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Free yourself from cosmological tyranny! Everything started in a big bang? Invisible dark matter? Black holes? Why accept such a weird cosmos? For all those who wonder about this bizarre universe, and those who want to overthrow the big bang, this handbook gives you 'just the facts': the observations that have shaped these ideas and theories. While the big bang holds the attention of scientists, it isn't perfect. The authors pull back the curtains, and show how cosmology really works. With this, you will know your enemy, cosmic revolutionary - arm yourself for the scientific arena where ideas must fight for survival! This uniquely-framed tour of modern cosmology gives a deeper understanding of the inner workings of this fascinating field. The portrait painted is realistic and raw, not idealized and airbrushed - it is science in all its messy detail, which doesn't pretend to have all the answers.
Background: Biallelic variants in POLR1C are associated with POLR3-related leukodystrophy (POLR3-HLD), or 4H leukodystrophy (Hypomyelination, Hypodontia, Hypogonadotropic Hypogonadism), and Treacher Collins syndrome (TCS). The clinical spectrum of POLR3-HLD caused by variants in this gene has not been described. Methods: A cross-sectional observational study involving 25 centers worldwide was conducted between 2016 and 2018. The clinical, radiologic and molecular features of 23 unreported and previously reported cases of POLR3-HLD caused by POLR1C variants were reviewed. Results: Most participants presented between birth and age 6 years with motor difficulties. Neurological deterioration was seen during childhood, suggesting a more severe phenotype than previously described. The dental, ocular and endocrine features often seen in POLR3-HLD were not invariably present. Five patients (22%) had a combination of hypomyelinating leukodystrophy and abnormal craniofacial development, including one individual with clear TCS features. Several cases did not exhibit all the typical radiologic characteristics of POLR3-HLD. A total of 29 different pathogenic variants in POLR1C were identified, including 13 new disease-causing variants. Conclusions: Based on the largest cohort of patients to date, these results suggest novel characteristics of POLR1C-related disorder, with a spectrum of clinical involvement characterized by hypomyelinating leukodystrophy with or without abnormal craniofacial development reminiscent of TCS.
Despite established clinical associations among major depression (MD), alcohol dependence (AD), and alcohol consumption (AC), the nature of the causal relationship between them is not completely understood. We leveraged genome-wide data from the Psychiatric Genomics Consortium (PGC) and UK Biobank to test for the presence of shared genetic mechanisms and causal relationships among MD, AD, and AC.
Linkage disequilibrium score regression and Mendelian randomization (MR) were performed using genome-wide data from the PGC (MD: 135 458 cases and 344 901 controls; AD: 10 206 cases and 28 480 controls) and UK Biobank (AC-frequency: 438 308 individuals; AC-quantity: 307 098 individuals).
Positive genetic correlation was observed between MD and AD (rgMD−AD = + 0.47, P = 6.6 × 10−10). AC-quantity showed positive genetic correlation with both AD (rgAD−AC quantity = + 0.75, P = 1.8 × 10−14) and MD (rgMD−AC quantity = + 0.14, P = 2.9 × 10−7), while there was negative correlation of AC-frequency with MD (rgMD−AC frequency = −0.17, P = 1.5 × 10−10) and a non-significant result with AD. MR analyses confirmed the presence of pleiotropy among these four traits. However, the MD-AD results reflect a mediated-pleiotropy mechanism (i.e. causal relationship) with an effect of MD on AD (beta = 0.28, P = 1.29 × 10−6). There was no evidence for reverse causation.
This study supports a causal role for genetic liability of MD on AD based on genetic datasets including thousands of individuals. Understanding mechanisms underlying MD-AD comorbidity addresses important public health concerns and has the potential to facilitate prevention and intervention efforts.
The past decade has seen the development of services for adults presenting with symptoms of autism spectrum disorder (ASD) in the UK. Compared with children, little is known about the phenotypic and genetic characteristics of these patients.
This e-cohort study aimed to examine the phenotypic and genetic characteristics of a clinically presenting sample of adults diagnosed with ASD by specialist services.
Individuals diagnosed with ASD as adults were recruited by the National Centre for Mental Health and completed self-report questionnaires, interviews and provided DNA; 105 eligible individuals were matched to 76 healthy controls. We investigated demographics, social history and comorbid psychiatric and physical disorders. Samples were genotyped, copy number variants (CNVs) were called and polygenic risk scores were calculated.
