Congenital heart disease (CHD) is the most frequent birth defect, affecting 0.8% of live births. Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo ...mutations. Here we compare the incidence of de novo mutations in 362 severe CHD cases and 264 controls by analysing exome sequencing of parent-offspring trios. CHD cases show a significant excess of protein-altering de novo mutations in genes expressed in the developing heart, with an odds ratio of 7.5 for damaging (premature termination, frameshift, splice site) mutations. Similar odds ratios are seen across the main classes of severe CHD. We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation. There are also two de novo mutations in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer. The combination of both activating (H3K4 methylation) and inactivating (H3K27 methylation) chromatin marks characterizes 'poised' promoters and enhancers, which regulate expression of key developmental genes. These findings implicate de novo point mutations in several hundreds of genes that collectively contribute to approximately 10% of severe CHD.
Local public health agencies play a central role in response to an influenza pandemic, and understanding the willingness of their employees to report to work is therefore a critically relevant ...concern for pandemic influenza planning efforts. Witte's Extended Parallel Process Model (EPPM) has been found useful for understanding adaptive behavior in the face of unknown risk, and thus offers a framework for examining scenario-specific willingness to respond among local public health workers. We thus aim to use the EPPM as a lens for examining the influences of perceived threat and efficacy on local public health workers' response willingness to pandemic influenza.
We administered an online, EPPM-based survey about attitudes/beliefs toward emergency response (Johns Hopkins approximately Public Health Infrastructure Response Survey Tool), to local public health employees in three states between November 2006-December 2007. A total of 1835 responses were collected for an overall response rate of 83%. With some regional variation, overall 16% of the workers in 2006-7 were not willing to "respond to a pandemic flu emergency regardless of its severity". Local health department employees with a perception of high threat and high efficacy--i.e., those fitting a 'concerned and confident' profile in the EPPM analysis--had the highest declared rates of willingness to respond to an influenza pandemic if required by their agency, which was 31.7 times higher than those fitting a 'low threat/low efficacy' EPPM profile.
In the context of pandemic influenza planning, the EPPM provides a useful framework to inform nuanced understanding of baseline levels of--and gaps in--local public health workers' response willingness. Within local health departments, 'concerned and confident' employees are most likely to be willing to respond. This finding may allow public health agencies to design, implement, and evaluate training programs focused on emergency response attitudes in health departments.
Hypertension Canada’s 2020 guidelines for the prevention, diagnosis, risk assessment, and treatment of hypertension in adults and children provide comprehensive, evidence-based guidance for health ...care professionals and patients. Hypertension Canada develops the guidelines using rigourous methodology, carefully mitigating the risk of bias in our process. All draft recommendations undergo critical review by expert methodologists without conflict to ensure quality. Our guideline panel is diverse, including multiple health professional groups (nurses, pharmacy, academics, and physicians), and worked in concert with experts in primary care and implementation to ensure optimal usability. The 2020 guidelines include new guidance on the management of resistant hypertension and the management of hypertension in women planning pregnancy.
Les lignes directrices 2020 d’Hypertension Canada pour la prévention, le diagnostic, l'évaluation des risques et le traitement de l'hypertension chez l’adulte et l’enfant fournissent aux professionnels de la santé et aux patients des conseils complets et fondés sur des données probantes. Hypertension Canada élabore ces lignes directrices en utilisant une méthodologie rigoureuse, en atténuant soigneusement le risque de partialité dans notre processus. Tous les projets de recommandations sont soumis à une évaluation critique par des experts en méthodologie, sans partialité, afin d'en garantir la qualité. Notre panel de lignes directrices est diversifié, comprenant de multiples groupes de professionnels de la santé (soins infirmiers, pharmacie, universitaire et médecins), et a travaillé de concert avec des experts en soins primaires et d’experts en mise en œuvre pour garantir une utilisation optimale. Les lignes directrices 2020 comprennent de nouvelles orientations sur la gestion de l'hypertension résistante et la prise en charge de l'hypertension chez les femmes qui planifient une grossesse.
