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Genome-scale analyses have revealed many transcription factor binding sites within, rather than upstream of genes, raising questions as to the function of these binding sites. Here, we use complementary approaches to map the regulon of theEscherichia colitranscription factor PhoB, a response regulator that controls transcription of genes involved in phosphate homeostasis. Strikingly, the majority of PhoB binding sites are located within genes, but these intragenic sites are not associated with detectable transcription regulation and are not evolutionarily conserved. Many intragenic PhoB sites are located in regions bound by H-NS, likely due to shared sequence preferences of PhoB and H-NS. However, these PhoB binding sites are not associated with transcription regulation even in the absence of H-NS. We propose that for many transcription factors, including PhoB, binding sites not associated with promoter sequences are transcriptionally inert, and hence are tolerated as genomic “noise”.IMPORTANCERecent studies have revealed large numbers of transcription factor binding sites within the genes of bacteria. The function, if any, of the vast majority of these binding sites has not been investigated. Here, we map the binding of the transcription factor PhoB across theEscherichia coligenome, revealing that the majority of PhoB binding sites are within genes. We show that PhoB binding sites within genes are not associated with regulation of the overlapping genes. Indeed, our data suggest that bacteria tolerate the presence of large numbers of non-regulatory, intragenic binding sites for transcription factors, and that these binding sites are not under selective pressure.

Background: Social health reflects one’s ability to form interpersonal relationships. Poor social health is a risk factor for cardiovascular disease (CVD), however an in-depth exploration of the link through CVD risk factors is lacking. Aim: To examine the relationship between social health (social isolation, social support, loneliness) and CVD risk factors among healthy older women and men. Methods: Data were from 11,498 healthy community-dwelling Australians aged ≥70 years from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and the ASPREE Longitudinal Study of Older Persons sub-study. Ten-year CVD risk was estimated using the Atherosclerotic CVD Risk Scale (ASCVDRS) and the Framingham Risk Score (FRS). Results: Physical inactivity and experiencing depressive symptoms were the only CVD risk factors that consistently differed by all three social health constructs. Loneliness was associated with greater ASCVDRS (women: β = 0.01, p

Transition metal dichalcogenides integrated within a high-quality microcavity support well-defined exciton polaritons. While the role of intralayer excitons in 2D polaritonics is well studied, interlayer excitons have been largely ignored due to their weak oscillator strength. Using a microscopic and material-realistic Wannier-Hopfield model, we demonstrate that MoS$_2$ homobilayers in a Fabry-Perot cavity support polaritons that exhibit a large interlayer exciton contribution, while remaining visible in linear optical spectra. Interestingly, with suitable tuning of the cavity length, the hybridization between intra- and interlayer excitons can be 'unmixed' due to the interaction with photons. We predict formation of polaritons where > 90% of the total excitonic contribution is stemming from the interlayer exciton. Furthermore, we explore the conditions on the tunneling strength and exciton energy landscape to push this to even 100%. Despite the extremely weak oscillator strength of the underlying interlayer exciton, optical energy can be effectively fed into the polaritons once the critical coupling condition of balanced radiative and scattering decay channels is met. These findings have a wide relevance for fields ranging from nonlinear optoelectronic devices to Bose-Einstein condensation., Main text: 19 pages, 5 figures Supplementary information: 8 pages, 6 figures

Pressure sensitive adhesives are familiar household items spanning applications in everyday repair, office supplies, and topical wound care. Through innovations in material and polymer science, pressure sensitive adhesives will advance from current commodity to novel specialty materials with resulting new clinical uses and improved patient care.

Atomically thin semiconductors such as transition metal dichalcogenide (TMD) monolayers exhibit a very strong Coulomb interaction, giving rise to a rich exciton landscape. This makes these materials highly attractive for efficient and tunable optoelectronic devices. In this Research Update, we review the recent progress in the understanding of exciton optics, dynamics, and transport, which crucially govern the operation of TMD-based devices. We highlight the impact of hexagonal boron nitride-encapsulation, which reveals a plethora of many-particle states in optical spectra, and we outline the most novel breakthroughs in the field of exciton-polaritonics. Moreover, we underline the direct observation of exciton formation and thermalization in TMD monolayers and heterostructures in recent time-resolved, angle-resolved photoemission spectroscopy studies. We also show the impact of exciton density, strain, and dielectric environment on exciton diffusion and funneling. Finally, we put forward relevant research directions in the field of atomically thin semiconductors for the near future.

INTRODUCTIONChest imaging is necessary for diagnosis of COVID-19 pneumonia, but current risk stratification tools do not consider radiographic severity. We quantified radiographic heterogeneity among inpatients with COVID-19 with the Radiographic Assessment of Lung Edema (RALE) score on Chest X-rays (CXRs).METHODSWe performed independent RALE scoring by ≥2 reviewers on baseline CXRs from 425 inpatients with COVID-19 (discovery dataset), we recorded clinical variables and outcomes, and measured plasma host-response biomarkers and SARS-CoV-2 RNA load from subjects with available biospecimens.RESULTSWe found excellent inter-rater agreement for RALE scores (intraclass correlation co-efficient=0.93). The required level of respiratory support at the time of baseline CXRs (supplemental oxygen or non-invasive ventilation [n=178]; invasive-mechanical ventilation [n=234], extracorporeal membrane oxygenation [n=13]) was significantly associated with RALE scores (median [interquartile range]: 20.0[14.1-26.7], 26.0[20.5-34.0] and 44.5[34.5-48.0], respectively, pCONCLUSIONReproducible assessment of radiographic severity revealed significant associations with clinical and physiologic severity, host-response biomarkers and clinical outcome in COVID-19 pneumonia. Incorporation of radiographic severity assessments may provide prognostic and treatment allocation guidance in patients hospitalized with COVID-19.

