher in women (2·3%) than in men (1·4%; OR 1·67, 95% CI 1·38–2·04). The overall estimate for open repair also was higher in women (5·4%) than in men (2·8%; OR 1·76, 95% CI 1·35–2·30). Interpretation Compared with men, a smaller proportion of women are eligible for EVAR, a higher proportion of women are not offered intervention, and operative mortality is much higher in women for both EVAR and open repair. The management of abdominal aortic aneurysm in women needs improvement. Funding National Institute for Health Research (UK).
Abstract More than 36 yr have passed since the discovery of the infrared excess from circumstellar dust orbiting the white dwarf G29-38, which at 17.5 pc it is the nearest and brightest of its class. ...The precise morphology of the orbiting dust remains only marginally constrained by existing data, subject to model-dependent inferences, and thus fundamental questions of its dynamical origin and evolution persist. This study presents a means to constrain the geometric distribution of the emitting dust using stellar pulsations measured at optical wavelengths as a variable illumination source of the dust, which reradiates primarily in the infrared. By combining optical photometry from the Whole Earth Telescope with 0.7–2.5 μ m spectroscopy obtained with SpeX at NASA’s Infrared Telescope Facility, we detect luminosity variations at all observed wavelengths, with variations at most wavelengths corresponding to the behavior of the pulsating stellar photosphere, but toward the longest wavelengths the light curves probe the corresponding time variability of the circumstellar dust. In addition to developing methodology, we find the pulsation amplitudes decrease with increasing wavelength for principal pulsation modes, yet increase beyond ≈2 μ m for nonlinear combination frequencies. We interpret these results as combination modes derived from the principal modes of identical ℓ values and discuss the implications for the morphology of the warm dust. We also draw attention to some discrepancies between our findings and theoretical expectations for the results of the nonlinearity imposed by the surface convection zone on mode–mode interactions and on the behavior of the first harmonic of the highest-amplitude pulsation mode.
Australian Merino breeders have traditionally selected animals for breeding predominately on the basis of wool characteristics. Over recent decades, an increasing proportion of Merino breeders are ...interested in producing a ewe that can be used for prime-lamb production, but that also performs well for wool characteristics. Correlations between ultrasound carcass traits and other traits such as wool, internal parasite resistance and reproduction traits, are not very well known. The aims of this study were three-fold: (1) to estimate the genetic relationships between ultrasound carcass traits and wool, internal parasite resistance and reproduction traits, (2) to determine the value of recording ultrasound carcass traits in Merino breeding programs, and (3) to evaluate the impact of improving ewe genetic merit for fatness on their reproduction performance. Ultrasound fat and eye muscle depth had small to moderate genetic correlations with most traits, with positive correlations observed for bodyweight, fibre diameter, fibre curvature and reproduction, and negative correlations observed for fleece weight, fibre diameter coefficient of variation, worm egg count and breech wrinkle. As expected on the basis of these genetic correlations, estimated breeding values for fat depth of ewes had a positive association with their observed reproduction performance, but the effect explained only minimal variation in reproductive performance, and was extremely variable among flocks and years. A range of measurement scenarios was investigated for three standard MERINOSELECT indexes. Measuring fat and eye muscle depth resulted in 3%, 4% and 21% additional economic index gain for the fine, medium and dual purpose indexes, respectively, whereas measuring reproduction traits directly resulted in 17%, 27% and 45% additional gain in the economic index. Dual purpose index gains benefited more from measuring ultrasound carcass traits as it is the only index with a direct economic value placed on carcass traits. Measuring fat and eye muscle depth also resulted in a greater reduction in worm egg count. The results indicated that desirable genetic progress can be made in wool, ultrasound carcass, internal parasite resistance and number of lambs born and weaned simultaneously using multiple trait selection to account for the mix of favourable and unfavourable correlations between these traits. These results also demonstrated that the best method to maximise economic gain is to measure as many traits (or closely correlated traits) in the breeding objective as possible.
PDF
