bluuebunny/crossref_metadata_2025 huggingface dataset:
Attention to speech: mapping distributed and selective attention systems
Authors: Agmon Galit , Yahav Paz Har-Shai , Ben-Shachar Michal , Golumbic Elana Zion
Published: November 2021

When faced with situations where many people talk at once, individuals can employ different listening strategies to deal with the cacophony of speech sounds and to achieve different goals. In this fMRI study, we investigated how the pattern of neural activity is affected by the type of attention applied to speech in a simulated “cocktail party.” Specifically, we compared brain activation patterns when listeners “attended selectively” to only one speaker and ignored all others, versus when they “distributed their attention” and followed several concurrent speakers. Conjunction analysis revealed a highly overlapping network of regions activated for both types of attention, including auditory association cortex (bilateral STG/STS) and frontoparietal regions related to speech processing and attention (bilateral IFG/insula, right MFG, left IPS). Activity within nodes of this network, though, was modulated by the type of attention required as well as the number of competing speakers. Auditory and speech-processing regions exhibited higher activity during distributed attention, whereas frontoparietal regions were activated more strongly during selective attention. These results suggest a common “attention to speech” network, which provides the computational infrastructure to deal effectively with multi-speaker input, but with sufficient flexibility to implement different prioritization strategies and to adapt to different listener goals.
Alert system-supported lay defibrillation and basic life-support for cardiac arrest at home
Authors: Stieglis Remy , Zijlstra Jolande A , Riedijk Frank , Smeekes Martin , van der Worp Wim E , Tijssen Jan G P , Zwinderman Aeilko H , Blom Marieke T , Koster Rudolph W
Published: November 2021

Aims

Automated external defibrillators (AEDs) are placed in public, but the majority of out-of-hospital cardiac arrests (OHCA) occur at home.

Methods and results

In residential areas, 785 AEDs were placed and 5735 volunteer responders were recruited. For suspected OHCA, dispatchers activated nearby volunteer responders with text messages, directing two-thirds to an AED first and one-third directly to the patient. We analysed survival (primary outcome) and neurologically favourable survival to discharge, time to first defibrillation shock, and cardiopulmonary resuscitation (CPR) before Emergency Medical Service (EMS) arrival of patients in residences found with ventricular fibrillation (VF), before and after introduction of this text-message alert system. Survival from OHCAs in residences increased from 26% to 39% {adjusted relative risk (RR) 1.5 [95% confidence interval (CI): 1.03–2.0]}. RR for neurologically favourable survival was 1.4 (95% CI: 0.99–2.0). No CPR before ambulance arrival decreased from 22% to 9% (RR: 0.5, 95% CI: 0.3–0.7). Text-message-responders with AED administered shocks to 16% of all patients in VF in residences, while defibrillation by EMS decreased from 73% to 39% in residences (P < 0.001). Defibrillation by first responders in residences increased from 22 to 40% (P < 0.001). Use of public AEDs in residences remained unchanged (6% and 5%) (P = 0.81). Time from emergency call to defibrillation decreased from median 11.7 to 9.3 min; mean difference –2.6 (95% CI: –3.5 to –1.6).

Conclusion

Introducing volunteer responders directed to AEDs, dispatched by text-message was associated with significantly reduced time to first defibrillation, increased bystander CPR and increased overall survival for OHCA patients in residences found with VF.
Alirocumab after acute coronary syndrome in patients with a history of heart failure
Authors: White Harvey D , Schwartz Gregory G , Szarek Michael , Bhatt Deepak L , Bittner Vera A , Chiang Chern-En , Diaz Rafael , Goodman Shaun G , Jukema Johan Wouter , Loy Megan , Pagidipati Neha , Pordy Robert , Ristić Arsen D , Zeiher Andreas M , Wojdyla Daniel M , Steg Philippe Gabriel ,   for the ODYSSEY OUTCOMES Investigators
Published: November 2021

Aims

Patients with heart failure (HF) have not been shown to benefit from statins. In a post hoc analysis, we evaluated outcomes in ODYSSEY OUTCOMES in patients with vs. without a history of HF randomized to the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab or placebo.

Methods and results

Among 18 924 patients with recent acute coronary syndrome (ACS) receiving intensive or maximum-tolerated statin treatment, the primary outcome of major adverse cardiovascular events (MACE) was compared in patients with or without a history of HF. The pre-specified secondary outcome of hospitalization for HF was also analysed. Overall, 2815 (14.9%) patients had a history of HF. Alirocumab reduced low-density lipoprotein cholesterol and lipoprotein(a) similarly in patients with or without HF. Overall, alirocumab reduced MACE compared with placebo [hazard ratio (HR): 0.85; 95% confidence interval (CI): 0.78–0.93; P = 0.0001]. This effect was observed among patients without a history of HF (HR: 0.78; 95% CI: 0.70–0.86; P < 0.0001), but not in those with a history of HF (HR: 1.17; 95% CI: 0.97–1.40; P = 0.10) (P  interaction = 0.0001). Alirocumab did not reduce hospitalization for HF, overall or in patients with or without prior HF.

