We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.
To save content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about saving content to .
To save content items to your Kindle, first ensure no-reply@cambridge.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about saving to your Kindle.
Note you can select to save to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
The global population and status of Snowy Owls Bubo scandiacus are particularly challenging to assess because individuals are irruptive and nomadic, and the breeding range is restricted to the remote circumpolar Arctic tundra. The International Union for Conservation of Nature (IUCN) uplisted the Snowy Owl to “Vulnerable” in 2017 because the suggested population estimates appeared considerably lower than historical estimates, and it recommended actions to clarify the population size, structure, and trends. Here we present a broad review and status assessment, an effort led by the International Snowy Owl Working Group (ISOWG) and researchers from around the world, to estimate population trends and the current global status of the Snowy Owl. We use long-term breeding data, genetic studies, satellite-GPS tracking, and survival estimates to assess current population trends at several monitoring sites in the Arctic and we review the ecology and threats throughout the Snowy Owl range. An assessment of the available data suggests that current estimates of a worldwide population of 14,000–28,000 breeding adults are plausible. Our assessment of population trends at five long-term monitoring sites suggests that breeding populations of Snowy Owls in the Arctic have decreased by more than 30% over the past three generations and the species should continue to be categorised as Vulnerable under the IUCN Red List Criterion A2. We offer research recommendations to improve our understanding of Snowy Owl biology and future population assessments in a changing world.
Reducing rehospitalization has been a primary focus of hospitals and payors. Recurrence of Clostridioides difficile infection (CDI) is common and often results in rehospitalization. Factors that influence rehospitalization for CDI are not well understood.
Objective:
To determine the risk factors that influence rehospitalization caused by CDI.
Design:
A retrospective cohort study from January 1, 2018, to December 31, 2018, of patients aged ≥18 who tested positive for C. difficile while hospitalized.
Setting:
Academic hospital.
Methods:
The risk of rehospitalization was assessed across exposures during and after the index hospitalization using a Cox proportional hazards model. The primary outcome of this study was 60-day CDI-related rehospitalization.
Results:
There were 559 hospitalized patients with a positive CD test during the study period, and 408 patients were included for analysis. All-cause rehospitalization was 46.1% within 60 days of the index hospital discharge. Within 60 days of discharge, 68 patients developed CDI, of which 72.5% (49 of 68) were rehospitalized specifically for the management of CDI. The risk of rehospitalization in patients with CDI was higher among patients who were exposed to systemic antibiotics ([adjusted hazard ratio] aHR: 2.78; 95% CI, 1.36–5.64) and lower among patients who had post-discharge follow-up addressing C. difficile (aHR: 0.53; 95% CI, 0.28–0.98).
Conclusions:
Exposure to systemic antibiotics increased the risk of rehospitalization due to CDI, while post-discharge follow-up decreased the risk of rehospitalization due to CDI. Comprehensive transitions of care for hospitalized patients with C. difficile may reduce the risk of CDI-related rehospitalization.
Social determinants of health (SDoH), such as food and financial insecurity and food assistance, are potentially modifiable factors that may influence breastfeeding initiation and duration. Knowledge gaps exist regarding the relationship between these SDoH and infant feeding practices. We explored the relationships of food and financial insecurity and food assistance with the continuation of breastfeeding at four months postpartum among mothers and whether race and ethnicity modified these associations.
Design:
Mothers retrospectively reported food and financial insecurity and receipt of food assistance (e.g. Women, Infants and Children and Supplemental Nutrition Assistance Program) during pregnancy with their first child and infant feeding practices (exclusive/mostly breastfeeding v. exclusive/mostly formula feeding) following the birth of their first child. Sociodemographic-adjusted modified Poisson regressions estimated prevalence ratios and 95 % CI.
Setting:
Minneapolis-St. Paul, Minnesota.
Participants:
Mothers who participated in the Life-course Experiences And Pregnancy study (LEAP) (n 486).
Results:
Ten percent of mothers reported food insecurity, 43 % financial insecurity and 22 % food assistance during their pregnancies. At four months postpartum, 63 % exclusively/mostly breastfed and 37 % exclusively/mostly formula-fed. We found a lower adjusted prevalence of breastfeeding at four months postpartum for mothers who reported experiencing food insecurity (0·65; 0·43–0·98) and receiving food assistance (0·66; 0·94–0·88) relative to those who did not. For financial insecurity (aPR 0·92; 0·78, 1·08), adjusted estimates showed little evidence of an association.
