Correction of disease-causing mutations in human embryos holds the potential to reduce the burden of inherited genetic disorders and improve fertility treatments for couples with disease-causing ...mutations in lieu of embryo selection. Here, we evaluate repair outcomes of a Cas9-induced double-strand break (DSB) introduced on the paternal chromosome at the EYS locus, which carries a frameshift mutation causing blindness. We show that the most common repair outcome is microhomology-mediated end joining, which occurs during the first cell cycle in the zygote, leading to embryos with non-mosaic restoration of the reading frame. Notably, about half of the breaks remain unrepaired, resulting in an undetectable paternal allele and, after mitosis, loss of one or both chromosomal arms. Correspondingly, Cas9 off-target cleavage results in chromosomal losses and hemizygous indels because of cleavage of both alleles. These results demonstrate the ability to manipulate chromosome content and reveal significant challenges for mutation correction in human embryos.
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•Cas9-mediated DSB induction and repair by end joining occurs within hours•End joining provides an efficient way to restore reading frames without mosaicism•Unrepaired DSBs persist through mitosis and result in frequent chromosome loss•Off-target effects of Cas9 cause indels as well as chromosome loss
CRISPR-Cas9 gene editing in early human embryos leads to frequent loss of the targeted chromosome, indicating that human germline gene editing would pose a substantial risk for aneuploidy and other adverse genetic consequences
Like other congregate living settings, military basic training has been subject to outbreaks of COVID-19. We sought to identify improved strategies for preventing outbreaks in this setting using an ...agent-based model of a hypothetical cohort of trainees on a U.S. Army post. Our analysis revealed unique aspects of basic training that require customized approaches to outbreak prevention, which draws attention to the possibility that customized approaches may be necessary in other settings, too. In particular, we showed that introductions by trainers and support staff may be a major vulnerability, given that those individuals remain at risk of community exposure throughout the training period. We also found that increased testing of trainees upon arrival could actually increase the risk of outbreaks, given the potential for false-positive test results to lead to susceptible individuals becoming infected in group isolation and seeding outbreaks in training units upon release. Until an effective transmission-blocking vaccine is adopted at high coverage by individuals involved with basic training, need will persist for non-pharmaceutical interventions to prevent outbreaks in military basic training. Ongoing uncertainties about virus variants and breakthrough infections necessitate continued vigilance in this setting, even as vaccination coverage increases.
Epigenetic clocks, developed using DNA methylation data, have been widely used to quantify biological aging in multiple tissues/cells. However, many existing epigenetic clocks are weakly correlated ...with each other, suggesting they may capture different biological processes. We utilize multi‐omics data from diverse human tissue/cells to identify shared features across eleven existing epigenetic clocks. Despite the striking lack of overlap in CpGs, multi‐omics analysis suggested five clocks (Horvath1, Horvath2, Levine, Hannum, and Lin) share transcriptional associations conserved across purified CD14+ monocytes and dorsolateral prefrontal cortex. The pathways enriched in the shared transcriptional association suggested links between epigenetic aging and metabolism, immunity, and autophagy. Results from in vitro experiments showed that two clocks (Levine and Lin) were accelerated in accordance with two hallmarks of aging—cellular senescence and mitochondrial dysfunction. Finally, using multi‐tissue data to deconstruct the epigenetic clock signals, we developed a meta‐clock that demonstrated improved prediction for mortality and robustly related to hallmarks of aging in vitro than single clocks.
We compared 11 existing epigenetic clocks on the basis of their functional characteristics, transcriptional associations, and ability to capture hallmarks of aging. We then decomposed their signals and recombined them into a “meta‐clock.” This meta‐clock showed stronger prediction of all‐cause mortality than any one epigenetic clock and was able to distinguish tumor from normal tissue and capture epigenetic changes in two types of senescence (replicative and oncogene induced).