Conclusion

Alirocumab reduced MACE in patients without a history of HF but not in patients with a history of HF. Alirocumab did not reduce hospitalizations for HF in either group. Patients with a history of HF are a high-risk group that does not appear to benefit from PCSK9 inhibition after ACS.
Frailty and Depression in Late Life: A High-Risk Comorbidity With Distinctive Clinical Presentation and Poor Antidepressant Response
Authors: Brown Patrick J , Ciarleglio Adam , Roose Steven P , Montes Garcia Carolina , Chung Sarah , Fernandes Sara , Rutherford Bret R
Published: November 2021

Background

To investigate the longitudinal relationship between physical frailty, the clinical representation of accelerated biological aging, and antidepressant medication response in older adults with depressive illness.

Methods

An 8-week randomized placebo-controlled trial (escitalopram or duloxetine) followed by 10 months of open antidepressant medication treatment (augmentation, switch strategies) was conducted in an outpatient research clinic. 121 adults aged 60 years or older with major depressive disorder (MDD) or persistent depressive disorder and a 24-item Hamilton Rating Scale for Depression (HRSD) ≥16 were enrolled. Primary measures assessed serially over 12 months include response (50% reduction from baseline HRSD score), remission (HRSD score <10), and frailty (non/intermediate frail [0–2 deficits] vs frail [≥3 deficits]); latent class analysis was used to classify longitudinal frailty trajectories.

Results

A 2-class model best fit the data, identifying a consistently low frailty risk (63% of the sample) and consistently high frailty risk (37% of the sample) trajectory. Response and remission rates (ps ≤ .002) for adults in the high-risk frailty class were at least 21 percentage points worse than those in the low-risk class over 12 months. Furthermore, subsequent frailty was associated with previous frailty (ps ≤ .01) but not previous response or remission (ps ≥ .10).

Conclusions

Antidepressant medication is poorly effective for MDD occurring in the context of frailty in older adults. Furthermore, even when an antidepressant response is achieved, this response does little to improve their frailty. These data suggest that standard psychiatric assessment of depressed older adults should include frailty measures and that novel therapeutic strategies to address comorbid frailty and depression are needed.
Sources of anxiety among health care workers in Tehran during the COVID-19 pandemic
Authors: Daneshvar Elahe , Otterbach Steffen , Alameddine Mohamad , Safikhani Hamidreza , Sousa-Poza Alfonso
Published: November 2021

By applying multivariate regression to 2020 survey data from four Tehran hospitals, we measure eight recognized sources of Coronavirus disease 2019 (COVID-19) pandemic-related anxiety among 723 healthcare workers (HCWs) with diverse sociodemographic characteristics employed across different hospital areas and positions. The most prominent anxiety source identified is the risk of workplace COVID-19 contraction and transmission to family, followed by uncertainty about organizational support for personal and family needs in the event of worker infection. A supplemental qualitative analysis of 68 respondents in the largest hospital identifies four additional anxiety sources, namely, health, finances, workload, and leadership. This evidence of the multifaceted nature of anxiety sources among HCWs highlights the differentiated approaches that hospital policymakers must take to combat anxiety.
Barriers and facilitators affecting physical activity among adults in Saudi Arabia during COVID-19 quarantine
Authors: Alqahtani Abdulfattah S , Baattaiah Baian A , Alharbi Mutasim D , Khan Fayaz , Aldhahi Monira I
Published: November 2021

The quarantine period in Saudi Arabia from May to June 2020 due to the coronavirus disease (COVID-19) pandemic prevented many people from engaging in physical activity (PA), which may have had negative effects on their health. Therefore, it is important to understand the factors, barriers, and facilitators affecting PA of people during quarantine. This cross-sectional study was conducted using an electronic survey that was distributed to adults between 18 and 69 years old. The survey included demographic-related questions and the International Physical Activity Questionnaire-Short Form. The survey was completed by 1859 participants ranging in age from 18 to 69 years old (42.5% male, 57.5% female). The major factors influencing exercise were being male (odds ratio [OR] = 1.26; 95% confidence interval [CI] 1.03–1.53), being single (OR = 1.37; 95% CI 1.12–1.67), completing higher education at a Master/Doctorate level (OR = 1.83; 95% CI 1.23–2.72), and being resilient (OR = 1.05; 95% CI 1.03–1.08). The facilitators for doing regular exercise were having enough space at home (OR = 1.62), free time (OR = 1.77), good motivation (OR = 1.56), and being free from work (OR = 1.43) and family responsibilities (OR = 1.40). Sex, marital status, level of education and resilience were important factors affecting the type and level of PA during the quarantine period resulting from the COVID-19 pandemic.
The F-box protein, FBXO7, is required to maintain chromosome stability in humans
Authors: Palmer Michaela C L , Neudorf Nicole M , Farrell Ally C , Razi Tooba , Lichtensztejn Zelda , McManus Kirk J
Published: November 2021

Despite the high morbidity and mortality rates associated with colorectal cancer (CRC), the aberrant genes and mechanisms driving CRC pathogenesis remain poorly understood. Chromosome instability (CIN), or ongoing changes in chromosome numbers, is a predominant form of genome instability associated with ~85% of CRCs, suggesting it may be a key mechanism driving CRC oncogenesis. CIN enables the acquisition of copy number alterations conferring selective growth, proliferation and survival advantages that promote cellular transformation. Despite these associations, the aberrant genes underlying CIN remain largely unknown. Candidate CIN gene FBXO7 encodes an F-box protein, a subunit of the SKP1-CUL1-FBOX (SCF) complex that confers substrate specificity to the complex and targets proteins for subsequent degradation by the 26S proteasome. Recently, the genes encoding the three core SCF complex members were identified as CIN genes; however, it is unknown whether F-box proteins exhibit similar integral roles in maintaining chromosome stability. Using short- small interfering RNA (siRNA) and long- (CRISPR/Cas9) term approaches, we show that reduced FBXO7 expression induces CIN in various colonic epithelial cell contexts, whereas FBXO7 knockout clones also exhibit hallmarks associated with cellular transformation, namely increased clonogenic and anchorage-independent growth. Collectively, these data demonstrate that FBXO7 is required to maintain genome stability identifying FBXO7 a novel CIN gene whose reduced expression may contribute to CRC development and progression.
Hear No Evil, See No Evil: Motivated Reasoning, Drone Warfare, and the Effects of Message Framing on US Public Opinion
Authors: Rowling Charles M , Blauwkamp Joan M
Published: November 2021

