Since 2005, advances in next‐generation sequencing technologies have revolutionized biological science. The analysis of environmental DNA through the use of specific gene markers such as ...species‐specific DNA barcodes has been a key application of next‐generation sequencing technologies in ecological and environmental research. Access to parallel, massive amounts of sequencing data, as well as subsequent improvements in read length and throughput of different sequencing platforms, is leading to a better representation of sample diversity at a reasonable cost. New technologies are being developed rapidly and have the potential to dramatically accelerate ecological and environmental research. The fast pace of development and improvements in next‐generation sequencing technologies can reflect on broader and more robust applications in environmental DNA research. Here, we review the advantages and limitations of current next‐generation sequencing technologies in regard to their application for environmental DNA analysis.
To understand why the virtual design strategies that organizations create to foster innovation may in fact hinder it, we unpack four characteristics often associated with the term "virtuality" ...(geographic dispersion, electronic dependence, structural dynamism, and national diversity) and argue that each hinders innovation through unique mechanisms, many of which can be overcome by creating a psychologically safe communication climate. We first tested the plausibility of our arguments using indepth qualitative analysis of interviews with 177 members of 14 teams in a variety of industries. A second study constituted a more formal test of hypotheses using survey data collected from 266 members of 56 aerospace design teams. Results show that the four characteristics are not highly intercorrelated, that they have independent and differential effects on innovation, and that a psychologically safe communication climate helps mitigate the challenges they pose. We discuss the implications of these findings for theory and research.
Medical assistance in dying (MAiD) was legalized across Canada in June 2016. Some have expressed concern that patient requests for MAiD might be driven by poor access to palliative care and that ...social and economic vulnerability of patients may influence access to or receipt of MAiD. To examine these concerns, we describe Ontario's early experience with MAiD and compare MAiD decedents with the general population of decedents in Ontario.
We conducted a retrospective cohort study comparing all MAiD-related deaths with all deaths in Ontario, Canada, between June 7, 2016, and Oct. 31, 2018. Clinical and demographic characteristics were collected for all MAiD decedents and compared with those of all Ontario decedents when possible. We used logistic regression analyses to describe the association of demographic and clinical factors with receipt of MAiD.
A total of 2241 patients (50.2% women) were included in the MAiD cohort, and 186 814 in the general Ontario decedent cohort. Recipients of MAiD reported both physical (99.5%) and psychologic suffering (96.4%) before the procedure. In 74.4% of cases, palliative care providers were involved in the patient's care at the time of the MAiD request. The statutory 10-day reflection period was shortened for 26.6% of people. Compared with all Ontario decedents, MAiD recipients were younger (mean 74.4 v. 77.0 yr, standardized difference 0.18);, more likely to be from a higher income quintile (24.9% v. 15.6%, standardized difference across quintiles 0.31); less likely to reside in an institution (6.3% v. 28.0%, standardized difference 0.6); more likely to be married (48.5% v. 40.6%) and less likely to be widowed (25.7% v. 35.8%, standardized difference 0.34); and more likely to have a cancer diagnosis (64.4% v. 27.6%, standardized difference 0.88 for diagnoses comparisons).
Recipients of MAiD were younger, had higher income, were substantially less likely to reside in an institution and were more likely to be married than decedents from the general population, suggesting that MAiD is unlikely to be driven by social or economic vulnerability. Given the high prevalence of physical and psychologic suffering, despite involvement of palliative care providers in caring for patients who request MAiD, future studies should aim to improve our understanding and treatment of the specific types of suffering that lead to a MAiD request.
Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one
(cystic fibrosis transmembrane conductance ...regulator) allele, but it has not been evaluated in children <12 years of age.
To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with
-minimal function or
-
genotypes.
In this 24-week open-label phase 3 study, children (
= 66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 h) whereas children weighing ⩾30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h).
The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most commonly reported adverse events included cough, headache, and pyrexia; in most of the children who had adverse events, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the percentage of predicted FEV
(10.2 percentage points; 95% confidence interval CI, 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index
(-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age
-score increased over the 24-week treatment period when compared with the pretreatment baseline.
Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one
allele, supporting its use in this patient population. Clinical trial registered with www.clinicaltrials.gov (NCT03691779).