When longshore transport systems encounter tidal inlets, complex mechanisms are involved in bypassing sand to downdrift barriers. Here, this process is examined at Plum Island Sound and Essex Inlets, Massachusetts, USA. One major finding from this study is that sand is transferred along the coast—especially at tidal inlets—by parcels, in discrete steps, and over decadal-scale periods. The southerly orientation of the main-ebb channel at Plum Island Sound, coupled with the landward migration of bars from the ebb delta to the central portion of the downdrift Castle Neck barrier island, have formed a beach protuberance. During the constructional phase, sand is sequestered at the protuberance and the spit-end of the barrier becomes sediment starved, leading to shoreline retreat and a broadening of the spit platform at the mouth to Essex Bay (downdrift side of Castle Neck). Storm-induced sand transport from erosion of the spit and across the spit platform is washed into Essex Bay, filling channels and enlarging flood deltas. This study illustrates the pathways and processes of sand transfer along the shoreline of a barrier-island/tidal-inlet system and provides an important example of the processes that future hydrodynamic and sediment-transport modeling should strive to replicate.

Migratory species are particularly vulnerable to climate change because habitat throughout their entire migration cycle must be suitable for the species to persist. For migratory species in rivers, predicting climate change impacts is especially difficult because there is a lack of spatially continuous and seasonally varying stream temperature data, habitat conditions can vary for an individual throughout its life cycle, and vulnerability can vary by life stage and season. To predict thermal impacts on migratory riverine populations, we first expanded a spatial stream network model to predict mean monthly temperature for 465,775 river km in the western U.S., and then applied simple yet plausible future stream temperature change scenarios. We then joined stream temperature predictions to 44,396 spatial observations and life-stage-specific phenology (timing) for 26 ecotypes (i.e., geographically distinct population groups expressing one of the four distinct seasonal migration patterns) of Chinook salmon (Oncorhynchus tshawytscha), a phenotypically diverse anadromous salmonid that is ecologically and economically important but declining throughout its range. Thermal stress, assessed for each life stage and ecotype based on federal criteria, was influenced by migration timing rather than latitude, elevation, or migration distance such that sympatric ecotypes often showed differential thermal exposure. Early-migration phenotypes were especially vulnerable due to prolonged residency in inland streams during the summer. We evaluated the thermal suitability of 31,699 stream km which are currently blocked by dams to explore reintroduction above dams as an option to mitigate the negative effects of our warmer stream temperature scenarios. Our results showed that negative impacts of stream temperature warming can be offset for almost all ecotypes if formerly occupied habitat above dams is made available. Our approach of combining spatial distribution and phenology data with spatially explicit and temporally explicit temperature predictions enables researchers to examine thermal exposure of migrating populations that use seasonally varying habitats.

Twisted atomically thin semiconductors are characterized by moir\'{e} excitons. Their optical signatures and selection rules are well understood. However, their hybridization with photons in the strong coupling regime for heterostructures integrated in an optical cavity has not been in the focus of research yet. Here, we combine an excitonic density matrix formalism with a Hopfield approach to provide microscopic insights into moir\'{e} exciton polaritons. In particular, we show that exciton-light coupling, polariton energy, and even the number of polariton branches can be controlled via the twist angle. We find that these new hybrid light-exciton states become delocalized relative to the constituent excitons due to the mixing with light and higher-energy excitons. The system can be interpreted as a natural quantum metamaterial with a periodicity that can be engineered via the twist angle. Our study presents a significant advance in microscopic understanding and control of moir\'{e} exciton polaritons in twisted atomically thin semiconductors.

Various types of Alfvén eigenmodes (AEs) have been destabilized by fast ions over a broad frequency range from ∼80 kHz to ∼700 kHz in a series of JET experiments in mixed D–3He plasmas heated with the three-ion ICRF scenario (2020 Nocente et al Nucl. Fusion 60 124006). In this paper, we identify the radial localization of AEs using an X-mode reflectometer, a multiline interferometer and soft x-ray diagnostics. The analysis is focused on the most representative example of these measurements in JET pulse #95691, where two different types of Alfvén cascade (AC) eigenmodes were observed. These modes originate from the presence of a local minimum of the safety factor q min. In addition to ACs with frequencies below the frequency of toroidal Alfvén eigenmodes (TAEs), ACs with frequencies above the TAE frequency were destabilized by energetic ions. Both low- (f ≈ 80–180 kHz) and high-frequency (f ≈ 330–450 kHz) ACs were localized in the central regions of the plasma. The characteristics of the high-frequency ACs are investigated in detail numerically using HELENA, CSCAS and MISHKA codes. The resonant conditions for the mode excitation are found to be determined by passing ions of rather high energy of several hundred keV and similar to those established in JT-60U with negative-ion-based NBI (2005 Takechi et al Phys. Plasmas 12 082509). The computed radial mode structure is found to be consistent with the experimental measurements. In contrast to low-frequency ACs observed most often, the frequency of the high-frequency ACs decreases with time as the value of q min decreases. This feature is in a qualitative agreement with the analytical model of the high-frequency ACs in Breizman et al (2003 Phys. Plasmas 10 3649). The high-frequency AC could be highly relevant for future ITER and fusion reactor plasmas dominated by ∼MeV energetic ions, including a significant population of passing fast ions.