We conducted a poll with a survey-experimental design to examine whether variations in how the US policy of drone warfare was framed significantly impacted public support. Consistent with scholarship on motivated reasoning and valence framing, we find that respondents could be primed to express significantly greater or lesser support based on questions that either affirmed or challenged: the strategic value, international legality, domestic legality, or technological capability of drone strikes or whether they cause collateral damage. While affirming the policy generally had insignificant effects on opinion reports, compared to the control group, challenges to the policy produced significant decreases in American support for drone warfare. These results illustrate the importance of exposing citizens to contested discourse on controversial public policy.
Growth of Local Height Functions Along Orbits of Self-Morphisms on Projective Varieties
Authors: Matsuzawa Yohsuke
Published: November 2021

We consider the limit $$ \begin{align*} & \lim_{n\to \infty} \sum_{v\in S} \lambda_{Y,v}(f^{n}(x))/h_{H}(f^{n}(x)) \end{align*}$$where $f \colon X \longrightarrow X$ is a surjective self-morphism on a smooth projective variety $X$ over a number field, $S$ is a finite set of places, $ \lambda _{Y,v}$ is a local height function associated with a proper closed subscheme $Y \subset X$, and $h_{H}$ is an ample height function on $X$. We give a geometric condition that ensures that the limit is zero, unconditionally when $\dim Y=0$ and assuming Vojta’s conjecture when $\dim Y\geq 1$. In particular, we prove (one is unconditional, one is assuming Vojta’s conjecture) dynamical Lang–Siegel type theorems, that is, the relative sizes of coordinates of orbits on ${{\mathbb {P}}}^{N}$ are asymptotically the same with trivial exceptions. These results are higher dimensional generalization of Silverman’s classical result.
Utilization of CRISPR interference to investigate the contribution of genes to pathogenesis in a macrophage model of Mycobacterium tuberculosis infection
Authors: Cheung Chen-Yi , McNeil Matthew B , Cook Gregory M
Published: November 2021

Objectives

There is an urgent need for novel drugs that target unique cellular pathways to combat infections caused by Mycobacterium tuberculosis. CRISPR interference (CRISPRi)-mediated transcriptional repression has recently been developed for use in mycobacteria as a genetic tool for identifying and validating essential genes as novel drug targets. Whilst CRISPRi has been applied to extracellular bacteria, no studies to date have determined whether CRISPRi can be used in M. tuberculosis infection models.

Methods

Using the human monocytic macrophage-like THP-1 cell line as a model for M. tuberculosis infection we investigated if CRISPRi can be activated within intracellular M. tuberculosis.

Results

The transcriptional repression of two candidate M. tuberculosis genes, i.e. mmpL3 and qcrB, leads to a reduction in viable M. tuberculosis within infected THP-1 cells. The reduction in viable colonies is dependent on both the level of CRISPRi-mediated repression and the duration of repression.

Conclusions

These results highlight the utility of CRISPRi in exploring mycobacterial gene function and essentiality under a variety of conditions pertinent to host infection.
Impact of Rapid Susceptibility Testing System on the Management of Gram-Negative Bacteremia in a Network of Community Hospitals
Authors: Ganapathiraju Ice , Weichman Brittani , Rogers Kathie L , Bushman Amanda M , Rosa Rossana
Published: November 2021

Background

Rapid initiation of optimal antimicrobial therapy is crucial for the management of Gram-negative (GN) bacteremia. We aimed to evaluate the impact of Accelerate PhenoTM (AxDx) system on change in therapy and length of stay among patients with GN bacteremia.

Methods

We conducted a retrospective cohort study of adult patients hospitalized who had at least 1 blood culture with presence of Enterobacterales. We compared clinical outcomes among patients who had their blood cultures processed through standard methods alone vs AxDx.

Results

We identified 255 bacteremia episodes among 243 unique patients. In the AxDx group, 31.1% of patients had deescalation of antibiotics within 48 h from blood culture collection compared to 20.0% of patients in the control group (P = 0.09). We found no impact of AxDx on the odds of deescalation at 48 h from blood culture collection [odds ratio (OR) 1.80 (95% CI 0.91–3.56), P = 0.09] or Gram stain report [OR 1.61 (95% CI 0.86–3.01), P = 0.14]. Escalation in therapy at 48 h from blood culture collection occurred in 16.8% and 16.9% of patients in the AxDx and control groups, respectively (P = 0.99). There was no impact on the odds of escalation at 48 h from blood culture collection [OR 0.99 (95% CI 0.47–2.11), P = 0.99] or Gram stain report [OR 1.26 (95% CI 0.57–2.80), P = 0.57]. No differences were seen in length of stay and mortality between the 2 groups.

