MHz gravitational wave constraints with decameter Michelson interferometers

A new detector, the Fermilab Holometer, consists of separate yet identical 39-meter Michelson interferometers. Strain sensitivity achieved is better than 10[superscript -21]/√Hz between 1 to 13 MHz from a 130-h data set. This measurement exceeds the sensitivity and frequency range made from previous high frequency gravitational wave experiments by many orders of magnitude. Constraints are placed on a stochastic background at 382 Hz resolution. The 3σ upper limit on Ω[subscript GW], the gravitational wave energy density normalized to the closure density, ranges from 5.6×10[superscript 12] at 1 MHz to 8.4×10[superscript 15] at 13 MHz. Another result from the same data set is a search for nearby primordial black hole binaries (PBHB). There are no detectable monochromatic PBHBs in the mass range 0.83–3.5×10[superscript 21]  g between the Earth and the Moon. Projections for a chirp search with the same data set increase the mass range to 0.59-2.5×10[superscript 25]  g and distances out to Jupiter. This result presents a new method for placing limits on a poorly constrained mass range of primordial black holes. Additionally, solar system searches for PBHBs place limits on their contribution to the total dark matter fraction.United States. Dept. of Energy (Contract DE-AC02-07CH11359)United States. Dept. of Energy (Early Career Research Program FNAL FWP 11-03)Templeton FoundationNational Science Foundation (U.S.) (Grants PHY- 1205254 and DGE-1144082)National Aeronautics and Space Administration (Grant NNX09AR38G)Fermi Research AllianceUniversity of Chicago. Kavli Institute for Cosmological PhysicsUniversity of Chicago. Fermilab Strategic Collaborative InitiativesScience Support ConsortiumNational Science Foundation (U.S.). Graduate Research Fellowship Program (Grant DGE-0638477)Universities Research Association (U.S.). Visiting Scholars Progra

Application of Intervention Mapping to develop a community-based health promotion pre-pregnancy intervention for adolescent girls in rural South Africa: Project Ntshembo (Hope).

BACKGROUND: South Africa (SA) is undergoing multiple transitions with an increasing burden of non-communicable diseases and high levels of overweight and obesity in adolescent girls and women. Adolescence is key to addressing trans-generational risk and a window of opportunity to intervene and positively impact on individuals' health trajectories into adulthood. Using Intervention Mapping (IM), this paper describes the development of the Ntshembo intervention, which is intended to improve the health and well-being of adolescent girls in order to limit the inter-generational transfer of risk of metabolic disease, in particular diabetes risk. METHODS: This paper describes the application of the first four steps of IM. Evidence is provided to support the selection of four key behavioural objectives: viz. to eat a healthy, balanced diet, increase physical activity, reduce sedentary behaviour, and promote reproductive health. Appropriate behaviour change techniques are suggested and a theoretical framework outlining components of relevant behaviour change theories is presented. It is proposed that the Ntshembo intervention will be community-based, including specialist adolescent community health workers who will deliver a complex intervention comprising of individual, peer, family and community mobilisation components. CONCLUSIONS: The Ntshembo intervention is novel, both in SA and globally, as it is: (1) based on strong evidence, extensive formative work and best practice from evaluated interventions; (2) combines theory with evidence to inform intervention components; (3) includes multiple domains of influence (community through to the individual); (4) focuses on an at-risk target group; and (5) embeds within existing and planned health service priorities in SA

A communal catalogue reveals Earth's multiscale microbial diversity

Our growing awareness of the microbial world's importance and diversity contrasts starkly with our limited understanding of its fundamental structure. Despite recent advances in DNA sequencing, a lack of standardized protocols and common analytical frameworks impedes comparisons among studies, hindering the development of global inferences about microbial life on Earth. Here we present a meta-analysis of microbial community samples collected by hundreds of researchers for the Earth Microbiome Project. Coordinated protocols and new analytical methods, particularly the use of exact sequences instead of clustered operational taxonomic units, enable bacterial and archaeal ribosomal RNA gene sequences to be followed across multiple studies and allow us to explore patterns of diversity at an unprecedented scale. The result is both a reference database giving global context to DNA sequence data and a framework for incorporating data from future studies, fostering increasingly complete characterization of Earth's microbial diversity.Peer reviewe

Long-Term Prognosis of Patients With Transient Ischemic Attack or Stroke and Symptomatic Vascular Disease in Multiple Arterial Beds.