Conclusions:
We found a lower level of breastfeeding among mothers experiencing food insecurity and using food assistance. Resources to support longer breastfeeding duration for mothers are needed. Moreover, facilitators, barriers and mechanisms of breastfeeding initiation and duration must be identified.
OBJECTIVES/GOALS: Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). In this study, we perform an epigenetic-focused functional genomics screen in GBM organoids and identify WDR5 as an essential epigenetic regulator in the SOX2-enriched, therapy resistant cancer stem cell niche. METHODS/STUDY POPULATION: Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We developed a spatially resolved loss-of-function screen in GBM patient-derived organoids to identify essential epigenetic regulators in the SOX2-enriched, therapy resistant niche. Our niche-specific screens identified WDR5, an H3K4 histone methyltransferase responsible for activating specific gene expression, as indispensable for GBM CSC growth and survival. RESULTS/ANTICIPATED RESULTS: In GBM CSC models, WDR5 inhibitors blocked WRAD complex assembly and reduced H3K4 trimethylation and expression of genes involved in CSC-relevant oncogenic pathways. H3K4me3 peaks lost with WDR5 inhibitor treatment occurred disproportionally on POU transcription factor motifs, required for stem cell maintenance and including the POU5F1(OCT4)::SOX2 motif. We incorporated a SOX2/OCT4 motif driven GFP reporter system into our CSC cell models and found that WDR5 inhibitor treatment resulted in dose-dependent silencing of stem cell reporter activity. Further, WDR5 inhibitor treatment altered the stem cell state, disrupting CSC in vitro growth and self-renewal as well as in vivo tumor growth. DISCUSSION/SIGNIFICANCE: Our results unveiled the role of WDR5 in maintaining the CSC state in GBM and provide a rationale for therapeutic development of WDR5 inhibitors for GBM and other advanced cancers. This conceptual and experimental framework can be applied to many cancers, and can unmask unique microenvironmental biology and rationally designed combination therapies.
The Astrobiology Graduate Conference (AbGradCon) is an annual conference both organized for and by early-career researchers, postdoctoral fellows, and students as a way to train the next generation of astrobiologists and develop a robust network of cohorts moving forward. AbGradCon 2021 was held virtually on 14–17 September 2021, hosted by the Earth-Life Science Institute (ELSI) of Tokyo Institute of Technology after postponement of the in-person event in 2020 due to the COVID-19 pandemic. The meeting consisted of presentations by 120 participants from a variety of fields, two keynote speakers, and other career-building events and workshops. Here, we report on the organizational and executional aspects of AbGradCon 2021, including the meeting participant demographics, various digital aspects introduced specifically for a virtual edition of the meeting, and the abstract submission and evaluation process. The abstract evaluation process of AbGradCon 2021 is unique in that all evaluations are done by the peers of the applicants, and as astrobiology is inherently a broad discipline, the abstract evaluation process revealed a number of trends related to multidisciplinarity of the astrobiology field. We believe that meetings like AbGradCon can provide a unique opportunity for students and early career researchers in astrobiology to experience community building, inter- and multidisciplinary collaboration, and career training and would be a welcome sight in other fields as well. We hope that this report provides inspiration and a basic roadmap for organizing future conferences in any field with similar goals.
Background: Children with pathogenic variations in SCN8A can present with early infantile epileptic encephalopathy-13, benign familial infantile seizures-5 or intellectual disability alone without epilepsy. In this case series, we discuss six children with variants in SCN8A managed at BC Children’s Hospital. Methods: We describe clinical and genetic results on six individuals with SCN8A variants identified via clinical or research next-generation sequencing. Functional consequences of two SCN8A variants were assessed using electrophysiological analyses in transfected cells. Results: Clinical findings ranged from normal development with well-controlled epilepsy to significant developmental delay with treatment-resistant epilepsy. Phenotypes and genotypes in our cohort are described in the table below. Functional analysis supported gain-of-function in P2 and loss-of-function in P4. Conclusions: Our cohort expands the clinical and genotypic spectrum of SCN8A-related disorders. We establish functional evidence for two missense variants in SCN8A, including LoF variant in a patient with intellectual disability, and autism spectrum disorder without seizures.