Conclusions

The impact of rapid identification and susceptibility technologies may differ according to the setting in which they are implemented.
Virtual Reality Therapy to Control Burn Pain: Systematic Review of Randomized Controlled Trials
Authors: de Jesus Catalã Cristina Antonia , Pan Raquel , Rossetto Kron-Rodrigues Meline , de Oliveira Freitas Noélle
Published: November 2021

Virtual reality therapy has been shown to be an excellent alternative to non-pharmacological treatment for the control of burn pain. The objective was to evaluate the effects of virtual reality therapy on pain control in people who have suffered burns published in the scientific literature. Systematic review carried out as recommended by Cochrane. The search was carried out in the Embase, PubMed, Lilacs, and Cochrane Library databases, in the period from March 2021. Randomized clinical trials were included without language restriction and year of publication. The risk of bias was assessed using the Cochrane tool. Of the 3755 articles found, only 17 articles were selected for reading in full. Of these, only four articles met the inclusion criteria. The results of the studies showed that the use of virtual reality therapy reduced the intensity of pain in children and adolescents with burns, despite the fact that most results are not statistically significant. No selected study had a high risk of bias. Virtual reality therapy has been shown to be effective in controlling pain, reducing the time spent thinking about it and greater distraction during the procedures. However, most randomized clinical trials results were not statistically significant in at least one of the moments when pain was assessed. It is noteworthy that randomized clinical trials are still necessary to administer virtual reality therapy, especially in adults.
Are genome-edited micro-organisms covered by Directive 2009/41/EC?—implications of the CJEU’s judgment in the case C-528/16 for the contained use of genome-edited micro-organisms
Authors: Dederer Hans-Georg , Hamburger David
Published: November 2021

In its judgement of July 25, 2018, the Court of Justice of the European Union (CJEU) in the case C-528/16, Confédération paysanne and Others, held that organisms obtained by techniques of mutagenesis are ‘genetically modified organisms’ (GMOs). It follows from the Court’s reasoning that genome-edited organisms, ie organisms resulting from techniques of directed mutagenesis, are GMOs as well and are fully regulated by Directive 2001/18/EC. However, Directive 2001/18/EC only stipulates rules for the deliberate release and placing on the market of GMOs. By contrast, the European Union (EU) has adopted a separate set of rules laid down in Directive 2009/41/EC, which apply to the so-called ‘contained use’ of ‘genetically modified micro-organisms’ (GMMs). Whether also genome-edited micro-organisms are GMMs and, thus, subject to Directive 2009/41/EC is of crucial importance since contained use activities with genome-edited micro-organisms are currently carried out extensively, eg in laboratories and research facilities. An in-depth legal analysis shows that the CJEU’s interpretation of Directive 2001/18/EC can be extended to Directive 2009/41/EC which means that, in the end, genome-edited micro-organisms are GMMs invariably subject to Directive 2009/41/EC.
System parameters of three short-period cataclysmic variable stars
Authors: Wild J F , Littlefair S P , Ashley R P , Breedt E , Brown A J , Dhillon V S , Dyer M J , Green M J , Kerry P , Marsh T R , Parsons S G , Sahman D I
Published: November 2021

Using photometric ULTRACAM observations of three new short-period cataclysmic variables (CVs), we model the primary eclipse light curves to extract the orbital separation, masses, and radii of their component stars. We find donor masses of $0.060\pm 0.008\, {\rm M_\odot }$, $0.042\pm 0.001\, {\rm M_\odot }$, and $0.042\pm 0.004\, {\rm M_\odot }$, two being very low-mass sub-stellar donors, and one within 2σ of the hydrogen burning limit. All three of the new systems lie close to the empirical evolutionary sequence that has emerged from observations of the last decade. We briefly re-evaluate the long-standing discrepancy between observed donor mass and radius data, and theoretical CV evolutionary tracks. By looking at the difference in the observed period at each mass and the period predicted by the modelled evolutionary sequences, we qualitatively examine the form of excess angular momentum loss that is missing from the models below the period gap. We show indications that the excess angular momentum loss missing from CV models grows in importance relative to gravitational losses as the period decreases. Detailed CV evolutionary models are necessary to draw more quantitative conclusions in the future.
Ensembl Genomes 2022: an expanding genome resource for non-vertebrates
Authors: Yates Andrew D , Allen James , Amode Ridwan M , Azov Andrey G , Barba Matthieu , Becerra Andrés , Bhai Jyothish , Campbell Lahcen I , Carbajo Martinez Manuel , Chakiachvili Marc , Chougule Kapeel , Christensen Mikkel , Contreras-Moreira Bruno , Cuzick Alayne , Da Rin Fioretto Luca , Davis Paul , De Silva Nishadi H , Diamantakis Stavros , Dyer Sarah , Elser Justin , Filippi Carla V , Gall Astrid , Grigoriadis Dionysios , Guijarro-Clarke Cristina , Gupta Parul , Hammond-Kosack Kim E , Howe Kevin L , Jaiswal Pankaj , Kaikala Vinay , Kumar Vivek , Kumari Sunita , Langridge Nick , Le Tuan , Luypaert Manuel , Maslen Gareth L , Maurel Thomas , Moore Benjamin , Muffato Matthieu , Mushtaq Aleena , Naamati Guy , Naithani Sushma , Olson Andrew , Parker Anne , Paulini Michael , Pedro Helder , Perry Emily , Preece Justin , Quinton-Tulloch Mark , Rodgers Faye , Rosello Marc , Ruffier Magali , Seager James , Sitnik Vasily , Szpak Michal , Tate John , Tello-Ruiz Marcela K , Trevanion Stephen J , Urban Martin , Ware Doreen , Wei Sharon , Williams Gary , Winterbottom Andrea , Zarowiecki Magdalena , Finn Robert D , Flicek Paul
Published: November 2021

