bluuebunny/crossref_metadata_2025_split huggingface dataset:
The anchor point algorithm: A morphometric analysis of anatomic landmarks to guide placement of temporary aortic Rescue stent grafts for noncompressible torso hemorrhage
Authors: Go Catherine , Fish Larry , Chun Youngjae , Alarcon Louis , Tillman Bryan W. 
Published: January 2022

BACKGROUND
Noncompressible hemorrhage remains a high-mortality injury, which requires rapid damage control within minutes to avoid exsanguination. Retrievable stent grafts offer perfusion preserving hemorrhage damage control, and yet algorithms for device selection and positioning are lacking for an anatomically diverse human population. We hypothesized that easily acquired external measurements could be used to rapidly triage patients to receive one of several presized stents and that these metrics may further predict a single target on the aorta by which to optimize both mesenteric perfusion and aortic hemorrhage control.

METHODS
Metrics were acquired from computed tomography imaging of 203 male and female patients aged 18 to 50 years. Algorithms for metric based triage and stent sizing were examined against the cohort for effectiveness. Linear regression was used to predict a single target on the aorta for alignment of a multitiered stent. Next, the relationship of the anchor point to the palpable xiphoid was determined.

RESULTS
Clavicle to pubis measurements correlated with aortic length and was used to triage patients to one of three stent grafts. Stents for each triage group were sized to achieve >75% coverage of aortic Zones 1 and 3 in most patients while preserving carotid and visceral perfusion. A metric/sex-based equation that predicts the location of the superior mesenteric artery relative to the palpable xiphoid was derived. By alignment of a single point on the stent with this target, known as the anchor point, the remainder of the stent can be rapidly deployed while minimizing coverage of critical branches. When applied back to the cohort, only 10.4% had potential serious branch coverage events predicted.

CONCLUSION
Simple anatomic metrics offer rapid triage in this study population to one of three presized stent grafts and predict the location of key vascular branches. Confirmatory human trials will be essential to demonstrate safety and effectiveness of this approach.

LEVEL OF EVIDENCE
Prognostic/Epidemiological; Level IV.
It is time to look in the mirror: Individual surgeon outcomes after emergent trauma laparotomy
Authors: Hu Parker , Jansen Jan O. , Uhlich Rindi , Hashmi Zain G. , Gelbard Rondi B. , Kerby Jeffrey , Cox Daniel , Holcomb John B. 
Published: January 2022

BACKGROUND
Multiple quality indicators are used by trauma programs to decrease variation and improve outcomes. However, little if any provider level outcomes related to surgical procedures are reviewed. Emergent trauma laparotomy (ETL) is arguably the signature case that trauma surgeons perform on a regular basis, but few data exist to facilitate benchmarking of individual surgeon outcomes. As part of our comprehensive performance improvement program, we examined outcomes by surgeon for those who routinely perform ETL.

METHODS
A retrospective cohort study of patients undergoing ETL directly from the trauma bay by trauma faculty from December 2019 to February 2021 was conducted. Patients were excluded from mortality analysis if they required resuscitative thoracotomy for arrest before ETL. Surgeons were compared by rates of damage control and mortality at multiple time points.

RESULTS
There were 242 ETL (7–32 ETLs per surgeon) performed by 14 faculties. Resuscitative thoracotomy was performed in 7.0% (n = 17) before ETL. Six patients without resuscitative thoracotomy died intraoperatively and damage-control laparotomy was performed on 31.9% (n = 72 of 226 patients). Mortality was 4.0% (n = 9) at 24 hours and 7.1% (n = 16) overall. Median Injury Severity Score (p = 0.21), new injury severity score (p = 0.21), and time in emergency department were similar overall among surgeons (p = 0.15), while operative time varied significantly (40–469 minutes; p = 0.005). There were significant differences between rates of individual surgeon's mortality (range [hospital mortality], 0–25%) and damage-control laparotomy (range, 14–63%) in ETL.

CONCLUSION
Significant differences exist in outcomes by surgeon after ETL. Benchmarking surgeon level performance is a necessary natural progression of quality assurance programs for individual trauma centers. Additional data from multiple centers will be vital to allow for development of more granular quality metrics to foster introspective case review and quality improvement.

LEVEL OF EVIDENCE
Therapeutic/care management, level III.
Intensive physical therapy after emergency laparotomy: Pilot phase of the Incidence of Complications following Emergency Abdominal surgery Get Exercising randomized controlled trial
Authors: Boden Ianthe , Sullivan Kate , Hackett Claire , Winzer Brooke , Hwang Rita , Story David , Denehy Linda 
Published: January 2022

BACKGROUND
Postoperative pneumonia and delayed physical recovery are significant problems after emergency laparotomy. No randomized controlled trial has assessed the feasibility, safety, or effectiveness of intensive postoperative physical therapy in this high-risk acute population.

METHODS
The internal pilot phase of the Incidence of Complications after Emergency Abdominal Surgery: Get Exercising (ICEAGE) trial was a prospective, randomized controlled trial that evaluated the feasibility, safety, and clinical trial processes of providing intensive physical therapy immediately following emergency laparotomy. Fifty consecutive patients were recruited at the principal participating hospital and randomly assigned to standard-care or intensive physical therapy of twice daily coached breathing exercises for 2 days and 30 minutes of daily supervised rehabilitation over the first 5 postoperative days.