Ozone pollution has been prevalent in the El Paso-Juárez Airshed (EPJA), especially in the past few decades, and it has been on the rise recently. The spatial and temporal distribution of the tropospheric ozone and several key meteorological factors that influence its concentration has not been adequately understood. Therefore, this investigation comprehensively examined 57 high and 48 low ozone episodes occurring in this region during 2013–2019. We found that the interannual ozone concentration in EPJA was strongly affected by anthropogenic emissions. On the other hand, seasonal ozone variations are due to meteorological variables (among them, solar radiation, planetary boundary layer, and winds) in addition to biogenic emission factors. High ozone events are characterized by calm winds, shallow planetary boundary layer (PBL), whereas low ozone events were marked with strong winds, precipitation, and deep PBL. Synoptic and mesoscale wind patterns for these ozone episodes were identified and characterized. Most of the high ozone episodes occurred when an anticyclonic circulation aloft was associated with a 500-mile middle and upper tropospheric high-pressure region over the EPJA. During these events, stable air masses with convective available potential energies (CAPE) values of less than 450 J/kg were found. The importance of surface topography is illustrated by the fact that stations close to the Rio Grande River show a bimodal distribution of wind direction according to the valley axis. High ozone episodes occur with a surface easterly wind that is decoupled from winds above the Franklin mountains.

Identification of specific risk factors for posttraumatic stress disorder (PTSD) versus depression after trauma has been challenging, in part due to the high comorbidity of these disorders. As exposure to trauma triggers activation of the hypothalamic-pituitary-adrenal (HPA)-axis, examining atypical stress responses via HPA-axis hormones, namely cortisol, may help in the delineation of these disorders. Indeed, extant research demonstrates that, following stress, individuals with chronic PTSD exhibit hypocortisolism (e.g., lower cortisol response than controls), while those with chronic depression exhibit hypercortisolism (e.g., higher response than controls). Less is known about the role of cortisol and these seemingly disparate profiles immediately following traumatic injury as well as whether cortisol can be used as a predictor of future development of PTSD versus depression symptoms. In this study cortisol was measured blood from 172 traumatic injury survivors during hospitalization (on average 2.5 days post-injury). PTSD and depression severity were assessed from Clinician Assessed PTSD Scale (CAPS-5) six-eight months later using a two-factor dimensional approach that measures trauma-specific symptoms of PTSD versus dysphoria (akin to depression). Cluster analysis was used to group individuals based on post-injury cortisol, PTSD, and dysphoria. Results demonstrated that trauma survivors who only developed symptoms of dysphoria at six months (with minimal symptoms of PTSD) were differentiated by high post-injury cortisol compared to other groups. By contrast, individuals who developed symptoms of both PTSD and dysphoria were differentiated by low post-injury cortisol and most severe symptoms of PTSD. Findings provide support for the presence of subgroups of trauma survivors defined, in part, by post-trauma cortisol.

Social hierarchies within groups define the distribution of resources and provide benefits that support the collective group or favor dominant members. The progression of individuals through social hierarchies is a valuable characteristic for quantifying population dynamics. On coral reefs, a number of small site-attached fish maintain size-based hierarchical communities where individuals queue through social ranks. The cost of waiting in a lower-ranked position is outweighed by the reduced risk of eviction and mortality. Clownfish exist in stable social groups with subordinate individuals queuing to be part of the dominant breeding pair. Site attachment to their host anemone, complex social interactions, and relatively low predation rates make them ideal model organisms to assess changes in group dynamics through time in their natural environment. Here, we investigate the rank changes, and isometric growth rates of individual orange clownfish, Amphiprion percula, from 247 naturally occurring social groups in Kimbe Island, Papua New Guinea (5°12’13.54” S, 150°22’32.69” E). We use DNA profiling to assign and track individuals over an eight-year time period in 2011 and 2019. Over half of the individuals survived alongside two or three members of their original social group, with twelve breeding pairs persisting over the study period. Half of the surviving individuals increased in rank and experienced double the growth rate of those that maintained their rank. Examining rank change over a long-term period in a wild fish population gives new insights and highlights the complexity and importance of rank and social hierarchy in communal site-attached reef fish.Subject Area: behavior, ecology, evolution

BACKGROUND: Posttraumatic Stress Disorder (PTSD) is a debilitating disorder and there is no current accurate prediction of who develops it after trauma. Neurobiologically, individuals with chronic PTSD exhibit aberrant resting-state functional connectivity (rsFC) between the hippocampus and other brain regions (e.g., amygdala, prefrontal cortex, posterior cingulate), and these aberrations correlate with severity of illness. Prior small-scale research (n < 25) has also shown that hippocampal-rsFC measured acutely after trauma is predictive of future severity using an ROI-based approach. While a promising biomarker, to-date no study has employed a data-driven approach to test whole-brain hippocampal-FC patterns in forecasting the development of PTSD symptoms. METHODS: Ninety-eight adults at risk of PTSD were recruited from the emergency department following traumatic injury and completed resting functional magnetic resonance imaging (rsfMRI; 8min) within 1-month; 6-months later they completed the Clinician-Administered PTSD Scale (CAPS-5) for assessment of PTSD symptom severity. Whole-brain rsFC values with bilateral hippocampi were extracted (CONN) and used in a machine learning kernel ridge regression analysis (PRoNTo); both a k-folds (k=10) and 70/30 testing vs. training split approach were used for cross-validation (1,000 iterations to bootstrap confidence intervals for significance values). RESULTS: Acute hippocampal-rsFC significantly predicted CAPS-5 scores at 6-months (r=0.30, p=0.006; MSE=120.58, p=0.006; R(2)=0.09, p=0.025). In post-hoc analyses, hippocampal-rsFC remained significant after controlling for demographics, PTSD symptoms at baseline, and depression, anxiety, and stress severity at 6-months (B=0.59, SE=0.20, p=0.003). CONCLUSIONS: Findings suggest functional connectivity of the hippocampus across the brain acutely after traumatic injury is associated with prospective PTSD symptom severity.