Ensembl Genomes (https://www.ensemblgenomes.org) provides access to non-vertebrate genomes and analysis complementing vertebrate resources developed by the Ensembl project (https://www.ensembl.org). The two resources collectively present genome annotation through a consistent set of interfaces spanning the tree of life presenting genome sequence, annotation, variation, transcriptomic data and comparative analysis. Here, we present our largest increase in plant, metazoan and fungal genomes since the project's inception creating one of the world's most comprehensive genomic resources and describe our efforts to reduce genome redundancy in our Bacteria portal. We detail our new efforts in gene annotation, our emerging support for pangenome analysis, our efforts to accelerate data dissemination through the Ensembl Rapid Release resource and our new AlphaFold visualization. Finally, we present details of our future plans including updates on our integration with Ensembl, and how we plan to improve our support for the microbial research community. Software and data are made available without restriction via our website, online tools platform and programmatic interfaces (available under an Apache 2.0 license). Data updates are synchronised with Ensembl's release cycle.
Sensory neuron transcriptomes reveal complex neuron-specific function and regulation of mec-2/Stomatin splicing
Authors: Liang Xiaoyu , Calovich-Benne Canyon , Norris Adam
Published: November 2021

The function and identity of a cell is shaped by transcription factors controlling transcriptional networks, and further shaped by RNA binding proteins controlling post-transcriptional networks. To overcome limitations inherent to analysis of sparse single-cell post-transcriptional data, we leverage the invariant Caenorhabditis elegans cell lineage, isolating thousands of identical neuron types from thousands of isogenic individuals. The resulting deep transcriptomes facilitate splicing network analysis due to increased sequencing depth and uniformity. We focus on mechanosensory touch-neuron splicing regulated by MEC-8/RBPMS. We identify a small MEC-8-regulated network, where MEC-8 establishes touch-neuron isoforms differing from default isoforms found in other cells. MEC-8 establishes the canonical long mec-2/Stomatin isoform in touch neurons, but surprisingly the non-canonical short isoform predominates in other neurons, including olfactory neurons, and mec-2 is required for olfaction. Forced endogenous isoform-specific expression reveals that the short isoform functions in olfaction but not mechanosensation. The long isoform is functional in both processes. Remarkably, restoring the long isoform completely rescues mec-8 mutant mechanosensation, indicating a single MEC-8 touch-neuron target is phenotypically relevant. Within the long isoform we identify a cassette exon further diversifying mec-2 into long/extra-long isoforms. Neither is sufficient for mechanosensation. Both are simultaneously required, likely functioning as heteromers to mediate mechanosensation.
DNA methylation variation along the cancer epigenome and the identification of novel epigenetic driver events
Authors: Heery Richard , Schaefer Martin H
Published: November 2021

While large-scale studies applying various statistical approaches have identified hundreds of mutated driver genes across various cancer types, the contribution of epigenetic changes to cancer remains more enigmatic. This is partly due to the fact that certain regions of the cancer genome, due to their genomic and epigenomic properties, are more prone to dysregulated DNA methylation than others. Thus, it has been difficult to distinguish which promoter methylation changes are really driving carcinogenesis from those that are mostly just a reflection of their genomic location. By developing a novel method that corrects for epigenetic covariates, we reveal a small, concise set of potential epigenetic driver events. Interestingly, those changes suggest different modes of epigenetic carcinogenesis: first, we observe recurrent inactivation of known cancer genes across tumour types suggesting a higher convergence on common tumour suppressor pathways than previously anticipated. Second, in prostate cancer, a cancer type with few recurrently mutated genes, we demonstrate how the epigenome primes tumours towards higher tolerance of other aberrations.
Management of obesity in kidney transplant candidates and recipients: A clinical practice guideline by the DESCARTES Working Group of ERA
Authors: Oniscu Gabriel C , Abramowicz Daniel , Bolignano Davide , Gandolfini Ilaria , Hellemans Rachel , Maggiore Umberto , Nistor Ionut , O'Neill Stephen , Sever Mehmet Sukru , Koobasi Muguet , Nagler Evi V
Published: November 2021

The clinical practice guideline Management of Obesity in Kidney Transplant Candidates and Recipients was developed to guide decision-making in caring for people with end-stage kidney disease (ESKD) living with obesity. The document considers the challenges in defining obesity, weighs interventions for treating obesity in kidney transplant candidates as well as recipients and reflects on the impact of obesity on the likelihood of wait-listing as well as its effect on transplant outcomes. It was designed to inform management decisions related to this topic and provide the backdrop for shared decision-making. This guideline was developed by the European Renal Association’s Developing Education Science and Care for Renal Transplantation in European States working group. The group was supplemented with selected methodologists to supervise the project and provide methodological expertise in guideline development throughout the process. The guideline targets any healthcare professional treating or caring for people with ESKD being considered for kidney transplantation or having received a donor kidney. This includes nephrologists, transplant physicians, transplant surgeons, general practitioners, dialysis and transplant nurses. Development of this guideline followed an explicit process of evidence review. Treatment approaches and guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence and the strength of recommendations followed the Grading of Recommendations Assessment, Development and Evaluation approach. Limitations of the evidence are discussed and areas of future research are presented.
Infectious Disease Images: A Remarkable, Free Resource
Authors: Radcliffe Christopher , Grant Matthew
Published: November 2021