BACKGROUND AND PURPOSE Cerebrovascular, coronary, and peripheral vascular disease have common underlying arterial pathology and risk factors, but the clinical significance of multiple-territory disease in patients with transient ischemic attack (TIA)/ischemic stroke is unclear, particularly whether the number of clinically affected territories still predicts long-term outcome on current standard secondary prevention therapies. METHODS In a population-based study of 92 728 individuals in Oxfordshire, United Kingdom (Oxford Vascular Study), we studied patients presenting with TIA/ischemic stroke (2002-2014) in relation to the number of other vascular beds (coronary, peripheral) affected by symptomatic (current or previous) disease. We compared the risk factor profile and long-term prognosis in patients with single- versus multiple-territory disease. RESULTS Among 2554 patients with 10 679 patient-years of follow-up, 1842 (72.1%) had single- (TIA/stroke only), 608 (23.8%) double-, and 104 (4.1%) triple-territory symptomatic vascular disease. The number of affected vascular beds increased with the number of atherosclerotic risk factors (<0.0001). Compared with patients with TIA/stroke only, those with multiple-territory disease had more hypertension (age/sex-adjusted odds ratio [OR], 3.43; 95% confidence interval [CI], 2.76-4.27; <0.0001), diabetes mellitus (OR, 2.89; 95% CI, 2.27-3.66; <0.0001), hypercholesterolemia (OR, 4.67; 95% CI, 3.85-5.66; <0.0001), and current or previous smoking (OR, 1.52; 95% CI, 1.26-1.84; <0.0001). Triple-territory disease was particularly strongly associated with hypercholesterolemia (OR, 6.80; 95% CI, 4.39-10.53; <0.0001). Despite more intensive secondary prevention in patients with multiple-territory disease, the 5-year risk of vascular death increased steeply with the number of territories affected (17.2% versus 30.0% versus 42.9%; <0.0001). Compared with patients with single-territory, patients with multiple-territory disease also had higher postacute long-term risks (90 days to 10 years) of recurrent ischemic stroke (age/sex-adjusted hazard ratio, 1.38; 95% CI, 1.04-1.81; =0.02) and nonstroke acute vascular events (hazard ratio, 3.06; 95% CI, 2.23-4.20; <0.0001). CONCLUSIONS Number of affected vascular beds appeared to be a simple clinical rule in identifying TIA/ischemic stroke patients who are at high long-term risk of nonstroke vascular events and vascular death

"Must you make an app?" A qualitative exploration of socio-technical challenges and opportunities for designing digital maternal and child health solutions in Soweto, South Africa

Participatory and digital health approaches have the potential to create solutions to health issues and related inequalities. A project called Co-Designing Community-based ICTs Interventions for Maternal and Child Health in South Africa (CoMaCH) is exploring such solutions in four different sites across South Africa. The present study captures initial qualitative research that was carried out in one of the urban research sites in Soweto. The aim was twofold: 1) to develop a situation analysis of existing services and the practices and preferences of intended end-users, and 2) to explore barriers and facilitators to utilising digital health for community-based solutions to maternal and child health from multiple perspectives. Semi-structured interviews were conducted with 28 participants, including mothers, other caregivers and community health workers. Four themes were developed using a framework method approach to thematic analysis: coping as a parent is a priority; existing services and initiatives lack consistency, coverage and effective communication; the promise of technology is limited by cost, accessibility and crime; and, information is key but difficult to navigate. Solutions proposed by participants included various digital-based and non-digital channels for accessing reliable health information or education; community engagement events and social support; and, community organisations and initiatives such as saving schemes or community gardens. This initial qualitative study informs later co-design phases, and raises ethical and practical questions about participatory intervention development, including the flexibility of researcher-driven endeavours to accommodate community views, and the limits of digital health solutions vis-à-vis material needs and structural barriers to health and wellbeing