Of individuals with ASD, 89.5% had at least one comorbid psychiatric diagnosis, with depression (62.9%) and anxiety (55.2%) being the most common. The ASD group experienced more neurological comorbidities than controls, particularly migraine headache. They were less likely to have married or be in work, and had more alcohol-related problems. There was a significantly higher load of autism common genetic variants in the adult ASD group compared with controls, but there was no difference in the rate of rare CNVs.
This study provides important information about psychiatric comorbidity in adult ASD, which may inform clinical practice and patient counselling. It also suggests that the polygenic load of common ASD-associated variants may be important in conferring risk within the non-intellectually disabled population of adults with ASD.
The relative burden and risk of readmission for people with personality disorders in hospital settings is unknown.
To compare hospital use of people with personality disorder with that of people with other mental health diagnoses, such as psychoses and affective disorders.
Naturalistic study of hospital presentations for mental health in a large community catchment. Mixed-effects Cox regression and survival curves were generated to examine risk of readmission for each group.
Of 2894 people presenting to hospital, patients with personality disorder represented 20.5% of emergency and 26.6% of in-patients. Patients with personality disorder or psychoses were 2.3 times (95% CI 1.79–2.99) more likely than others to re-present within 28 days. Personality disorder diagnosis increases rate of readmission by a factor of 8.7 (s.e. = 0.31), marginally lower than psychotic disorders (10.02, s.e. = 0.31).
Personality disorders place significant demands on in-patient and emergency departments, similar to that of psychoses in terms of presentation and risk of readmission.
We identified a pseudo-outbreak of Mycobacterium avium in an outpatient bronchoscopy clinic following an increase in clinic procedure volume. We terminated the pseudo-outbreak by increasing the frequency of automated endoscope reprocessors (AER) filter changes from quarterly to monthly. Filter changing schedules should depend on use rather than fixed time intervals.
Accurate assessments of population sizes and trends are fundamental for effective species conservation, particularly for social and long-lived species in which low reproductive rates, aging demographic structure and Allee effects could interact to drive rapid population declines. In the parrots (Order Psittaciformes) these life history characteristics have combined with habitat loss and capture for the pet trade to lead to widespread endangerment, with over 40% of species classified under some level of threat. Here we report the results of a population survey of one such species, the Yellow-naped Amazon, Amazona auropalliata, that is classified as ‘Endangered’ on the IUCN Red List. We conducted a comprehensive survey in June and July of 2016 of 44 night roosts of the populations in contiguous Pacific lowlands of northern Costa Rica and southern Nicaragua and compared numbers in Costa Rica to those found in a similar survey conducted in June 2005. In 2016 we counted 990 birds across 25 sites surveyed in Costa Rica and 692 birds across 19 sites surveyed in Nicaragua for a total population estimate of only 1,682 birds. Comparisons of 13 sites surveyed in both 2005 and 2016 in Costa Rica showed a strong and statistically significant decline in population numbers over the 11-year period. Assessment of group sizes approaching or leaving roosts indicated that less than 25% of groups consisted of three or more birds; there was a significantly higher proportion of these putative family groups observed in Nicaragua than Costa Rica. Taken together, these results are cause for substantial concern for the health of this species in a region that has previously been considered its stronghold, and suggest that stronger conservation action should be undertaken to protect remaining populations from capture for the pet trade and loss of key habitat.
Potentially modifiable risk factors for developing dementia have been identified. However, risk factors for increased mortality in patients with diagnosed dementia are not well understood. Identifying factors that influence prognosis would help clinicians plan care and address unmet needs.
To investigate diagnosed depression and sociodemographic factors as predictors of mortality in patients with dementia in UK secondary clinical care services.
We conducted a cohort study of patients with a dementia diagnosis in an electronic health records database in a UK National Health Service mental health trust.
In 3374 patients with 10 856 person-years of follow-up, comorbid depression was not associated with mortality (adjusted hazard ratio 0.94; 95% CI 0.71–1.24). Single patients had higher mortality than those who were married (adjusted hazard ratio 1.25; 95% CI 1.03–1.50). Patients of Asian ethnicity had lower mortality rates than White British patients (adjusted hazard ratio 0.50; 95% CI 0.34–0.73).
Clinically diagnosed depression does not increase mortality in patients with dementia. Patients who are single are a potential high-mortality risk group. Lower mortality rates in Asian patients with dementia that have been reported in the USA also apply in the UK.