Infectious Disease Images (idimages.org) features several hundred with a vast array of diagnoses. The website is organized by cases and images and boasts an atlas with scores of bacteria, viruses, fungi, parasites, and ectoparasites. As a free resource, Infectious Disease Images lends itself nicely to both learners and educators at all levels.
Can we harness digital technologies and physiology to hasten genetic gain in US maize breeding?
Authors: Diepenbrock Christine H , Tang Tom , Jines Michael , Technow Frank , Lira Sara , Podlich Dean , Cooper Mark , Messina Carlos
Published: November 2021

Plant physiology can offer invaluable insights to accelerate genetic gain. However, translating physiological understanding into breeding decisions has been an ongoing and complex endeavor. Here we demonstrate an approach to leverage physiology and genomics to hasten crop improvement. A half-diallel maize (Zea mays) experiment resulting from crossing 9 elite inbreds was conducted at 17 locations in the USA corn belt and 6 locations at managed stress environments between 2017 and 2019 covering a range of water environments from 377 to 760 mm of evapotranspiration and family mean yields from 542 to 1,874 g m−2. Results from analyses of 35 families and 2,367 hybrids using crop growth models linked to whole-genome prediction (CGM–WGP) demonstrated that CGM–WGP offered a predictive accuracy advantage compared to BayesA for untested genotypes evaluated in untested environments (r = 0.43 versus r = 0.27). In contrast to WGP, CGMs can deal effectively with time-dependent interactions between a physiological process and the environment. To facilitate the selection/identification of traits for modeling yield, an algorithmic approach was introduced. The method was able to identify 4 out of 12 candidate traits known to explain yield variation in maize. The estimation of allelic and physiological values for each genotype using the CGM created in silico phenotypes (e.g. root elongation) and physiological hypotheses that could be tested within the breeding program in an iterative manner. Overall, the approach and results suggest a promising future to fully harness digital technologies, gap analysis, and physiological knowledge to hasten genetic gain by improving predictive skill and definition of breeding goals.
Reinforcement of CHH methylation through RNA-directed DNA methylation ensures sexual reproduction in rice
Authors: Wang Lili , Zheng Kezhi , Zeng Longjun , Xu Dachao , Zhu Tianxin , Yin Yumeng , Zhan Huadong , Wu Yufeng , Yang Dong-Lei
Published: November 2021

DNA methylation is an important epigenetic mark that regulates the expression of genes and transposons. RNA-directed DNA methylation (RdDM) is the main molecular pathway responsible for de novo DNA methylation in plants. Although the mechanism of RdDM has been well studied in Arabidopsis (Arabidopsis thaliana), most mutations in RdDM genes cause no remarkable developmental defects in Arabidopsis. Here, we isolated and cloned Five Elements Mountain 1 (FEM1), which encodes RNA-dependent RNA polymerase 2 (OsRDR2) in rice (Oryza sativa). Mutation in OsRDR2 abolished the accumulation of 24-nt small interfering RNAs, and consequently substantially decreased genome-wide CHH (H = A, C, or T) methylation. Moreover, male and female reproductive development was disturbed, which led to sterility in osrdr2 mutants. We discovered that OsRDR2-dependent DNA methylation may regulate the expression of multiple key genes involved in stamen development, meiosis, and pollen viability. In wild-type (WT) plants but not in osrdr2 mutants, genome-wide CHH methylation levels were greater in panicles, stamens, and pistils than in seedlings. The global increase of CHH methylation in reproductive organs of the WT was mainly explained by the enhancement of RdDM activity, which includes OsRDR2 activity. Our results, which revealed a global increase in CHH methylation through enhancement of RdDM activity in reproductive organs, suggest a crucial role for OsRDR2 in the sexual reproduction of rice.
F-box protein EBF1 and transcription factor ABI5-like regulate banana fruit chilling-induced ripening disorder
Authors: Song Zunyang , Lai Xiuhua , Yao Yulin , Qin Jiajia , Ding Xiaochun , Zheng Qiuli , Pang Xuequn , Chen Weixin , Li Xueping , Zhu Xiaoyang
Published: November 2021

Cold stress adversely affects plant production, both qualitatively and quantitatively. Banana (Musa acuminata) is sensitive to cold stress and suffers chilling injury (CI) when stored under 11°C, causing abnormal fruit softening. However, the mechanism underlying the abnormal fruit softening due to CI remains obscure. This study uncovered the coordinated transcriptional mechanism of ethylene F-box (EBF1) protein and abscisic acid-insensitive 5 (ABI5)-like protein in regulating chilling-induced softening disorders of Fenjiao banana. Cold stress severely inhibited the transcript and protein levels of EBF1, ABI5-like, and fruit softening-related genes. The ABI5-like protein bound to the promoters of key starch and cell wall degradation-related genes such as β-amylase 8 (BAM8), pectate lyase 8 (PL8), and β-D-xylosidase23-like (XYL23-like) and activated their activities. EBF1 physically interacted with ABI5-like and enhanced the transcriptional activity of the key starch and cell wall degradation-related genes but did not ubiquitinate or degrade ABI5-like protein. This promoted fruit ripening and ameliorated fruit CI in a manner similar to the effect of exogenous abscisic acid treatment. The ectopic and transient overexpression of EBF1 and ABI5-like genes in tomato (Solanum lycopersicum) and Fenjiao banana accelerated fruit ripening and softening by promoting ethylene production, starch and cell wall degradation, and decreasing fruit firmness. EBF1 interacted with EIL4 but did not ubiquitinate or degrade EIL4, which is inconsistent with the typical role of EBF1/2 in Arabidopsis (Arabidopsis thaliana). These results collectively highlight that the interaction of EBF1 and ABI5-like controls starch and cell wall metabolism in banana, which is strongly inhibited by chilling stress, leading to fruit softening and ripening disorder.
An in situ sequencing approach maps PLASTOCHRON1 at the boundary between indeterminate and determinate cells
Authors: Laureyns Reinout , Joossens Jessica , Herwegh Denia , Pevernagie Julie , Pavie Benjamin , Demuynck Kirin , Debray Kevin , Coussens Griet , Pauwels Laurens , Van Hautegem Tom , Bontinck Michiel , Strable Josh , Nelissen Hilde
Published: November 2021