Background: Little is known about what distinguishes those who are resilient after trauma from those at risk for developing posttraumatic stress disorder (PTSD). Previous work indicates white matter integrity may be a useful biomarker in predicting PTSD. Research has shown changes in the integrity of three white matter tracts—the cingulum bundle, corpus callosum (CC), and uncinate fasciculus (UNC)—in the aftermath of trauma relate to PTSD symptoms. However, few have examined the predictive utility of white matter integrity in the acute aftermath of trauma to predict prospective PTSD symptom severity in a mixed traumatic injury sample.Method: Thus, the current study investigated acute brain structural integrity in 148 individuals being treated for traumatic injuries in the Emergency Department of a Level 1 trauma center. Participants underwent diffusion-weighted magnetic resonance imaging 2 weeks post-trauma and completed several self-report measures at 2-weeks (T1) and 6 months (T2), including the Clinician Administered PTSD Scale for DSM-V (CAPS-5), post-injury.Results: Consistent with previous work, T1 lesser anterior cingulum fractional anisotropy (FA) was marginally related to greater T2 total PTSD symptoms. No other white matter tracts were related to PTSD symptoms.Conclusions: Results demonstrate that in a traumatically injured sample with predominantly subclinical PTSD symptoms at T2, acute white matter integrity after trauma is not robustly related to the development of chronic PTSD symptoms. These findings suggest the timing of evaluating white matter integrity and PTSD is important as white matter differences may not be apparent in the acute period after injury.

Caught in the act, DNA reaction intermediates in bacterial genomes may illuminate disease-driving regions in human chromosomes., Chromosomal fragile sites are implicated in promoting genome instability, which drives cancers and neurological diseases. Yet, the causes and mechanisms of chromosome fragility remain speculative. Here, we identify three spontaneous fragile sites in the Escherichia coli genome and define their DNA damage and repair intermediates at high resolution. We find that all three sites, all in the region of replication termination, display recurrent four-way DNA or Holliday junctions (HJs) and recurrent DNA breaks. Homology-directed double-strand break repair generates the recurrent HJs at all of these sites; however, distinct mechanisms of DNA breakage are implicated: replication fork collapse at natural replication barriers and, unexpectedly, frequent shearing of unsegregated sister chromosomes at cell division. We propose that mechanisms such as both of these may occur ubiquitously, including in humans, and may constitute some of the earliest events that underlie somatic cell mosaicism, cancers, and other diseases of genome instability.

Background To date, over 2 million people worldwide have died with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To describe the experience in Ireland, this study examined associations between underlying conditions and the following outcomes: mortality, admission to hospital or admission to the intensive care unit (ICU) among those infected with COVID-19. Methods This study used data from the Health Protection Surveillance Centre in Ireland and included confirmed cases of COVID-19 from the first wave of the pandemic between March and July 2020. Two cohorts were included: all cases (community and hospital) and hospital admissions only. For all cases, health outcome data included mortality and hospitalisation. For hospitalised cases, outcome data included mortality and ICU admission. Logistic regression was used to examine associations between underlying conditions and outcomes across both cohorts. Results are presented as adjusted odds ratios (OR) and 95% confidence intervals (CIs). Findings There were 19,789 cases included in analysis, which encompassed 1,476 (7.5%) deaths, 2,811 (14.2%) hospitalisations, and 438 (2.2%) ICU admissions of whom 90 (20.5%) died. Significantly higher risk of mortality, hospitalisation and ICU admission was associated with having chronic heart disease, a BMI ≥40kg/m2 and male sex. Additionally, diagnosis of a chronic neurological condition (OR 1.41; 95%CI:1.17, 1.69), chronic kidney disease (OR 1.74; 95%CI:1.35, 2.24) and cancer (OR 2.77; 95%CI:2.21, 3.47) were significantly associated with higher risk of mortality among all cases, with similar patterns of association observed for mortality among hospitalised cases. Interpretation The identification of underlying conditions among COVID-19 cases may help identify those at highest risk of the worst health outcomes and inform preventive strategies to improve outcomes. Funding This study was supported by the Health Service Executive, Health Protection Surveillance Centre. KEB and MM are funded by the Health Research Board (RL-15-1579 and EIA-2019-012 respectively).