Introduction: Patients with chronic diseases are known to benefit from exercise. Such patients often visit the emergency department (ED). There are few studies examining prescribing exercise in the ED. We wished to study if exercise prescription in the ED is feasible and effective. Methods: In this pilot prospective block randomized trial, patients in the control group received routine care, whereas the intervention group received a combined written and verbal prescription for moderate exercise (150 minutes/week). Both groups were followed up by phone at 2 months. The primary outcome was achieving 150 min of exercise per week. Secondary outcomes included change in exercise, and differences in reported median weekly exercise. Comparisons were made by Mann-Whitney and Fishers tests (GraphPad). Results: Follow-up was completed for 22 patients (11 Control; 11 Intervention). Baseline reported median (with IQR) weekly exercise was similar between groups; Control 0(0-0)min; Intervention 0(0-45)min. There was no difference between groups for the primary outcome of 150 min/week at 2 months (Control 3/11; Intervention 4/11, RR 1.33 (95%CI 0.38-4.6;p=1.0). There was a significant increase in median exercise from baseline in both groups, but no difference between the groups (Control 75(10-225)min; Intervention 120(52.5-150)min;NS). 3 control patients actually received exercise prescription as part of routine care. A post-hoc comparison of patients receiving intervention vs. no intervention, revealed an increase in patients meeting the primary target of 150min/week (No intervention 0/8; Intervention 7/14, RR 2.0 (95%CI 1.2-3.4);p=0.023). Conclusion: Recruitment was feasible, however our study was underpowered to quantify an estimated effect size. As a significant proportion of the control group received the intervention (as part of standard care), any potential measurable effect was diluted. The improvement seen in patients receiving intervention and the increase in reported exercise in both groups (possible Hawthorne effect) suggests that exercise prescription for ED patients may be beneficial.
To summarize and discuss logistic and administrative challenges we encountered during the Benefits of Enhanced Terminal Room (BETR) Disinfection Study and lessons learned that are pertinent to future utilization of ultraviolet (UV) disinfection devices in other hospitals
Multicenter cluster randomized trial
SETTING AND PARTICIPANTS
Nine hospitals in the southeastern United States
All participating hospitals developed systems to implement 4 different strategies for terminal room disinfection. We measured compliance with disinfection strategy, barriers to implementation, and perceptions from nurse managers and environmental services (EVS) supervisors throughout the 28-month trial.
Implementation of enhanced terminal disinfection with UV disinfection devices provides unique challenges, including time pressures from bed control personnel, efficient room identification, negative perceptions from nurse managers, and discharge volume. In the course of the BETR Disinfection Study, we utilized several strategies to overcome these barriers: (1) establishing safety as the priority; (2) improving communication between EVS, bed control, and hospital administration; (3) ensuring availability of necessary resources; and (4) tracking and providing feedback on compliance. Using these strategies, we deployed ultraviolet (UV) disinfection devices in 16,220 (88%) of 18,411 eligible rooms during our trial (median per hospital, 89%; IQR, 86%–92%).
Implementation of enhanced terminal room disinfection strategies using UV devices requires recognition and mitigation of 2 key barriers: (1) timely and accurate identification of rooms that would benefit from enhanced terminal disinfection and (2) overcoming time constraints to allow EVS cleaning staff sufficient time to properly employ enhanced terminal disinfection methods.
Unravelling apparent paradoxes has proven to be a powerful tool for understanding the complexities of special relativity. In this paper, we focus upon one such paradox, namely Bell’s spaceship paradox, examining the relative motion of two uniformly accelerating spaceships. We consider the view from either spaceship, with the exchange of photons between the two. This recovers the well-known result that the leading spaceship loses sight of the trailing spaceship as it is redshifted and disappears behind what is known as the ‘Rindler horizon’. An immediate impact of this is that if either spaceship tries to measure the separation through ‘radar ranging’, bouncing photons off one another, they would both eventually fail to receive any of the photon ‘pings’ that they emit. We find that the view from this trailing spaceship is, however, starkly different, initially, seeing the leading spaceship with an increasing blueshift, followed by a decreasing blueshift. We conclude that, while the leading spaceship loses sight of the trailing spaceship, for the trailing spaceship the view of the separation between the two spaceships, and the apparent angular size of the leading spaceship, approach asymptotic values. Intriguingly, for particular parameterisation of the journey of the two spaceships, these asymptotic values are identical to those properties seen before the spaceships began accelerating, and the view from the trailing spaceship becomes identical to when the two spaceships were initially at rest.