Clinical autonomic nervous system laboratories in Europe: a joint survey of the European Academy of Neurology and the European Federation of Autonomic Societies

© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Background and purpose: Disorders of the autonomic nervous system (ANS) are common conditions, but it is unclear whether access to ANS healthcare provision is homogeneous across European countries. The aim of this study was to identify neurology-driven or interdisciplinary clinical ANS laboratories in Europe, describe their characteristics and explore regional differences. Methods: We contacted the European national ANS and neurological societies, as well as members of our professional network, to identify clinical ANS laboratories in each country and invite them to answer a web-based survey. Results: We identified 84 laboratories in 22 countries and 46 (55%) answered the survey. All laboratories perform cardiovascular autonomic function tests, and 83% also perform sweat tests. Testing for catecholamines and autoantibodies are performed in 63% and 56% of laboratories, and epidermal nerve fiber density analysis in 63%. Each laboratory is staffed by a median of two consultants, one resident, one technician and one nurse. The median (interquartile range [IQR]) number of head-up tilt tests/laboratory/year is 105 (49-251). Reflex syncope and neurogenic orthostatic hypotension are the most frequently diagnosed cardiovascular ANS disorders. Thirty-five centers (76%) have an ANS outpatient clinic, with a median (IQR) of 200 (100-360) outpatient visits/year; 42 centers (91%) also offer inpatient care (median 20 [IQR 4-110] inpatient stays/year). Forty-one laboratories (89%) are involved in research activities. We observed a significant difference in the geographical distribution of ANS services among European regions: 11 out of 12 countries from North/West Europe have at least one ANS laboratory versus 11 out of 21 from South/East/Greater Europe (p = 0.021). Conclusions: This survey highlights disparities in the availability of healthcare services for people with ANS disorders across European countries, stressing the need for improved access to specialized care in South, East and Greater Europe.info:eu-repo/semantics/publishedVersio

The UK10K project identifies rare variants in health and disease.

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P &lt; 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Burden of disease scenarios for 204 countries and territories, 2022–2050: a forecasting analysis for the Global Burden of Disease Study 2021