The long-term ecological success of compensatory freshwater wetland projects has come into question based on follow-up monitoring studies over the past few decades. Given that wetland restoration may ...require many years to decades to converge to desired outcomes, long-term monitoring of successional patterns may increase our ability to fully evaluate success of wetland mitigation projects or guide adaptive management when needed. In Portsmouth, New Hampshire a 4 ha wetland was constructed in an abandoned gravel quarry as off-site compensatory mitigation for impacts to a scrub-shrub swamp associated with property expansion. Building upon prior evaluations from 1992 and 2002, we conducted a floral survey in 2020 to compare results with prior surveys to document vegetation successional trends over time. In addition, we monitored the avian community throughout the growing season as a measure of habitat quality. The plant community mirrored documented successional trends of freshwater wetland restoration projects as native hydrophytes dominated species composition. Plant species composition stabilized as the rate of turnover, the measurement of succession, declined by nearly half after 17 years. Researchers should consider long-term monitoring of specific sites to better understand successional patterns of created wetlands as we documented long time frames required for the development of scrub-shrub swamps, red maple swamps, and sedge meadows. High species richness was attributed to beaver activity, topographic heterogeneity from Carex stricta tussocks, and the seed bank from the application of peat from the original wetland. Habitat heterogeneity of open water, herbaceous cover, and woody vegetation supports a diverse avian community including 11 wetland dependent species. Although the mitigation project has not created the full area of lost scrub-shrub swamp after 35 years, it has developed a structurally complex habitat and diverse avian community that effectively provides the functions and values of the impacted system.
AMPA receptors (AMPARs) are tetrameric ion channels assembled from GluA1-GluA4 subunits that mediate the majority of fast excitatory synaptic transmission in the brain. In the hippocampus, most ...synaptic AMPARs are composed of GluA1/2 or GluA2/3 with the GluA2 subunit preventing Ca(2+) influx. However, a small number of Ca(2+)-permeable GluA1 homomeric receptors reside in extrasynaptic locations where they can be rapidly recruited to synapses during synaptic plasticity. Phosphorylation of GluA1 S845 by the cAMP-dependent protein kinase (PKA) primes extrasynaptic receptors for synaptic insertion in response to NMDA receptor Ca(2+) signaling during long-term potentiation (LTP), while phosphatases dephosphorylate S845 and remove synaptic and extrasynaptic GluA1 during long-term depression (LTD). PKA and the Ca(2+)-activated phosphatase calcineurin (CaN) are targeted to GluA1 through binding to A-kinase anchoring protein 150 (AKAP150) in a complex with PSD-95, but we do not understand how the opposing activities of these enzymes are balanced to control plasticity. Here, we generated AKAP150ΔPIX knock-in mice to selectively disrupt CaN anchoring in vivo. We found that AKAP150ΔPIX mice lack LTD but express enhanced LTP at CA1 synapses. Accordingly, basal GluA1 S845 phosphorylation is elevated in AKAP150ΔPIX hippocampus, and LTD-induced dephosphorylation and removal of GluA1, AKAP150, and PSD-95 from synapses are impaired. In addition, basal synaptic activity of GluA2-lacking AMPARs is increased in AKAP150ΔPIX mice and pharmacologic antagonism of these receptors restores normal LTD and inhibits the enhanced LTP. Thus, AKAP150-anchored CaN opposes PKA phosphorylation of GluA1 to restrict synaptic incorporation of Ca(2+)-permeable AMPARs both basally and during LTP and LTD.
Objective Elective induction of labor has been discouraged over concerns regarding increased complications. We evaluated the mode of delivery and maternal and neonatal morbidities in low-risk ...patients whose labor was electively induced or expectantly managed at term. Study Design This was a retrospective cross-sectional study from 12 US institutions (19 hospitals), 2002 through 2008 (Safe Labor Consortium). Healthy women with viable, vertex singleton pregnancies at 37-41 weeks of gestation were included. Women electively induced in each week were compared with women managed expectantly. The primary outcome was mode of delivery. Results Of 131,243 low-risk deliveries, 13,242 (10.1%) were electively induced. The risk of cesarean delivery was lower at each week of gestation with elective induction vs expectant management regardless of parity and modified Bishop score (for unfavorable nulliparous patients at: 37 weeks = 18.6% vs 34.2%, adjusted odds ratio, 0.40; 95% confidence interval, 0.18–0.88; 38 weeks = 28.4% vs 35.4%, 0.65 0.49–0.85; 39 weeks = 23.6% vs 38.5%, 0.47 0.38–0.57; 40 weeks = 32.3% vs 42.3%, 0.70 0.59–0.81). Maternal infections were significantly lower with elective inductions. Major, minor, and respiratory neonatal morbidity composites were lower with elective inductions at ≥38 weeks (for nulliparous patients at: 38 weeks = adjusted odds ratio, 0.43; 95% confidence interval, 0.26–0.72; 39 weeks = 0.75 0.61–0.92; 40 weeks = 0.65 0.54–0.80). Conclusion Elective induction of labor at term is associated with decreased risks of cesarean delivery and other maternal and neonatal morbidities compared with expectant management regardless of parity or cervical status on admission.