IMPORTANCE: Young contact sport athletes may be at risk for long-term neuropathologic disorders, including chronic traumatic encephalopathy (CTE). OBJECTIVE: To characterize the neuropathologic and ...clinical symptoms of young brain donors who were contact sport athletes. DESIGN, SETTING, AND PARTICIPANTS: This case series analyzes findings from 152 of 156 brain donors younger than 30 years identified through the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank who donated their brains from February 1, 2008, to September 31, 2022. Neuropathologic evaluations, retrospective telephone clinical assessments, and online questionnaires with informants were performed blinded. Data analysis was conducted between August 2021 and June 2023. EXPOSURES: Repetitive head impacts from contact sports. MAIN OUTCOMES AND MEASURES: Gross and microscopic neuropathologic assessment, including diagnosis of CTE, based on defined diagnostic criteria; and informant-reported athletic history and informant-completed scales that assess cognitive symptoms, mood disturbances, and neurobehavioral dysregulation. RESULTS: Among the 152 deceased contact sports participants (mean SD age, 22.97 4.31 years; 141 92.8% male) included in the study, CTE was diagnosed in 63 (41.4%; median IQR age, 26 24-27 years). Of the 63 brain donors diagnosed with CTE, 60 (95.2%) were diagnosed with mild CTE (stages I or II). Brain donors who had CTE were more likely to be older (mean difference, 3.92 years; 95% CI, 2.74-5.10 years) Of the 63 athletes with CTE, 45 (71.4%) were men who played amateur sports, including American football, ice hockey, soccer, rugby, and wrestling; 1 woman with CTE played collegiate soccer. For those who played football, duration of playing career was significantly longer in those with vs without CTE (mean difference, 2.81 years; 95% CI, 1.15-4.48 years). Athletes with CTE had more ventricular dilatation, cavum septum pellucidum, thalamic notching, and perivascular pigment-laden macrophages in the frontal white matter than those without CTE. Cognitive and neurobehavioral symptoms were frequent among all brain donors. Suicide was the most common cause of death, followed by unintentional overdose; there were no differences in cause of death or clinical symptoms based on CTE status. CONCLUSIONS AND RELEVANCE: This case series found that young brain donors exposed to repetitive head impacts were highly symptomatic regardless of CTE status, and the causes of symptoms in this sample are likely multifactorial. Future studies that include young brain donors unexposed to repetitive head impacts are needed to clarify the association among exposure, white matter and microvascular pathologic findings, CTE, and clinical symptoms.
Any near-term gains in reducing extreme poverty will be maintained only if environmental sustainability is also achieved.
The Millennium Development Goals (MDGs) are designed to inspire efforts to ...improve people's lives by, among other priorities, halving extreme poverty by 2015 (
1
). Analogously, concern about global decline in biodiversity and degradation of ecosystem services (
2
) gave rise in 1992 to the Convention on Biological Diversity (CBD). The CBD target “to achieve by 2010 a significant reduction of the current rate of biodiversity loss” was incorporated into the MDGs in 2002. Our lack of progress toward the 2010 target (
3
,
4
) could undermine achievement of the MDGs and poverty reduction in the long term. With increasing global challenges, such as population growth, climate change, and overconsumption of ecosystem services, we need further integration of the poverty alleviation and biodiversity conservation agendas.
The new global biodiversity framework (GBF) being developed under the Convention on Biological Diversity must drive action to reverse the ongoing decline of the Earth's biodiversity. Explicit, ...measurable goals that specify the outcomes we want to achieve are needed to set the course for this action. However, the current draft goals and targets fail to set out these clear outcomes. We argue that distinct outcome goals for species, ecosystems, and genetic diversity are essential and should specify net outcomes required for each. Net outcome goals such as “no net loss” do, however, have a controversial history, and loose specification can lead to perverse outcomes. We outline seven general principles to underpin net outcome goal setting that minimize risk of such perverse outcomes. Finally, we recommend inclusion of statements of impact in action targets that support biodiversity goals, and we illustrate the importance of this with an example from the draft GBF action targets. These modifications would help reveal the specific contribution each action would make to achieving the outcome goals and provide clarity on whether the successful achievement of action targets would be adequate to achieve the outcome goals and, in turn, the 2050 vision: living in harmony with nature.
Increasing fire severity and warmer, drier postfire conditions are making forests in the western United States (West) vulnerable to ecological transformation. Yet, the relative importance of and ...interactions between these drivers of forest change remain unresolved, particularly over upcoming decades. Here, we assess how the interactive impacts of changing climate and wildfire activity influenced conifer regeneration after 334 wildfires, using a dataset of postfire conifer regeneration from 10,230 field plots. Our findings highlight declining regeneration capacity across the West over the past four decades for the eight dominant conifer species studied. Postfire regeneration is sensitive to high-severity fire, which limits seed availability, and postfire climate, which influences seedling establishment. In the near-term, projected differences in recruitment probability between low- and high-severity fire scenarios were larger than projected climate change impacts for most species, suggesting that reductions in fire severity, and resultant impacts on seed availability, could partially offset expected climate-driven declines in postfire regeneration. Across 40 to 42% of the study area, we project postfire conifer regeneration to be likely following low-severity but not high-severity fire under future climate scenarios (2031 to 2050). However, increasingly warm, dry climate conditions are projected to eventually outweigh the influence of fire severity and seed availability. The percent of the study area considered unlikely to experience conifer regeneration, regardless of fire severity, increased from 5% in 1981 to 2000 to 26 to 31% by mid-century, highlighting a limited time window over which management actions that reduce fire severity may effectively support postfire conifer regeneration.
Evaluate the safety and effectiveness of an ab interno implanted (iStent inject) Trabecular Micro-Bypass System (Glaukos Corporation, San Clemente, CA) in combination with cataract surgery in ...subjects with mild to moderate primary open-angle glaucoma (POAG).
Prospective, randomized, single-masked, concurrently controlled, multicenter clinical trial.
Eyes with mild to moderate POAG and preoperative intraocular pressure (IOP) ≤24 mmHg on 1 to 3 medications, unmedicated diurnal IOP (DIOP) 21 to 36 mmHg, and cataract requiring surgery.