Table for P.120
Patients
Age/Sex
Development
Age ofseizure onset
Epilepsy type
Current antiseizure medication
Seizure frequency
Gene variant/Function
Inheritance
P1
14y/F
Profound GDD
5m
Infantile spasms, LGS, hyperkinetic movements
Clobazam
Daily
c.1238C>A (p.Ala413Asp)
De novo
P2
6y/F
Normal
3-7m
Focal epilepsy
Carbamazepine
Seizure free
c.5630A>G (p.Asn1877Ser)/GoF
Paternal
P3
4y/F
Normal
12m
Focal epilepsy
Clobazam, topiramate
Seizure free
c.4447G>A (p.Glu1483Lys)
De novo
P4
6y/F
GDD, autism
3y - EEG abnormality only
-
Sodium valproate (discontinued)
No clinical seizure
c.971G>A (p.Cys324Tyr)/LoF, VUS in KCNQ3
De novo
P5
7y/M
GDD
5m
Generalized seizures
Ethosuximide, acetazolamide
Daily
c.773C>T (p.Thr258Ile)
De novo
P6
19y/F
Normal
10y
Focal epilepsy
Carbamazepine
Seizure free
c.986A>G (p.Asp329Gly)
De novo
Abbreviations: *Father with similar history, y Years, m Months, GDD Global developmental delay, LGS Lennox-Gastaut syndrome, VUS Variant of unknown significance, LoF Loss-of-function, GoF Gain-of-function, EEG Electroencephalogram, F - Female, M - Male, CBD - Cannabidiol
Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders.
Methods
We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific.
Results
We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001).
Conclusions
Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD.
During the last fifteen years there has been a paradigm shift in the continuum modelling of granular materials; most notably with the development of rheological models, such as the $\mu (I)$-rheology (where $\mu$ is the friction and I is the inertial number), but also with significant advances in theories for particle segregation. This paper details theoretical and numerical frameworks (based on OpenFOAM) which unify these currently disconnected endeavours. Coupling the segregation with the flow, and vice versa, is not only vital for a complete theory of granular materials, but is also beneficial for developing numerical methods to handle evolving free surfaces. This general approach is based on the partially regularized incompressible $\mu (I)$-rheology, which is coupled to the gravity-driven segregation theory of Gray & Ancey (J. Fluid Mech., vol. 678, 2011, pp. 353–588). These advection–diffusion–segregation equations describe the evolving concentrations of the constituents, which then couple back to the variable viscosity in the incompressible Navier–Stokes equations. A novel feature of this approach is that any number of differently sized phases may be included, which may have disparate frictional properties. Further inclusion of an excess air phase, which segregates away from the granular material, then allows the complex evolution of the free surface to be captured simultaneously. Three primary coupling mechanisms are identified: (i) advection of the particle concentrations by the bulk velocity, (ii) feedback of the particle-size and/or frictional properties on the bulk flow field and (iii) influence of the shear rate, pressure, gravity, particle size and particle-size ratio on the locally evolving segregation and diffusion rates. The numerical method is extensively tested in one-way coupled computations, before the fully coupled model is compared with the discrete element method simulations of Tripathi & Khakhar (Phys. Fluids, vol. 23, 2011, 113302) and used to compute the petal-like segregation pattern that spontaneously develops in a square rotating drum.
Cognitive behavior therapy (CBT) is effective for most patients with a social anxiety disorder (SAD) but a substantial proportion fails to remit. Experimental and clinical research suggests that enhancing CBT using imagery-based techniques could improve outcomes. It was hypothesized that imagery-enhanced CBT (IE-CBT) would be superior to verbally-based CBT (VB-CBT) on pre-registered outcomes.
Methods
A randomized controlled trial of IE-CBT v. VB-CBT for social anxiety was completed in a community mental health clinic setting. Participants were randomized to IE (n = 53) or VB (n = 54) CBT, with 1-month (primary end point) and 6-month follow-up assessments. Participants completed 12, 2-hour, weekly sessions of IE-CBT or VB-CBT plus 1-month follow-up.