BACKGROUNDLong-term prognosis of WHO grade II low-grade gliomas (LGGs) is poor, with a high risk of recurrence and malignant transformation into high-grade gliomas. Given the relatively intact immune ...system of patients with LGGs and the slow tumor growth rate, vaccines are an attractive treatment strategy.METHODSWe conducted a pilot study to evaluate the safety and immunological effects of vaccination with GBM6-AD, lysate of an allogeneic glioblastoma stem cell line, with poly-ICLC in patients with LGGs. Patients were randomized to receive the vaccines before surgery (arm 1) or not (arm 2) and all patients received adjuvant vaccines. Coprimary outcomes were to evaluate safety and immune response in the tumor.RESULTSA total of 17 eligible patients were enrolled - 9 in arm 1 and 8 in arm 2. This regimen was well tolerated with no regimen-limiting toxicity. Neoadjuvant vaccination induced upregulation of type-1 cytokines and chemokines and increased activated CD8+ T cells in peripheral blood. Single-cell RNA/T cell receptor sequencing detected CD8+ T cell clones that expanded with effector phenotype and migrated into the tumor microenvironment (TME) in response to neoadjuvant vaccination. Mass cytometric analyses detected increased tissue resident-like CD8+ T cells with effector memory phenotype in the TME after the neoadjuvant vaccination.CONCLUSIONThe regimen induced effector CD8+ T cell response in peripheral blood and enabled vaccine-reactive CD8+ T cells to migrate into the TME. Further refinements of the regimen may have to be integrated into future strategies.TRIAL REGISTRATIONClinicalTrials.gov NCT02549833.FUNDINGNIH (1R35NS105068, 1R21CA233856), Dabbiere Foundation, Parker Institute for Cancer Immunotherapy, and Daiichi Sankyo Foundation of Life Science.
This clinical practice guideline (CPG) provides clinicians with recommendations regarding chemotherapy emetogenicity classification in pediatric oncology patients. This information is critically ...important for the appropriate selection of antiemetic prophylaxis. Recommendations are based on a systematic review limited to pediatric patients and a framework for classification when antiemetic prophylaxis is provided. Findings of 87 publications informed the emetogenicity classification of 49 single‐agent and 13 combination‐agent regimens. Information required for the classification of many chemotherapies commonly administered to pediatric patients is lacking. In the absence of pediatric data, consultation of methodologically sound CPGs aimed at adult oncology patients may be appropriate.
The emergence of methicillin-resistant Staphylococcus aureus (MRSA) poses an important threat in human and animal health. In this study, we ask whether resistance and virulence genes in S. aureus are ...homogeneously distributed or constrained by different animal hosts. We carried out whole genome sequencing of 114 S. aureus isolates from ten species of animals sampled from four New England states (USA) in 2017-2019. The majority of the isolates came from cats, cows and dogs. The maximum likelihood phylogenetic tree based on the alignment of 89,143 single nucleotide polymorphisms of 1173 core genes reveal 31 sequence types (STs). The most common STs were ST5, ST8, ST30, ST133 and ST2187. Every genome carried at least eight acquired resistance genes. Genes related to resistance found in all genomes included norA (fluoroquinolone), arlRS (fluoroquinolone), lmrS (multidrug), tet(38) (tetracycline) and mepAR (multidrug and tigecycline resistance). The most common superantigen genes were tsst-1, sea and sec. Acquired antibiotic resistance (n = 10) and superantigen (n = 9) genes of S. aureus were widely shared between S. aureus lineages and between strains from different animal hosts. These analyses provide insights for considering bacterial gene sharing when developing strategies to combat the emergence of high-risk clones in animals.
PDF