Using the Murchison Widefield Array (MWA), the low-frequency Square Kilometre Array precursor located in Western Australia, we have completed the GaLactic and Extragalactic All-sky MWA (GLEAM) ...survey, and present the resulting extragalactic catalogue, utilizing the first year of observations. The catalogue covers 24 831 square degrees, over declinations south of +30... and Galactic latitudes outside 10... of the Galactic plane, excluding some areas such as the Magellanic Clouds. It contains 307 455 radio sources with 20 separate flux density measurements across 72-231 MHz, selected from a time- and frequency-integrated image centred at 200 MHz, with a resolution of ...2 arcmin. Over the catalogued region, we estimate that the catalogue is 90 per cent complete at 170 mJy, and 50 per cent complete at 55 mJy, and large areas are complete at even lower flux density levels. Its reliability is 99.97 per cent above the detection threshold of 5..., which itself is typically 50 mJy. These observations constitute the widest fractional bandwidth and largest sky area survey at radio frequencies to date, and calibrate the low-frequency flux density scale of the southern sky to better than 10 per cent. This paper presents details of the flagging, imaging, mosaicking and source extraction/characterization, as well as estimates of the completeness and reliability. All source measurements and images are available online. This is the first in a series of publications describing the GLEAM survey results. (ProQuest: ... denotes formulae/symbols omitted.)
Due to the COVID-19 pandemic, many key neglected tropical disease (NTD) activities have been postponed. This hindrance comes at a time when the NTDs are progressing towards their ambitious goals for ...2030. Mathematical modelling on several NTDs, namely gambiense sleeping sickness, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases (STH), trachoma, and visceral leishmaniasis, shows that the impact of this disruption will vary across the diseases. Programs face a risk of resurgence, which will be fastest in high-transmission areas. Furthermore, of the mass drug administration diseases, schistosomiasis, STH, and trachoma are likely to encounter faster resurgence. The case-finding diseases (gambiense sleeping sickness and visceral leishmaniasis) are likely to have fewer cases being detected but may face an increasing underlying rate of new infections. However, once programs are able to resume, there are ways to mitigate the impact and accelerate progress towards the 2030 goals.
Acute pancreatitis (AP) is the most common gastrointestinal disease resulting in hospitalization in the United States with reports of over 270,000 hospitalizations and costs up to 2.6 billion dollars ...per year. AP is highly variable in disease course and outcome. Established in 1992, the original Atlanta classification system aimed to categorize the wide spectrum of AP by creating consensus-based terminology for AP types, severity, and complications. Though the original system standardized terminology, certain terms and definitions (i.e. pancreatic abscess) were unclear and often misused. The 2012 revised Atlanta classification (RAC) system updated terms, clarified definitions, and incorporated the medical community’s improved understanding of the physiology of AP. The resulting RAC effectively defined the morphologic types of pancreatitis, provided a more standardized system for disease severity grading, further classified the local retroperitoneal complications, and established objective measures to describe this highly variable but common disease. This review provides an update on the recent literature evaluating the RAC, discusses both the strengths and shortcomings of the RAC system (including problematic interobserver agreement), and considers improvements for future classification systems.
We leveraged the ability of EPIFIL transmission models fit to field data to evaluate the use of the WHO Transmission Assessment Survey (TAS) for supporting Lymphatic Filariasis (LF) intervention ...stopping decisions. Our results indicate that understanding the underlying parasite extinction dynamics, particularly the protracted transient dynamics involved in shifts to the extinct state, is crucial for understanding the impacts of using TAS for determining the achievement of LF elimination. These findings warn that employing stopping criteria set for operational purposes, as employed in the TAS strategy, without a full consideration of the dynamics of extinction could seriously undermine the goal of achieving global LF elimination.