Background: Portal placement is an important factor in performing a successful shoulder arthroscopy. Recent cadaveric studies have found variance in the anatomy of the glenohumeral joint. Our aim was to determine if computerized tomography (CT) images could be used to map the trajectory of the posterior portal objectively and then measure the distance between this trajectory and palpable landmarks to apply this knowledge to clinical practice. Methods: Two-dimensional multiplanar reformatted CT images were generated using OsiriX (Pixmeo, Switzerland) from CT images performed in a tertiary hospital over a 1-month period. The center of the glenoid was identified and a trajectory through it radiologically mapped. Horizontal and lateral measurements were taken from this trajectory to both the posterolateral edge of the acromion and tip of the coracoid. Results: Following application of inclusion and exclusion criteria, 226 shoulders were analyzed. Fifty scans were selected at random and re-reviewed by the primary examiner to assess intra-rater reliability which showed strong correlation and no significant differences between first and second measurements (P < .01, r > 0.6). The mean distance from acromion to portal trajectory was 1.39 cm inferiorly (95% confidence interval [CI] 1.31-1.48, standard deviation [SD] 0.65 cm) and 1.44 cm medially (95% CI 1.35-1.53, SD 0.71 cm). The mean distance from the coracoid to the trajectory was 1.71 cm inferiorly (95% CI 1.64-1.78, SD 0.55 cm) and 1.26 cm medially (95% CI 1-2-1.31, SD 0.45 cm). Paired t-test analysis between right and left shoulders within the same subject, where these data were available (n = 81), showed no significant difference (P > .05) between sides. Subset analysis was also performed between males and females, but only showed a significant difference between the vertical distance from the coracoid process to the center of the glenohumeral joint. This distance was shorter in females compared to males (1.56 cm in females compared to 1.84 cm in males, P < .001). Conclusions: Knowledge of shoulder anatomy is vital to the placement of arthroscopic portals, yet research on this topic has been based primarily on surface anatomy, small sample sized cadaveric studies or expert opinion alone. Our study shows that posterior portal placement in shoulder arthroscopy can be measured objectively using CT scanning.

The persistence of a parasite species in an ecological community is determined both by its environmental tolerance and host breadth. The relative contribution of these niche characteristics to parasite community structure is challenging to parse because host persistence is also a consequence of extrinsic environmental factors. We investigated haemosporidian parasites (genera Plasmodium, Leucocytozoon, and Haemoproteus) in a clade of avian hosts in eastern North America. Species in this clade of Catharus thrushes occupy specific elevational bands in a non‐phylogenetically determined manner. This allowed us to tease apart the effects of host relatedness and elevation on parasite community structure, diversity, and infection prevalence. We screened blood and tissue samples from 414 adult birds from four mountain ranges in the Appalachian Highlands for blood parasites using a cytochrome‐b‐nested PCR protocol and identified parasite lineages by sequencing. We found an overall infection prevalence of 88.4% and identified a total of 38 parasite lineages including six novel lineages. Parasite community patterns varied by genus. Host relatedness rather than elevational zone predicted the beta turnover and phylobeta turnover of Leucocytozoon parasites, indicating that closely related rather than geographically proximate host species had more similar parasites. This pattern was not seen in Plasmodium parasites because the diversity of this parasite genus varied considerably in the high elevational zones among mountain ranges, that is, a sky‐island effect. Haemoproteus parasites were rare in this study system. Our study suggests that the mechanisms that underlie community structuring vary between haemosporidian genera due to differences in the degree of host sharing among lineages.

IntroductionDirect-to-family clinical trials efficiently provide data while reducing the participation burden for children and their families. Although these trials can offer significant advantages over traditional clinical trials, the process of designing and implementing direct-to-family studies is poorly defined, especially in children with rheumatic disease. This paper provides lessons learnt from the design and implementation of a self-controlled, direct-to-family pilot trial aimed to evaluate the effects of a medication management device on adherence to hydroxychloroquine in paediatric SLE.MethodsSeveral design features accommodate a direct-to-family approach. Participants meeting eligibility criteria from across the USA were identified a priori through a disease registry, and all outcome data are collected remotely. The primary outcome (medication adherence) is evaluated using electronic medication event-monitoring, plasma drug levels, patient questionnaires and pill counts. Secondary and exploratory endpoints include (1) lupus disease activity measured by a remote SLE Disease Activity Index examination and the Systemic Lupus Activity Questionnaire; and (2) hydroxychloroquine pharmacokinetics and pharmacodynamics. Recruitment of the initial target of 20 participants was achieved within 10 days. Due to initial recruitment success, enrolment was increased to 26 participants. Additional participants who were interested were placed on a waiting list in case of dropouts during the study.Discussion and disseminationDirect-to-family trials offer several advantages but present unique challenges. Lessons learnt from the protocol development, design, and implementation of this trial will inform future direct-to-family trials for children and adults with rheumatic diseases. Additionally, the data collected remotely in this trial will provide critical information regarding the accuracy of teleresearch in lupus, the impact of adherence to hydroxychloroquine on disease activity and a pharmacokinetic analysis to inform paediatric-specific dosing of hydroxychloroquine.Trial registration numberClinicalTrials.gov Registry (NCT04358302).

Background A previous six-week (wk) study demonstrated the potential of the sodium-glucose linked transport inhibitor velagliflozin as a novel treatment for equine insulin dysregulation. The present study examined the safety and efficacy of velagliflozin over 16 wk. of treatment, and over 4 wk. of withdrawal. Twenty-four insulin dysregulated ponies were selected, based on their hyper-responsiveness to a diet challenge meal containing 3.8 g non-structural carbohydrates (NSC)/kg bodyweight (BW). Ponies with serum insulin > 90 μIU/mL either 2 or 4 h after feeding were enrolled, and randomly allocated to receive either velagliflozin (0.3 mg/kg BW orally once daily, n = 12), or a placebo (n = 10–12) for 16 wk. The subjects were fed 7.5 g NSC/kg BW/day to maintain a fat body condition. Safety was assessed through daily monitoring, veterinary examination, and the measurement of fasting blood glucose, biochemistry and haematology. Efficacy at reducing post-prandial hyperinsulinemia was assessed using a diet challenge every 8 wk. during treatment and 4 wk. after withdrawal. Results Velagliflozin was well accepted by all subjects and caused no adverse effects or hypoglycaemia. Post-prandial serum insulin (insulin Cmax) did not change significantly in the control animals over the entire study period (P = 0.101). In contrast, insulin Cmax (mean ± SE) concentrations fell over time in the velagliflozin-treated group from 205 ± 25 μIU/mL in wk. 0, to 119 ± 19 μIU/mL (P = 0.015) and 117 ± 15 μIU/ml (P = 0.029) after 8 and 16 wk. of treatment, respectively. Although the insulin Cmax in this group was not significantly lower than in controls at wk-8 (P = 0.061), it was lower at wk-16 (P = 0.003), and all 12 treated ponies were below the previously-determined risk threshold for laminitis at this time. After 4 wk. withdrawal, the insulin Cmax returned to 199 ± 36 μIU/mL in the treated group, with no rebound effect. Conclusions Velagliflozin appears to be a promising and safe treatment for equine insulin dysregulation, bringing post-prandial insulin concentrations below the laminitis risk threshold, albeit without normalising them. Electronic supplementary material The online version of this article (10.1186/s12917-019-1811-2) contains supplementary material, which is available to authorized users.