After uncomplicated cataract surgery, eyes were randomized 3:1 intraoperatively to ab interno implantation of iStent inject (Model G2-M-IS; treatment group, n = 387) or no stent implantation (control group, n = 118). Subjects were followed through 2 years postoperatively. Annual washout of ocular hypotensive medication was performed.
Effectiveness end points were ≥20% reduction from baseline in month 24 unmedicated DIOP and change in unmedicated month 24 DIOP from baseline. Safety measures included best spectacle-corrected visual acuity (BSCVA), slit-lamp and fundus examinations, gonioscopy, pachymetry, specular microscopy, visual fields, complications, and adverse events.
The groups were well balanced preoperatively, including medicated IOP (17.5 mmHg in both groups) and unmedicated DIOP (24.8±3.3 mmHg vs. 24.5±3.1 mmHg in the treatment and control groups, respectively, P = 0.33). At 24 months, 75.8% of treatment eyes versus 61.9% of control eyes experienced ≥20% reduction from baseline in unmedicated DIOP (P = 0.005), and mean reduction in unmedicated DIOP from baseline was greater in treatment eyes (7.0±4.0 mmHg) than in control eyes (5.4±3.7 mmHg; P < 0.001). Of the responders, 84% of treatment eyes and 67% of control eyes were not receiving ocular hypotensive medication at 23 months. Furthermore, 63.2% of treatment eyes versus 50.0% of control eyes had month 24 medication-free DIOP ≤18 mmHg (difference 13.2%; 95% confidence interval, 2.9-23.4). The overall safety profile of the treatment group was favorable and similar to that in the control group throughout the 2-year follow-up.
Clinically and statistically greater reductions in IOP without medication were achieved after iStent inject implantation with cataract surgery versus cataract surgery alone, with excellent safety through 2 years.
Importance Parkinsonism is associated with traumatic brain injury and chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impact (RHI) exposure, but ...the neuropathologic substrates that underlie parkinsonism in individuals with CTE are yet to be defined. Objective To evaluate the frequency of parkinsonism in individuals with CTE and the association of RHI and neuropathologic substrates with parkinsonism in these individuals. Design, Setting, and Participants This cross-sectional study included brain donors with neuropathologically diagnosed CTE without other significant neurodegenerative disease and with information on parkinsonism from the Understanding Neurologic Injury and Traumatic Encephalopathy brain bank between July 2015 and May 2022. Exposure Years of contact sports participation as a proxy for RHI. Main Outcomes and Measures The main outcomes were frequency of parkinsonism in individuals with CTE and associations between (1) RHI with substantia nigra (SN) Lewy bodies (LBs) and neurofibrillary tangles (NFTs); (2) LBs, NFTs, and arteriolosclerosis with SN neuronal loss; and (3) SN neuronal loss, LBs, NFTs, and arteriolosclerosis with parkinsonism, tested by age-adjusted logistic regressions. Results Of 481 male brain donors with neuropathologically diagnosed CTE, parkinsonism occurred frequently in individuals with CTE (119 24.7%; 362 75.3% did not have parkinsonism). Participants with parkinsonism had a higher mean (SD) age at death (71.5 13.0 years) than participants without parkinsonism (54.1 19.3 years) ( P < .001) and higher rates of dementia (104 87.4% vs 105 29.0%), visual hallucinations (45 37.8% vs 51 14.1%), and probable rapid eye movement sleep behavior disorder (52 43.7% vs 58 16.0%) ( P < .001 for all). Participants with parkinsonism had a more severe CTE stage (eg, stage IV: 35 29.4% vs 39 10.8%) and nigral pathology than those without parkinsonism (NFTs: 50 of 117 42.7% vs 103 of 344 29.9%; P = .01; neuronal loss: 61 of 117 52.1% vs 59 of 344 17.1%; P < .001; and LBs: 28 of 116 24.1% vs 20 of 342 5.8%; P < .001). Years of contact sports participation were associated with SN NFTs (adjusted odds ratio AOR, 1.04; 95% CI, 1.00-1.07; P = .03) and neuronal loss (AOR, 1.05; 95% CI, 1.01-1.08; P = .02). Nigral neuronal loss (AOR, 2.61; 95% CI, 1.52-4.47; P < .001) and LBs (AOR, 2.29; 95% CI, 1.15-4.57; P = .02) were associated with parkinsonism. However, SN neuronal loss was associated with SN LBs (AOR, 4.48; 95% CI, 2.25-8.92; P < .001), SN NFTs (AOR, 2.51; 95% CI, 1.52-4.15; P < .001), and arteriolosclerosis (AOR, 2.27; 95% CI, 1.33-3.85; P = .002). In American football players, regression analysis demonstrated that SN NFTs and neuronal loss mediated the association between years of play and parkinsonism in the context of CTE (β, 0.012; 95% CI, 0.001-0.038). Conclusions and Relevance In this cross-sectional study of contact sports athletes with CTE, years of contact sports participation were associated with SN tau pathology and neuronal loss, and these pathologies were associated with parkinsonism. Repetitive head impacts may incite neuropathologic processes that lead to symptoms of parkinsonism in individuals with CTE.
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