Summary Background Lymphatic filariasis is targeted for elimination as a public health problem by 2020. The principal approach used by current programmes is annual mass drug administration with two ...pairs of drugs with a good safety profile. However, one dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to clear the transmissible stage of the helminth completely in treated individuals. The aim of this study was to use modelling to assess the potential value of mass drug administration with the triple-drug regimen for accelerating elimination of lymphatic filariasis in different epidemiological settings. Methods We used three different transmission models to compare the number of rounds of mass drug administration needed to achieve a prevalence of microfilaraemia less than 1% with the triple-drug regimen and with current two-drug regimens. Findings In settings with a low baseline prevalence of lymphatic filariasis (5%), the triple-drug regimen reduced the number of rounds of mass drug administration needed to reach the target prevalence by one or two rounds, compared with the two-drug regimen. For areas with higher baseline prevalence (10–40%), the triple-drug regimen strikingly reduced the number of rounds of mass drug administration needed, by about four or five, but only at moderate-to-high levels of population coverage (>65%) and if systematic non-adherence to mass drug administration was low. Interpretation Simulation modelling suggests that the triple-drug regimen has potential to accelerate the elimination of lymphatic filariasis if high population coverage of mass drug administration can be achieved and if systematic non-adherence with mass drug administration is low. Future work will reassess these estimates in light of more clinical trial data and to understand the effect on an individual country's programme. Funding Bill & Melinda Gates Foundation.
Background Acute kidney injury (AKI) is a serious global public health problem. We aimed to quantify the risk of AKI associated with estimated glomerular filtration rate (eGFR), albuminuria ...(albumin-creatinine ratio ACR), age, sex, and race (African American and white). Study Design Collaborative meta-analysis. Setting & Population 8 general-population cohorts (1,285,049 participants) and 5 chronic kidney disease (CKD) cohorts (79,519 participants). Selection Criteria for Studies Available eGFR, ACR, and 50 or more AKI events. Predictors Age, sex, race, eGFR, urine ACR, and interactions. Outcome Hospitalized with or for AKI, using Cox proportional hazards models to estimate HRs of AKI and random-effects meta-analysis to pool results. Results 16,480 (1.3%) general-population cohort participants had AKI over a mean follow-up of 4 years; 2,087 (2.6%) CKD participants had AKI over a mean follow-up of 1 year. Lower eGFR and higher ACR were strongly associated with AKI. Compared with eGFR of 80 mL/min/1.73 m2 , the adjusted HR of AKI at eGFR of 45 mL/min/1.73 m2 was 3.35 (95% CI, 2.75-4.07). Compared with ACR of 5 mg/g, the risk of AKI at ACR of 300 mg/g was 2.73 (95% CI, 2.18-3.43). Older age was associated with higher risk of AKI, but this effect was attenuated with lower eGFR or higher ACR. Male sex was associated with higher risk of AKI, with a slight attenuation in lower eGFR but not in higher ACR. African Americans had higher AKI risk at higher levels of eGFR and most levels of ACR. Limitations Only 2 general-population cohorts could contribute to analyses by race; AKI identified by diagnostic code. Conclusions Reduced eGFR and increased ACR are consistent strong risk factors for AKI, whereas associations of AKI with age, sex, and race may be weaker in more advanced stages of CKD.
Abstract Background High rates of posttraumatic stress disorder (PTSD) and depressive symptoms have been observed in earthquake survivors from less developed areas of the world. This study, conducted ...three years after the 2005 Pakistan earthquake, aimed to identify potentially protective psychosocial factors associated with lower PTSD and depressive symptom levels. Methods Adult earthquake survivors ( N =200) were recruited from affected areas in Northwestern Pakistan and completed self-report questionnaires measuring PTSD and depressive symptoms, positive and negative affect, and four psychosocial variables (purpose in life, positive and negative religious coping, and social support). Results Sixty five percent of participants met criteria for probable PTSD. Purpose in life was associated with lower symptom levels and higher positive emotions. A form of negative religious coping (feeling punished by God for one’s sins or lack of spirituality) was associated with higher symptom levels and negative emotions. Higher perceived social support was associated with higher positive emotions. Other significant relationships were also identified. Limitations Limitations include the recruitment of a sample of convenience, a modest sample size, and the cross-sectional nature of the study. Conclusions Findings suggest that some psychosocial factors may be protective across cultures, and that the use of negative religious coping is associated with poorer mental health outcomes in earthquake survivors. This study can inform preventive and treatment interventions for earthquake survivors in Pakistan and other less industrialized countries as they develop mental health care services.
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