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Background: Supraphysiological insulin and incretin responses to a cereal-based diet have been described in horses and ponies with insulin dysregulation (ID). However, the hormonal responses to grazing have not yet been described. Objectives: To determine if there is a difference in the insulin and incretin responses to grazing pasture between insulin-dysregulated and healthy ponies. Animals: A cohort of 16 ponies comprising 5 with normal insulin regulation (NIR), 6 with moderate ID (MID), and 5 with severe ID (SID). Methods: In this case-control study, an oral glucose test (OGT) was used to determine the insulin responsiveness of each pony to PO carbohydrate before grazing pasture (4 hours) for 3 consecutive days. Serial blood samples collected during grazing were analyzed for glucose, insulin, glucose-dependent insulinotropic peptide (GIP) and active glucagon-like peptide-1 (aGLP-1), and compared among pony groups and day of pasture access. Results: The area under the insulin curve when grazing increased with ID severity (P

The SARS-CoV-2 pandemic has caused over 1 million deaths globally, mostly due to acute lung injury and acute respiratory distress syndrome, or direct complications resulting in multiple-organ failures. Little is known about the host tissue immune and cellular responses associated with COVID-19 infection, symptoms, and lethality. To address this, we collected tissues from 11 organs during the clinical autopsy of 17 individuals who succumbed to COVID-19, resulting in a tissue bank of approximately 420 specimens. We generated comprehensive cellular maps capturing COVID-19 biology related to patients’ demise through single-cell and single-nucleus RNA-Seq of lung, kidney, liver and heart tissues, and further contextualized our findings through spatial RNA profiling of distinct lung regions. We developed a computational framework that incorporates removal of ambient RNA and automated cell type annotation to facilitate comparison with other healthy and diseased tissue atlases. In the lung, we uncovered significantly altered transcriptional programs within the epithelial, immune, and stromal compartments and cell intrinsic changes in multiple cell types relative to lung tissue from healthy controls. We observed evidence of: alveolar type 2 (AT2) differentiation replacing depleted alveolar type 1 (AT1) lung epithelial cells, as previously seen in fibrosis; a concomitant increase in myofibroblasts reflective of defective tissue repair; and, putative TP63+ intrapulmonary basal-like progenitor (IPBLP) cells, similar to cells identified in H1N1 influenza, that may serve as an emergency cellular reserve for severely damaged alveoli. Together, these findings suggest the activation and failure of multiple avenues for regeneration of the epithelium in these terminal lungs. SARS-CoV-2 RNA reads were enriched in lung mononuclear phagocytic cells and endothelial cells, and these cells expressed distinct host response transcriptional programs. We corroborated the compositional and transcriptional changes in lung tissue through spatial analysis of RNA profiles in situ and distinguished unique tissue host responses between regions with and without viral RNA, and in COVID-19 donor tissues relative to healthy lung. Finally, we analyzed genetic regions implicated in COVID-19 GWAS with transcriptomic data to implicate specific cell types and genes associated with disease severity. Overall, our COVID-19 cell atlas is a foundational dataset to better understand the biological impact of SARS-CoV-2 infection across the human body and empowers the identification of new therapeutic interventions and prevention strategies.

Background: Technology is increasingly used to enhance pharmacy education. We sought to evaluate student learning and preparedness for community introductory pharmacy practice experiences (IPPEs) after implementation of “MyDispense” into experiential education. Methods: Both first-year pharmacy students and assigned community IPPE preceptors were eligible. Students were stratified based on previous community pharmacy experience (&lt, or ≥ 50 h), then randomized to complete MyDispense exercises before IPPE (group A) or after 24–32 h of IPPE (group B). We evaluated preceptors’ assessment of student readiness using a 6-item Likert scale survey and students’ readiness and opinion of MyDispense using an anonymous 9-item survey. Descriptive statistics were used to characterize data. The Mann–Whitney U test was used to compare groups and a p-value &lt, 0.05 was considered statistically significant. Results: Of 177 eligible students, 155 were randomized and 56 completed study. Group A included 32 students, 56.3% had prior community practice experience. Group B included 24 students, 50% had prior community practice experience. Forty-eight preceptors were enrolled. Students who completed exercises before rotation received higher preceptor scores for patient counseling of self-care and of medications (p &lt, 0.05 for both). Students self-assessed their counseling skills lower than all other skills, 30.4% and 42.9% of students felt mostly or always prepared to counsel for self-care and medications, respectively. Students found MyDispense straightforward, realistic, and appreciated the ability to practice in a safe, electronic, community pharmacy, patient-care environment. Conclusion: Simulation-based software, such as MyDispense, can enhance learner understanding of the prescription fill and counseling process in a community pharmacy practice setting.