The plant shoot apex houses the shoot apical meristem, a highly organized and active stem-cell tissue where molecular signaling in discrete cells determines when and where leaves are initiated. We optimized a spatial transcriptomics approach, in situ sequencing (ISS), to colocalize the transcripts of 90 genes simultaneously on the same section of tissue from the maize (Zea mays) shoot apex. The RNA ISS technology reported expression profiles that were highly comparable with those obtained by in situ hybridizations (ISHs) and allowed the discrimination between tissue domains. Furthermore, the application of spatial transcriptomics to the shoot apex, which inherently comprised phytomers that are in gradual developmental stages, provided a spatiotemporal sequence of transcriptional events. We illustrate the power of the technology through PLASTOCHRON1 (PLA1), which was specifically expressed at the boundary between indeterminate and determinate cells and partially overlapped with ROUGH SHEATH1 and OUTER CELL LAYER4 transcripts. Also, in the inflorescence, PLA1 transcripts localized in cells subtending the lateral primordia or bordering the newly established meristematic region, suggesting a more general role of PLA1 in signaling between indeterminate and determinate cells during the formation of lateral organs. Spatial transcriptomics builds on RNA ISH, which assays relatively few transcripts at a time and provides a powerful complement to single-cell transcriptomics that inherently removes cells from their native spatial context. Further improvements in resolution and sensitivity will greatly advance research in plant developmental biology.
The a Priori Truth of Modal Rationalism
Authors: Cleeveley Harry
Published: November 2021

Modal rationalism is the claim that for any proposition p, if it is ideally conceivable that p, then there is a metaphysically possible world, W, in which p is true. If true, modal rationalism must itself be an a priori truth. Moreover, modal rationalism is true just if there are no strong a posteriori necessities. But are there any strong necessities? In this paper, I set out a transcendental argument to show that there cannot be any, because they are not genuinely conceivable. I argue that if it were ideally conceivable that there are strong necessities, then it would be impossible for us to have any modal knowledge of the world. Given that we do have some modal knowledge of the world, it follows that strong necessities are not ideally conceivable and therefore that modal rationalism itself is an a priori truth.
Measurement and Mitigation of Intracochlear Pressure Transients During Cochlear Implant Electrode Insertion
Authors: Banakis Hartl Renee M. , Greene Nathaniel T.
Published: November 2021

Hypothesis:

High intracochlear pressure transients associated with cochlear implant placement are reduced with smaller, non-styleted arrays, and longer insertion durations.

Background:

With increasing focus on hearing preservation during cochlear implant surgery, atraumatic technique is of the utmost importance. Previous studies revealed that high intensity pressure transients can be generated during the insertion of implant electrodes. Resulting acoustic trauma may be one contributing factor to postoperative loss of residual hearing.

Methods:

Thirty ears in cadaveric specimens were surgically prepared with placement of intracochlear pressure sensors. Sequential implant insertions were made over 10, 30, or 60 seconds using seven randomly ordered electrode styles. Pressures were also measured during common post-insertion electrode manipulations and removal. Measurements were compared between electrode styles and characteristics using analysis of variance (ANOVA) and Pearson correlation.

Results:

Implant insertion and post-insertion manipulations produced high-intensity pressure transients with all electrodes tested, with some measurements exceeding 170 dB peak SPL. Average peak pressures were significantly lower for straight, non-stylet electrodes (p << 0.001). The likelihood of generating transients was lowest with the slowest insertions (p << 0.001).

Conclusions:

Cochlear implant insertion can generate transients in intralabyrinthine pressure levels equivalent to high intensity, impulsive acoustic stimuli known to cause hearing loss. Although transients were observed in all conditions, exposure may be mitigated by using non-styleted electrodes and slow insertion speeds. Additional surgical manipulations can also produce similar high-pressure events. Results from this investigation suggest that use of non-styleted electrodes, slow but steady insertion speeds, and avoidance of post-insertional manipulations are important to reduce cochlear trauma.
Resorbable Synthetic Ventral Hernia Repair in Contaminated Fields: Outcomes with Poly-4-Hydroxybutyrate Mesh
Authors: Christopher Adrienne N. , Morris Martin P. , Jia Hanna , Broach Robyn , Fischer John P.
Published: November 2021

Background:

Hernia repair in the setting of contamination poses unique challenges, including complications such as recurrence and mesh infection. The ideal contaminated hernia repair including type of mesh use remains controversial. Poly-4-hydroxybutyrate is a biosynthetic scaffold for soft-tissue reinforcement and hernia repair and is potentially useful in contaminated hernia repair. The authors aim to describe postoperative outcomes, recurrence, and patient-reported outcomes after contaminated hernia repair with poly-4-hydroxybutyrate.

