The emergence and spread of SARS-CoV-2 lineage B.1.1.7, first detected in the United Kingdom, has become a global public health concern because of its increased transmissibility. Over 2,500 COVID-19 ...cases associated with this variant have been detected in the United States (US) since December 2020, but the extent of establishment is relatively unknown. Using travel, genomic, and diagnostic data, we highlight that the primary ports of entry for B.1.1.7 in the US were in New York, California, and Florida. Furthermore, we found evidence for many independent B.1.1.7 establishments starting in early December 2020, followed by interstate spread by the end of the month. Finally, we project that B.1.1.7 will be the dominant lineage in many states by mid- to late March. Thus, genomic surveillance for B.1.1.7 and other variants urgently needs to be enhanced to better inform the public health response.
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•Flight data identify that NY, CA, and FL were high risk for importing B.1.1.7•B.1.1.7 was introduced separately to multiple US states starting in December 2020•Phylogenetic analysis shows evidence for domestic spread between regions in US•Exponential growth of B.1.1.7 projects that it will be the dominant lineage
The SARS-CoV-2 variant B.1.1.7 was introduced to the US in early December 2020 and soon became established within many communities. The primary points of entry into the US are identified as New York, California, and Florida, and exponential growth in these states resulted in spread to neighboring states.
High social value is fundamental to justifying these studies
Development of an effective vaccine is the clearest path to controlling the coronavirus disease 2019 (COVID-19) pandemic. To accelerate ...vaccine development, some researchers are pursuing, and thousands of people have expressed interest in participating in, controlled human infection studies (CHIs) with severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) (
1
,
2
). In CHIs, a small number of participants are deliberately exposed to a pathogen to study infection and gather preliminary efficacy data on experimental vaccines or treatments. We have been developing a comprehensive, state-of-the-art ethical framework for CHIs that emphasizes their social value as fundamental to justifying these studies. The ethics of CHIs in general are underexplored (
3
,
4
), and ethical examinations of SARS-CoV-2 CHIs have largely focused on whether the risks are acceptable and participants could give valid informed consent (
1
). The high social value of such CHIs has generally been assumed. Based on our framework, we agree on the ethical conditions for conducting SARS-CoV-2 CHIs (see the table). We differ on whether the social value of such CHIs is sufficient to justify the risks at present, given uncertainty about both in a rapidly evolving situation; yet we see none of our disagreements as insurmountable. We provide ethical guidance for research sponsors, communities, participants, and the essential independent reviewers considering SARS-CoV-2 CHIs.
Research on astronaut health and model organisms have revealed six features of spaceflight biology that guide our current understanding of fundamental molecular changes that occur during space ...travel. The features include oxidative stress, DNA damage, mitochondrial dysregulation, epigenetic changes (including gene regulation), telomere length alterations, and microbiome shifts. Here we review the known hazards of human spaceflight, how spaceflight affects living systems through these six fundamental features, and the associated health risks of space exploration. We also discuss the essential issues related to the health and safety of astronauts involved in future missions, especially planned long-duration and Martian missions.
An international group of spaceflight researchers detail how spaceflight affects human biology from the molecular to physiological level and identify key challenges for making space exploration compatible with human health.
Telomeres, repetitive terminal features of chromosomes essential for maintaining genome integrity, shorten with cell division, lifestyle factors and stresses, and environmental exposures, and so they ...provide a robust biomarker of health, aging, and age-related diseases. We assessed telomere length dynamics (changes over time) in three unrelated astronauts before, during, and after 1-year or 6-month missions aboard the International Space Station (ISS). Similar to our results for National Aeronautics and Space Administration’s (NASA’s) One-Year Mission twin astronaut (Garrett-Bakelman et al., 2019), significantly longer telomeres were observed during spaceflight for two 6-month mission astronauts. Furthermore, telomere length shortened rapidly after return to Earth for all three crewmembers and, overall, telomere length tended to be shorter after spaceflight than before spaceflight. Consistent with chronic exposure to the space radiation environment, signatures of persistent DNA damage responses were also detected, including mitochondrial and oxidative stress, inflammation, and telomeric and chromosomal aberrations, which together provide potential mechanistic insight into spaceflight-specific telomere elongation.
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•Telomere elongation during spaceflight was observed for two 6-month mission astronauts•Telomere elongation was not dependent on mission duration, sample, or measurement type•Chronic space radiation exposure was associated with persistent DNA damage responses•Telomeres shortened rapidly after return to Earth, and long-term individual differences were observed
Consistent with findings first observed for NASA’s One-Year Mission twin astronaut, Luxton et al. report spaceflight-specific telomere elongation in ISS crewmembers on shorter duration missions. Signatures of persistent DNA damage responses in the space radiation environment are also observed, providing potential mechanistic insight into telomere maintenance pathways during spaceflight.