Diverse DNA structures occur as reaction intermediates in various DNA-damage and -repair mechanisms, most of which results from replication stress. We harness the power of proteins evolutionarily optimized to bind and "trap" specific DNA reaction-intermediate structures, to quantify the structures, and discern the mechanisms of their occurrence in cells. The engineered proteins also allow genomic mapping of sites at which specific DNA structures occur preferentially, using a structure-trapping protein and ChIP-seq- or Cut-and-Tag-like methods. Genome-wide identification of sites with recurrent DNA-damage intermediates has illuminated mechanisms implicated in genome instability, replication stress, and chromosome fragility. Here, we describe X-seq, for identifying sites of recurrent four-way DNA junctions or Holliday-junctions (HJs). X-seq uses an engineered, catalysis-defective mutant of Escherichia coli RuvC HJ-specific endonuclease, RuvCDefGFP. X-seq signal indicates sites of recombinational DNA repair or replication-fork stalling and reversal. We also describe methods for genomic mapping of 3'-single-stranded DNA ends with SsEND-seq, in E. coli. Both methods allow genomic profiling of DNA-damage and -repair intermediates, which can precede genome instability, and are expected to have many additional applications including in other cells and organisms.

Key Points Question What factors are associated with use of hypofractionated vs conventional radiation therapy for prostate cancer, and is there a difference in patient-reported outcomes (PROs) at a population level? Findings In this cohort study of data from 6368 men with nonmetastatic prostate cancer, use of hypofractionation increased from 2.1% to 52.7% from the first half of 2016 to the second half of 2019 with no differences in PROs between those receiving hypofractionated radiation therapy and conventional radiation therapy. Substantial variation in use was found between jurisdictions, institutions, individual clinicians, and patient cohorts. Meaning Findings of this cohort study support the continued implementation of hypofractionated radiation therapy into routine practice and provide stakeholders with information that may be useful in targeting implementation strategies., Importance Randomized clinical trials in prostate cancer have reported noninferior outcomes for hypofractionated radiation therapy (HRT) compared with conventional RT (CRT); however, uptake of HRT across jurisdictions is variable. Objective To evaluate the use of HRT vs CRT in men with nonmetastatic prostate cancer and compare patient-reported outcomes (PROs) at a population level. Design, Setting, and Participants Registry-based cohort study from the Australian and New Zealand Prostate Cancer Outcomes Registry (PCOR-ANZ). Participants were men with nonmetastatic prostate cancer treated with primary RT (excluding brachytherapy) from January 2016 to December 2019. Data were analyzed in March 2021. Exposures HRT defined as 2.5 to 3.3 Gy and CRT defined as 1.7 to 2.3 Gy per fraction. Main Outcomes and Measures Temporal trends and institutional, clinicopathological, and sociodemographic factors associated with use of HRT were analyzed. PROs were assessed 12 months following RT using the Expanded Prostate Cancer Index Composite (EPIC)–26 Short Form questionnaire. Differences in PROs were analyzed by adjusting for age and National Comprehensive Cancer Network risk category. Results Of 8305 men identified as receiving primary RT, 6368 met the inclusion criteria for CRT (n = 4482) and HRT (n = 1886). The median age was 73.1 years (IQR, 68.2-77.3 years), 2.6% (168) had low risk, 45.7% (2911) had intermediate risk, 44.5% (2836) had high-/very high–risk, and 7.1% (453) had regional nodal disease. Use of HRT increased from 2.1% (9 of 435) in the first half of 2016 to 52.7% (539 of 1023) in the second half of 2019, with lower uptake in the high-/very high–risk (1.9% [4 of 215] to 42.4% [181 of 427]) compared with the intermediate-risk group (2.2% [4 of 185] to 67.6% [325 of 481]) (odds ratio, 0.26; 95% CI, 0.15-0.45). Substantial variability in the use of HRT for intermediate-risk disease remained at the institutional level (median 53.3%; range, 0%-100%) and clinician level (median 57.9%; range, 0%-100%) in the last 2 years of the study period. There were no clinically significant differences across EPIC-26 urinary and bowel functional domains or bother scores. Conclusions and Relevance In this cohort study, use of HRT for prostate cancer increased substantially from 2016. This population-level data demonstrated clinically equivalent PROs and supports the continued implementation of HRT into routine practice. The wide variation in practice observed at the jurisdictional, institutional, and clinician level provides stakeholders with information that may be useful in targeting implementation strategies and benchmarking services., This cohort study analyzes factors associated with the use of hypofractionated radiation therapy during the period from 2016 to 2019 and evaluates real-world patient-reported outcomes data for men with nonmetastatic prostate cancer receiving hypofractionated radiation therapy and conventional radiation therapy.