Methods:

Adult patients (≥18 years) undergoing a contaminated hernia repair with poly-4-hydroxybutyrate (Phasix) performed by a single plastic surgeon between January of 2015 and May of 2020 were identified. Patients with a ventral hernia defect and a Centers for Disease Control and Prevention wound class of II, III, or IV were included. Primary outcomes included recurrence, surgical-site infection, surgical-site occurrences, and surgical-site infection/occurrences requiring procedural interventions. As a secondary outcome, the authors assessed patient-reported outcomes as defined by the Abdominal Hernia-Q and Hernia-Related Quality of Life Survey.

Results:

Sixty patients were included with a median age of 52.5 and body mass index of 31 kg/m2. Median defect size was 300 cm2. Twenty-eight patients (46.7 percent) experienced a complication. The most common complications were surgical-site occurrence [n = 20 (33.3 percent)] and surgical-site infection [n = 10 (16.7 percent)]. Median follow-up was 24.2 months, with a recurrence rate of 8.3 percent (n = 4). Overall patient-reported outcomes improved postoperatively, and improvement was not affected by the presence of a complication.

Conclusions:

Poly-4-hydroxybutyrate use in contaminated hernia repair shows promising results with an acceptable safety profile. Although complications are frequent in this complex cohort, patient-reported outcomes improvement was significant even in patients with complications.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
An Update on the Diagnosis, Treatment, and Management of Occipital Neuralgia
Authors: Swanson Daniel , Guedry Ryan , Boudreaux Megan , Muhlenhaupt Emily , Kaye Alan D. , Viswanath Omar , Urits Ivan
Published: November 2021

This report intends to summarize the underlying pathophysiology, relevant symptoms, appropriate diagnostic workup, necessary imaging, and medical and surgical treatments of occipital neuralgia (ON). This was done through a comprehensive literature review of peer-reviewed literature throughout the most relevant databases. The current understanding of ON is that it causes neuropathic pain in the distribution of the greater occipital nerve, the lesser occipital nerve, the third occipital nerve or a combination of the 3. It is currently a subset of headaches although there is some debate if ON should be its own condition. Occipital neuralgia causes chronic, sharp, stabbing pain in the upper neck, back of the head, and behind the ears that can radiate to the front of the head. Diagnosis is typically clinical and patients present with intermittent, painful episodes associated with the occipital region and the nerves described above. Most cases are unilateral pain, however bilateral pain can be present and the pain can radiate to the frontal region and face. Physical examination is the first step in management of this disease and patients may demonstrate tenderness over the greater occipital and lesser occipital nerves. Anesthetics like 1% to 2% lidocaine or 0.25% to 0.5% bupivacaine can be used to block these nerves and antiinflammatory drugs like corticosteroids can be used in combination to prevent compressive symptoms. Other treatments like botulinum toxin and radiofrequency ablation have shown promise and require more research. Surgical decompression through resection of the obliquus capitis inferior is the definitive treatment however there are significant risks associated with this procedure.
Shock-Induced Endothelial Dysfunction is Present in Patients With Occult Hypoperfusion After Trauma
Authors: Kregel Heather R. , Hatton Gabrielle E. , Isbell Kayla D. , Henriksen Hanne H. , Stensballe Jakob , Johansson Per I. , Kao Lillian S. , Wade Charles E.
Published: November 2021

Background:

Shock-induced endothelial dysfunction, evidenced by elevated soluble thrombomodulin (sTM) and syndecan-1 (Syn-1), is associated with poor outcomes after trauma. The association of endothelial dysfunction and overt shock has been demonstrated; it is unknown if hypoperfusion in the setting of normal vital signs (occult hypoperfusion [OH]) is associated with endothelial dysfunction. We hypothesized that sTM and Syn-1 would be elevated in patients with OH when compared to patients with normal perfusion.

Methods:

A single-center study of patients requiring highest-level trauma activation (2012–2016) was performed. Trauma bay arrival plasma Syn-1 and sTM were measured by enzyme-linked immunosorbent assay. Shock was defined as systolic blood pressure (SBP) <90 mm Hg or heart rate (HR) ≥120 bpm. OH was defined as SBP ≥ 90, HR < 120, and base excess (BE) ≤−3. Normal perfusion was assigned to all others. Univariate and multivariable analyses were performed.

Results:

Of 520 patients, 35% presented with OH and 26% with shock. Demographics were similar between groups. Patients with normal perfusion had the lowest Syn-1 and sTM, while patients with OH and shock had elevated levels. OH was associated with increased sTM by 0.97 ng/mL (95% CI 0.39–1.57, p = 0.001) and Syn-1 by 14.3 ng/mL (95% CI −1.5 to 30.2, p = 0.08). Furthermore, shock was associated with increased sTM by 0.64 (95% CI 0.02–1.30, p = 0.04) and with increased Syn-1 by 23.6 ng/mL (95% CI 6.2–41.1, p = 0.008).

Conclusions:

Arrival OH was associated with elevated sTM and Syn-1, indicating endothelial dysfunction. Treatments aiming to stabilize the endothelium may be beneficial for injured patients with evidence of hypoperfusion, regardless of vital signs.