While the exchange of water through Yucatan Strait is reasonably well known, the age of the deep water in both the Caribbean Sea and Gulf of Mexico is not. We recently measured the radiocarbon (14C) concentrations in deep water in the Gulf of Mexico from a line of stations along 90°30′W. The mean apparent age of water below 900 m, the depth of the Florida Strait sill, was found to be about 740 yr relative to the 1950 14C standard. Depending on how the corrections for biological activity in the upper water are applied, this converts to a “true” age of between 231 ± 28 and 293 ± 74 yr. These ages agree with a previous estimate of the age of the deep water in the Gulf of Mexico based on heat flows, put upper limits on the age of the deep water in the Caribbean Sea, and provide constraints on modelers for the return of deep water from the Gulf of Mexico to the Caribbean. This might be important in the event of a future deep water oil or other chemical spill in the region.
Optical matching of ASTER (Advanced Spaceborne Thermal Emission and Reflection Radiometer) satellite image pairs is used to determine the surface velocities of major glaciers across the central Karakoram. The ASTER images were acquired in 2006 and 2007, and cover a 60×120km region over Baltoro glacier, Pakistan, and areas to the north and west. The surface velocities were compared with differential global position system (GPS) data collected on Baltoro glacier in summer 2005. The ASTER measurements reveal fine details about ice dynamics in this region. For example, glaciers are found to be active over their termini even where they are very heavily debris-covered. The characteristics of several surge-type glaciers were measured, with terminus advances of several hundred meters per year and the displacement of trunk glaciers as surge glaciers pushed into them. This study is the first synthesis of glacier velocities across this region, and provides a baseline against which both past and future changes can be compared.
Chagas disease is caused by infection with the insect-transmitted protozoan Trypanosoma cruzi, and is the most important parasitic infection in Latin America. The current drugs, benznidazole and nifurtimox, are characterized by limited efficacy and toxic side-effects, and treatment failures are frequently observed. The urgent need for new therapeutic approaches is being met by a combined effort from the academic and commercial sectors, together with major input from not-for-profit drug development consortia. With the disappointing outcomes of recent clinical trials against chronic Chagas disease, it has become clear that an incomplete understanding of parasite biology and disease pathogenesis is impacting negatively on the development of more effective drugs. In addition, technical issues, including difficulties in establishing parasitological cure in both human patients and animal models, have greatly complicated the assessment of drug efficacy. Here, we outline the major questions that need to be addressed and discuss technical innovations that can be exploited to accelerate the drug development pipeline.
We performed a spatial-temporal analysis to assess household risk factors for Ebola virus disease (Ebola) in a remote, severely-affected village. We defined a household as a family's shared living space and a case-household as a household with at least one resident who became a suspect, probable, or confirmed Ebola case from 1 August 2014 to 10 October 2014. We used Geographic Information System (GIS) software to calculate inter-household distances, performed space-time cluster analyses, and developed Generalized Estimating Equations (GEE). Village X consisted of 64 households; 42% of households became case-households over the observation period. Two significant space-time clusters occurred among households in the village; temporal effects outweighed spatial effects. GEE demonstrated that the odds of becoming a case-household increased by 4·0% for each additional person per household (P < 0·02) and 2·6% per day (P < 0·07). An increasing number of persons per household, and to a lesser extent, the passage of time after onset of the outbreak were risk factors for household Ebola acquisition, emphasizing the importance of prompt public health interventions that prioritize the most populated households. Using GIS with GEE can reveal complex spatial-temporal risk factors, which can inform prioritization of response activities in future outbreaks.
After CQ Cep, the system CX Cep has the shortest orbital period known among Galactic WR+O binaries. However, no definitive spectroscopic study is yet available for CX Cep, probably because of its relatively faint magnitude (B ≈ 13). We have therefore obtained and analyzed some 60 CCD spectra (3700-4900 Å, S/N ⋍ 100, 5 Å/2 pixels) in August and October 1987.
Four key policy challenges, framed here as dichotomies, are commonly associated with attempts to improve the use of natural resources in the socioecological commons. These dichotomies present tradeoffs when addressing market failures and in general seem to suggest the need to settle for second-best outcomes rather than first-best outcomes identified in stylized models. Citing examples, we argue that these models, while illustrating these dichotomies, also suggest means for circumventing them, and perhaps provide a degree of optimism about prospective outcomes in socioecological systems.