Results
Intention to treat analyses showed very large within-treatment effect sizes on the social interaction anxiety at all time points (ds = 2.09–2.62), with no between-treatment differences on this outcome or clinician-rated severity [1-month OR = 1.45 (0.45, 4.62), p = 0.53; 6-month OR = 1.31 (0.42, 4.08), p = 0.65], SAD remission (1-month: IE = 61.04%, VB = 55.09%, p = 0.59); 6-month: IE = 58.73%, VB = 61.89%, p = 0.77), or secondary outcomes. Three adverse events were noted (substance abuse, n = 1 in IE-CBT; temporary increase in suicide risk, n = 1 in each condition, with one being withdrawn at 1-month follow-up).
Conclusions
Group IE-CBT and VB-CBT were safe and there were no significant differences in outcomes. Both treatments were associated with very large within-group effect sizes and the majority of patients remitted following treatment.
Most clinical microbiology laboratories have replaced toxin immunoassay (EIA) alone with multistep testing (MST) protocols or nucleic acid amplification testing (NAAT) alone for the detection of C. difficile.
Objective:
Study the effect of changing testing strategies on C. difficile detection and strain diversity.
Design:
Retrospective study.
Setting:
A Veterans’ Affairs hospital.
Methods:
Initially, toxin EIA testing was replaced by an MST approach utilizing a glutamate dehydrogenase (GDH) and toxin EIA followed by tcdB NAAT for discordant results. After 18 months, MST was replaced by a NAAT-only strategy. Available patient stool specimens were cultured for C. difficile. Restriction endonuclease analysis (REA) strain typing and quantitative in vitro toxin testing were performed on recovered isolates.
Results:
Before MST (toxin EIA), 79 of 708 specimens (11%) were positive, and after MST (MST-A), 121 of 517 specimens (23%) were positive (P < .0001). Prior to NAAT-only testing (MST-B), 80 of the 490 specimens (16%) were positive by MST, and after NAAT-only testing was implemented, 67 of the 368 specimens (18%) were positive (P = nonsignificant). After replacing toxin EIA testing, REA strain group diversity increased (8, 13, 13, and 10 REA groups in the toxin EIA, MST-A, MST-B, and NAAT-only periods, respectively) and in vitro toxin concentration decreased. The average log10 toxin concentration of the isolates were 2.08, 1.88, 1.20 and 1.55 ng/mL for the same periods, respectively.
Conclusions:
MST and NAAT had similar detection rates for C. difficile. Compared to toxin testing alone, they detected increased diversity of C. difficile strains, many of which were low toxin producing.
In a European, phase 3 study (SPD489-325), lisdexamfetamine dimesylate (LDX) and osmotic-release oral system methylphenidate (OROS-MPH) were more effective than placebo in improving core symptoms in children and adolescents with attention-deficit/hyperactivity disorder (ADHD).
Objectives and aims
To compare post hoc the efficacy of LDX and OROS-MPH in study SPD489-325.
Methods
This 7-week, randomized, double-blind, parallel-group, dose-optimized, placebo-controlled trial enrolled patients aged 6-17 years with ADHD of at least moderate severity. Patients were randomized (1:1:1) to receive a once-daily dose of LDX (30, 50, 70 mg/day), OROS-MPH (18, 36, 54 mg/day) or placebo. Efficacy was assessed using the ADHD Rating Scale version IV (ADHD-RS-IV) and the Clinical Global Impression-Improvement (CGI-I) scale. Endpoint was defined as the last ontherapy treatment visit with a valid assessment.
Results
The full analysis set comprised 317 patients (LDX, n=104; placebo, n=106; OROS-MPH, n=107). The difference between LDX and OROS-MPH in least squares mean change (95% confidence interval [CI]) in ADHD-RS-IV total score from baseline to endpoint was statistically significant in favour of LDX (-5.6 [-8.4, -2.7]; p < 0.001; effect size, 0.541). The difference (LDX minus OROS-MPH) in the percentage of patients (95% CI) with an improved CGI-I score at endpoint was also statistically significant in favour of LDX (17.4 [5.0, 29.8]; p < 0.05).
Conclusions
This post hoc analysis indicated that LDX is significantly more effective than OROS-MPH in improving core symptoms and global functioning in children and adolescents with ADHD.
In a European, phase 3 study (SPD489-325), lisdexamfetamine dimesylate (LDX) was more effective than placebo in improving symptoms and global functioning in children and adolescents with attention-deficit/hyperactivity disorder (ADHD).
Objectives and aims
To evaluate the impact of age, sex and baseline disease severity on efficacy outcomes in SPD489- 325.