Background: Future trends in disease burden and drivers of health are of great interest to policy makers and the public at large. This information can be used for policy and long-term health investment, planning, and prioritisation. We have expanded and improved upon previous forecasts produced as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) and provide a reference forecast (the most likely future), and alternative scenarios assessing disease burden trajectories if selected sets of risk factors were eliminated from current levels by 2050. Methods: Using forecasts of major drivers of health such as the Socio-demographic Index (SDI; a composite measure of lag-distributed income per capita, mean years of education, and total fertility under 25 years of age) and the full set of risk factor exposures captured by GBD, we provide cause-specific forecasts of mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) by age and sex from 2022 to 2050 for 204 countries and territories, 21 GBD regions, seven super-regions, and the world. All analyses were done at the cause-specific level so that only risk factors deemed causal by the GBD comparative risk assessment influenced future trajectories of mortality for each disease. Cause-specific mortality was modelled using mixed-effects models with SDI and time as the main covariates, and the combined impact of causal risk factors as an offset in the model. At the all-cause mortality level, we captured unexplained variation by modelling residuals with an autoregressive integrated moving average model with drift attenuation. These all-cause forecasts constrained the cause-specific forecasts at successively deeper levels of the GBD cause hierarchy using cascading mortality models, thus ensuring a robust estimate of cause-specific mortality. For non-fatal measures (eg, low back pain), incidence and prevalence were forecasted from mixed-effects models with SDI as the main covariate, and YLDs were computed from the resulting prevalence forecasts and average disability weights from GBD. Alternative future scenarios were constructed by replacing appropriate reference trajectories for risk factors with hypothetical trajectories of gradual elimination of risk factor exposure from current levels to 2050. The scenarios were constructed from various sets of risk factors: environmental risks (Safer Environment scenario), risks associated with communicable, maternal, neonatal, and nutritional diseases (CMNNs; Improved Childhood Nutrition and Vaccination scenario), risks associated with major non-communicable diseases (NCDs; Improved Behavioural and Metabolic Risks scenario), and the combined effects of these three scenarios. Using the Shared Socioeconomic Pathways climate scenarios SSP2-4.5 as reference and SSP1-1.9 as an optimistic alternative in the Safer Environment scenario, we accounted for climate change impact on health by using the most recent Intergovernmental Panel on Climate Change temperature forecasts and published trajectories of ambient air pollution for the same two scenarios. Life expectancy and healthy life expectancy were computed using standard methods. The forecasting framework includes computing the age-sex-specific future population for each location and separately for each scenario. 95% uncertainty intervals (UIs) for each individual future estimate were derived from the 2·5th and 97·5th percentiles of distributions generated from propagating 500 draws through the multistage computational pipeline. Findings: In the reference scenario forecast, global and super-regional life expectancy increased from 2022 to 2050, but improvement was at a slower pace than in the three decades preceding the COVID-19 pandemic (beginning in 2020). Gains in future life expectancy were forecasted to be greatest in super-regions with comparatively low life expectancies (such as sub-Saharan Africa) compared with super-regions with higher life expectancies (such as the high-income super-region), leading to a trend towards convergence in life expectancy across locations between now and 2050. At the super-region level, forecasted healthy life expectancy patterns were similar to those of life expectancies. Forecasts for the reference scenario found that health will improve in the coming decades, with all-cause age-standardised DALY rates decreasing in every GBD super-region. The total DALY burden measured in counts, however, will increase in every super-region, largely a function of population ageing and growth. We also forecasted that both DALY counts and age-standardised DALY rates will continue to shift from CMNNs to NCDs, with the most pronounced shifts occurring in sub-Saharan Africa (60·1% [95% UI 56·8–63·1] of DALYs were from CMNNs in 2022 compared with 35·8% [31·0–45·0] in 2050) and south Asia (31·7% [29·2–34·1] to 15·5% [13·7–17·5]). This shift is reflected in the leading global causes of DALYs, with the top four causes in 2050 being ischaemic heart disease, stroke, diabetes, and chronic obstructive pulmonary disease, compared with 2022, with ischaemic heart disease, neonatal disorders, stroke, and lower respiratory infections at the top. The global proportion of DALYs due to YLDs likewise increased from 33·8% (27·4–40·3) to 41·1% (33·9–48·1) from 2022 to 2050, demonstrating an important shift in overall disease burden towards morbidity and away from premature death. The largest shift of this kind was forecasted for sub-Saharan Africa, from 20·1% (15·6–25·3) of DALYs due to YLDs in 2022 to 35·6% (26·5–43·0) in 2050. In the assessment of alternative future scenarios, the combined effects of the scenarios (Safer Environment, Improved Childhood Nutrition and Vaccination, and Improved Behavioural and Metabolic Risks scenarios) demonstrated an important decrease in the global burden of DALYs in 2050 of 15·4% (13·5–17·5) compared with the reference scenario, with decreases across super-regions ranging from 10·4% (9·7–11·3) in the high-income super-region to 23·9% (20·7–27·3) in north Africa and the Middle East. The Safer Environment scenario had its largest decrease in sub-Saharan Africa (5·2% [3·5–6·8]), the Improved Behavioural and Metabolic Risks scenario in north Africa and the Middle East (23·2% [20·2–26·5]), and the Improved Nutrition and Vaccination scenario in sub-Saharan Africa (2·0% [–0·6 to 3·6]). Interpretation: Globally, life expectancy and age-standardised disease burden were forecasted to improve between 2022 and 2050, with the majority of the burden continuing to shift from CMNNs to NCDs. That said, continued progress on reducing the CMNN disease burden will be dependent on maintaining investment in and policy emphasis on CMNN disease prevention and treatment. Mostly due to growth and ageing of populations, the number of deaths and DALYs due to all causes combined will generally increase. By constructing alternative future scenarios wherein certain risk exposures are eliminated by 2050, we have shown that opportunities exist to substantially improve health outcomes in the future through concerted efforts to prevent exposure to well established risk factors and to expand access to key health interventions

TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.Peer reviewe