Future multi-year crewed planetary missions will motivate advances in aerospace nutrition and telehealth. On Earth, the Human Cell Atlas project aims to spatially map all cell types in the human ...body. Here, we propose that a parallel Human Cell Space Atlas could serve as an openly available, global resource for space life science research. As humanity becomes increasingly spacefaring, high-resolution omics on orbit could permit an advent of precision spaceflight healthcare. Alongside the scientific potential, we consider the complex ethical, cultural, and legal challenges intrinsic to the human space omics discipline, and how philosophical frameworks may benefit from international perspectives.High-resolution omics data have facilitated the ongoing Human Cell Atlas project. In this Perspective, Rutter and colleagues propose that a parallel Human Cell Space Atlas initiative would provide a platform for spaceflight-associated research and healthcare.
Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell ...lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19
or CD19
disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial ( NCT03233854 ) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n = 17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n = 21), 62% of patients responded with 29% CR. Relapses were CD19
in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22
disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.
Abstract Common and rare alleles are now being annotated across millions of human genomes, and omics technologies are increasingly being used to develop health and treatment recommendations. However, ...these alleles have not yet been systematically characterized relative to aerospace medicine. Here, we review published alleles naturally found in human cohorts that have a likely protective effect, which is linked to decreased cancer risk and improved bone, muscular, and cardiovascular health. Although some technical and ethical challenges remain, research into these protective mechanisms could translate into improved nutrition, exercise, and health recommendations for crew members during deep space missions.
Toward discovery science of human brain function Biswal, Bharat B; Mennes, Maarten; Zuo, Xi-Nian ...
Proceedings of the National Academy of Sciences - PNAS,
03/2010, Letnik:
107, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common ...paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally related areas. Referred to as functional connectivity, these correlations yield detailed maps of complex neural systems, collectively constituting an individual's "functional connectome." Reproducibility across datasets and individuals suggests the functional connectome has a common architecture, yet each individual's functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain-behavior relationships, will require multicenter collaborative datasets. Here we initiate this endeavor by gathering R-fMRI data from 1,414 volunteers collected independently at 35 international centers. We demonstrate a universal architecture of positive and negative functional connections, as well as consistent loci of inter-individual variability. Age and sex emerged as significant determinants. These results demonstrate that independent R-fMRI datasets can be aggregated and shared. High-throughput R-fMRI can provide quantitative phenotypes for molecular genetic studies and biomarkers of developmental and pathological processes in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/.
Background:
Reconstruction using autograft remains the gold standard surgical treatment for anterior cruciate ligament (ACL) injuries. However, up to 10% to 15% of patients will suffer a graft ...failure in the future. Cadaveric studies have demonstrated that the addition of suture tape augmentation to ACL autograft constructs can increase graft strength and reduce elongation under cyclical loading.
Purpose/Hypothesis:
This study aimed to investigate the clinical outcomes and rerupture rates after ACL reconstruction (ACLR) with suture tape augmentation. We hypothesized that augmentation with suture tape would lead to lower rerupture rates.
Study Design:
Case series; Level of evidence, 4.
Methods:
Patients undergoing primary ACLR using hamstring or patellar tendon autografts augmented with suture tape between 2015 and 2019 were recruited prospectively. Patients with multiligament injuries or a concomitant lateral extra-articular procedure were excluded. Patients were observed in person for 6 months, and patient-reported outcome measures (PROMs) were collected at 2 and 5 years postoperatively. All patients were contacted, and records were reviewed to determine the incidence of graft failure. PROMs collected were as follows: Knee injury and Osteoarthritis Outcome Score (KOOS), Veterans RAND 12-Item Health Survey (VR-12), Tegner and Marx activity scores, and visual analog scale for pain (VAS).
Results:
A total of 97 patients, with a mean age of 34.7 (±13.4) years, were included (76% men; 52 hamstring and 45 patellar tendon grafts). The mean graft diameter was 8 (±1) mm. There was 1 rerupture (1.1%) out of the 90 patients who were contactable at a mean of 5 years postoperatively. Median KOOS scores at 2 years were as follows: Pain, 94; Symptoms, 86; Activities of Daily Living, 99; Sport and Recreation, 82; and Quality of Life, 81. The postoperative scores were significantly higher than the preoperative scores (P < .001). The VR-12 Physical score improved from 43 preoperatively to 55 at 2 years and remained at 56 at 5 years. The VAS pain, Tegner, and Marx scores were 0, 6, and 9, respectively, at 2 years postoperatively. There was no difference in PROMs between graft types.
Conclusion:
This study demonstrates encouraging results of suture tape augmentation of autograft ACLR for both hamstring and patellar tendon grafts. The failure rate of 1.1% at a mean follow-up of 5 years is lower than published rates for reconstruction, and PROMs results are satisfactory. The technique is safe to use and may permit a return to the preinjury sporting level with a lower chance of reinjury.
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