This paper summarizes the physical principles behind the novel three-ion scenarios using radio frequency waves in the ion cyclotron range of frequencies (ICRF). We discuss how to transform mode conversion electron heating into a new flexible ICRF technique for ion cyclotron heating and fast-ion generation in multi-ion species plasmas. The theoretical section provides practical recipes for selecting the plasma composition to realize three-ion ICRF scenarios, including two equivalent possibilities for the choice of resonant absorbers that have been identified. The theoretical findings have been convincingly confirmed by the proof-of-principle experiments in mixed H?D plasmas on the Alcator C-Mod and JET tokamaks, using thermal 3He and fast D ions from neutral beam injection as resonant absorbers. Since 2018, significant progress has been made on the ASDEX Upgrade and JET tokamaks in H?4He and H?D plasmas, guided by the ITER needs. Furthermore, the scenario was also successfully applied in JET D?3He plasmas as a technique to generate fusion-born alpha particles and study effects of fast ions on plasma confinement under ITER-relevant plasma heating conditions. Tuned for the central deposition of ICRF power in a small region in the plasma core of large devices such as JET, three-ion ICRF scenarios are efficient in generating large populations of passing fast ions and modifying the q-profile. Recent experimental and modeling developments have expanded the use of three-ion scenarios from dedicated ICRF studies to a flexible tool with a broad range of different applications in fusion research. AB - This paper summarizes the physical principles behind the novel three-ion scenarios using radio frequency waves in the ion cyclotron range of frequencies (ICRF). We discuss how to transform mode conversion electron heating into a new flexible ICRF technique for ion cyclotron heating and fast-ion generation in multi-ion species plasmas. The theoretical section provides practical recipes for selecting the plasma composition to realize three-ion ICRF scenarios, including two equivalent possibilities for the choice of resonant absorbers that have been identified. The theoretical findings have been convincingly confirmed by the proof-of-principle experiments in mixed H?D plasmas on the Alcator C-Mod and JET tokamaks, using thermal 3He and fast D ions from neutral beam injection as resonant absorbers. Since 2018, significant progress has been made on the ASDEX Upgrade and JET tokamaks in H?4He and H?D plasmas, guided by the ITER needs. Furthermore, the scenario was also successfully applied in JET D?3He plasmas as a technique to generate fusion-born alpha particles and study effects of fast ions on plasma confinement under ITER-relevant plasma heating conditions. Tuned for the central deposition of ICRF power in a small region in the plasma core of large devices such as JET, three-ion ICRF scenarios are efficient in generating large populations of passing fast ions and modifying the q-profile. Recent experimental and modeling developments have expanded the use of three-ion scenarios from dedicated ICRF studies to a flexible tool with a broad range of different applications in fusion research. The authors are grateful to the anonymous reviewers for their constructive comments that allowed us to improve the paper, I. Voitsekhovitch for her valuable comments and suggestions during the paper preparation, and to H. Meyer and J. Faustin for fruitful discussions. We thank the ITPA Energetic Particle Physics Topical Group for its support. This work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014–2018 and 2019–2020 under Grant Agreement No. 633053. The views and opinions expressed herein do not necessarily reflect those of the European Commission. Part of this work was also carried out in the framework of projects done for the ITER Scientist Fellow Network (ISFN). ITER is the Nuclear Facility INB No. 174. The views and opinions expressed herein do not necessarily reflect those of the ITER Organization. This publication is provided for scientific purposes only. Its contents should not be considered as commitments from the ITER Organization as a nuclear operator in the frame of the licensing process. Peer Reviewed "Article signat per 67 autors/es: Ye. O. Kazakov, J. Ongena, J. C. Wright, S. J. Wukitch, V. Bobkov, J. Garcia, V. G. Kiptily, M. J. Mantsinen, M. Nocente, M. Schneider, H. Weisen, Y. Baranov, M. Baruzzo, R. Bilato, A. Chomiczewska, R. Coelho, T. Craciunescu K. Crombé, M. Dreval, R. Dumont, P. Dumortier, F. Durodié, J. Eriksson, M. Fitzgerald, J. Galdon-Quiroga, D. Gallart, M. Garcia-Muñoz, L. Giacomelli, C. Giroud, J. Gonzalez-Martin, A. Hakola, P. Jacquet, T. Johnson, A. Kappatou, D. Keeling, D. King, K. K. Kirov, P. Lamalle, M. Lennholm, E. Lerche, M. Maslov, S. Mazzi, S. Menmuir, I. Monakhov5, F. Nabais, M. F. F. Nave, R. Ochoukov, A. R. Polevoi, S. D. Pinches, U. Plank, D. Rigamonti, M. Salewski, P. A. Schneider, S. E. Sharapov, Ž. Štancar, A. Thorman, D. Valcarcel, D. Van Eester, M. Van Schoor, J. Varje, M. Weiland, N. Wendler, JET Contributors, ASDEX Upgrade Team, EUROfusion MST1 Team, and Alcator C-Mod Team"

Characterising and monitoring biological diversity to foster sustainable ecosystems is highly recommended as urban centres rapidly expand. However, much of New York City’s biodiversity remains undescribed, including in the historically degraded, but recovering Bronx River Estuary. In a pilot study to identify organisms and characterise biodiversity patterns there, 18S rRNA gene amplicons (V1–V3 region), obtained from river sediments and surface waters of Hunts Point Riverside and Soundview Parks, were sequenced. Across 48 environmental samples collected over three seasons in 2015 and 2016, following quality control and contaminant removal, 2,763 Amplicon Sequence Variants (ASVs) were identified from 1,918,463 sequences. Rarefaction analysis showed sufficient sampling depth, and community composition varied over time and by substrate at the study sites over the sampling period. Protists, plants, fungi and animals, including organisms of management concern, such as Eastern oysters (Crassostrea virginica), wildlife pathogens and groups related to Harmful Algal Blooms, were detected. The most common taxa identified in river sediments were annelid worms, nematodes and diatoms. In the water column, the most commonly observed organisms were diatoms, algae of the phylum Cryptophyceae, ciliates and dinoflagellates. The presented dataset demonstrates the reach of 18S rRNA metabarcoding for characterising biodiversity in an urban estuary.

Correction to: ACS Omega 2017, 2 (7), 3640−3646. DOI: 10.1021/acsomega.7b00726