Methods
This 7-week, double-blind, parallel-group, dose-optimized study enrolled patients aged 6-17 years with ADHD. Patients were randomized (1:1:1) to once-daily LDX (30, 50 or 70mg/day), osmotic-release oral system methylphenidate (OROS-MPH; 18, 36 or 54mg/day) or placebo. Efficacy outcomes were analysed in patients dichotomized by age (6-12 years [n=229] or 13-17 years [n=88]), sex (male [n=255] or female [n=62]) and baseline ADHD Rating Scale version IV (ADHD-RSIV) total score (28-41 [n=161] or 42-54 [n=152]). Endpoint was the last on-treatment visit with a valid assessment.
Results
At endpoint, differences (active-placebo) in least-squares mean changes from baseline in ADHD-RS-IV total scores were statistically significant in all age, sex and ADHD-RS-IV total score subgroups for LDX (p< 0.001; effect sizes, 1.68-2.26) and OROS-MPH (p< 0.01; effect sizes, 0.88-1.46). Proportions of patients with a Clinical Global Impressions-Improvement rating of 1 (very much improved) or 2 (much improved) were statistically significantly greater than placebo at endpoint in all subgroups receiving LDX (p< 0.01) and in all subgroups except females receiving OROS-MPH (p< 0.05).
Conclusions
LDX showed greater efficacy than placebo in children and adolescents with ADHD, regardless of their age, sex or baseline disease severity.
The rocky shores of the north-east Atlantic have been long studied. Our focus is from Gibraltar to Norway plus the Azores and Iceland. Phylogeographic processes shape biogeographic patterns of biodiversity. Long-term and broadscale studies have shown the responses of biota to past climate fluctuations and more recent anthropogenic climate change. Inter- and intra-specific species interactions along sharp local environmental gradients shape distributions and community structure and hence ecosystem functioning. Shifts in domination by fucoids in shelter to barnacles/mussels in exposure are mediated by grazing by patellid limpets. Further south fucoids become increasingly rare, with species disappearing or restricted to estuarine refuges, caused by greater desiccation and grazing pressure. Mesoscale processes influence bottom-up nutrient forcing and larval supply, hence affecting species abundance and distribution, and can be proximate factors setting range edges (e.g., the English Channel, the Iberian Peninsula). Impacts of invasive non-native species are reviewed. Knowledge gaps such as the work on rockpools and host–parasite dynamics are also outlined.
Dense granular flows can spontaneously self-channelise by forming a pair of parallel-sided static levees on either side of a central flowing channel. This process prevents lateral spreading and maintains the flow thickness, and hence mobility, enabling the grains to run out considerably further than a spreading flow on shallow slopes. Since levees commonly form in hazardous geophysical mass flows, such as snow avalanches, debris flows, lahars and pyroclastic flows, this has important implications for risk management in mountainous and volcanic regions. In this paper an avalanche model that incorporates frictional hysteresis, as well as depth-averaged viscous terms derived from the $\unicode[STIX]{x1D707}(I)$-rheology, is used to quantitatively model self-channelisation and levee formation. The viscous terms are crucial for determining a smoothly varying steady-state velocity profile across the flowing channel, which has the important property that it does not exert any shear stresses at the levee–channel interfaces. For a fixed mass flux, the resulting boundary value problem for the velocity profile also uniquely determines the width and height of the channel, and the predictions are in very good agreement with existing experimental data for both spherical and angular particles. It is also shown that in the absence of viscous (second-order gradient) terms, the problem degenerates, to produce plug flow in the channel with two frictionless contact discontinuities at the levee–channel margins. Such solutions are not observed in experiments. Moreover, the steady-state inviscid problem lacks a thickness or width selection mechanism and consequently there is no unique solution. The viscous theory is therefore a significant step forward. Fully time-dependent numerical simulations to the viscous model are able to quantitatively capture the process in which the flow self-channelises and show how the levees are initially emplaced behind the flow head. Both experiments and numerical simulations show that the height and width of the channel are not necessarily fixed by these initial values, but respond to changes in the supplied mass flux, allowing narrowing and widening of the channel long after the initial front has passed by. In addition, below a critical mass flux the steady-state solutions become unstable and time-dependent numerical simulations are able to capture the transition to periodic erosion–deposition waves observed in experiments.