RESULTS
Interventions were provided exactly as per protocol in 35% (78 of 221 patients) of planned treatment sessions. Main barriers to protocol delivery were physical therapist unavailability on weekends (59 of 221 patients [27%]), awaiting patient consent (18 of 99 patients [18%]), and patient fatigue (26 of 221 patients [12%]). Despite inhibitors to treatment delivery, the intervention group still received twice as many breathing exercise sessions and four times the amount of physical therapy over the first 5 postoperative days (23 minutes [interquartile range, 12–29 minutes] vs. 86 minutes [interquartile range, 53–121 minutes]; p < 0.001). One adverse event was reported from 78 rehabilitation sessions (1.3%), which resolved fully on cessation of activity without escalation of medical care.

CONCLUSION
Intensive postoperative physical therapy can be delivered safely and successfully to patients in the first week after emergency laparotomy. The ICEAGE trial protocol resulted in intervention group participants receiving more coached breathing exercises and spending significantly more time physically active over the first 5 days after surgery compared with standard care. It was therefore recommended to progress into the multicenter phase of ICEAGE to definitively test the effect of intensive physical therapy to prevent pneumonia and improve physical recovery after emergency laparotomy.

LEVEL OF EVIDENCE
Therapeutic/Care Management; Level II.
A new nitronyl nitroxide radical with salicylic acid framework attenuates blood–brain barrier disruption and oxidative stress in a rat model of middle cerebral artery occlusion
Authors: Chen Lei , Ma Shanbo , Shi Min , Wang Qiaofeng , Miao Yi 
Published: January 2022

Objectives
A new nitronyl nitroxide radical with a salicylic acid framework (SANR) has been demonstrated to exert antioxidant effects in the previous study by our team. The current study has assessed the protective effect of SANR on cerebral ischemia and reperfusion (I/R) in rat models.

Methods
Sprague–Dawley rats were randomly divided into four groups: sham, I/R, 10, and 20 mg/kg SANR + I/R groups. A total of 120 min of middle cerebral artery occlusion (MCAO) caused cerebral ischemia. Survival rates were calculated, and neurological deficits were evaluated by a blinded experimenter. Cerebral infarct area, apoptosis cells, and blood–brain barrier (BBB) leakage were measured by 2,3,5-triphenyltetrazolium chloride staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and Evans blue assay, respectively. Reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and 8-hydroxy-2-deoxyguanosine (8-OHdG) also were detected to assess oxidation damage caused by cerebral I/R.

Results
Treatment with SANR significantly promoted survival of rats with cerebral I/R injury. SANR meliorated neurologic deficit and infarct area, improved BBB permeability, and reduced neuronal apoptosis. SANR also reduced ROS levels and the content of MDA and increased SOD and GSH-Px activity in a dose-dependent manner. Furthermore, SANR could inhibit the expression of 8-OHdG.

Conclusion
Our results suggested that SANR has a neuroprotective effect against cerebral I/R injury, and its effect mechanism is related to the antioxidant function.
Drug Contraindications in Comorbid Diseases: a Protein Interactome Perspective
Authors: Karunakaran Kalyani B. , Ganapathiraju Madhavi K. , Jain Sanjeev , Brahmachari Samir K. , Balakrishnan N. 
Published: January 2022

AbstractAdverse drug reactions (ADRs) are leading causes of death and drug withdrawals and frequently cooccur with comorbidities. However, systematic studies on the effects of drugs in comorbidities are lacking. Drug interactions with the cellular protein-protein interaction (PPI) network give rise to ADRs. We selected 6 comorbid disease pairs, identified the drugs used in the treatment of the individual diseases ‘A’ and ‘B’– 44 drugs in anxiety and depression, 128 in asthma and hypertension, 48 in chronic obstructive pulmonary disease and heart failure, 58 in type 2 diabetes and obesity, 58 in Parkinson’s disease and schizophrenia, and 84 in rheumatoid arthritis and osteoporosis – and categorized them based on whether they aggravate the comorbid condition. We constructed drug target networks (DTNs) and examined their enrichment among genes in disease A/B PPI networks, expressed across 53 tissues and involved in ~1000 pathways. To pinpoint the biological features characterizing the DTNs, we performed principal component analysis and computed the Euclidean distance between DTN component scores and feature loading values. DTNs of disease A drugs not contraindicated in B were affiliated with proteins common to A/B networks or uniquely found in the B network, similarly regulated common pathways, and disease-B specific pathways and tissues. DTNs of disease A drugs contraindicated in B were affiliated with common proteins or those uniquely found in the A network, differentially regulated common pathways, and disease A-specific pathways and tissues. Hence, DTN enrichment in pathways, tissues, and PPI networks of comorbid diseases will help identify drugs contraindications in comorbidities.
Structure-Based Survey of the Human Proteome for Opportunities in Proximity Pharmacology
Authors: Rovers Evianne , Schapira Matthieu 
Published: January 2022

ABSTRACTProximity pharmacology (ProxPharm) is a novel paradigm in drug discovery where a small molecule brings two proteins in close proximity to elicit a signal, generally from one protein onto another. The potential of ProxPharm compounds as a new therapeutic modality is firmly established by proteolysis targeting chimeras (PROTACs) that bring an E3 ubiquitin ligase in proximity to a target protein to induce ubiquitination and subsequent degradation of the target protein. The concept can be expanded to induce other post-translational modifications via the recruitment of different types of protein-modifying enzymes. To survey the human proteome for opportunities in proximity pharmacology, we systematically mapped non-catalytic drug binding pockets on the structure of protein-modifying enzymes available from the Protein Databank. In addition to binding sites exploited by previously reported ProxPharm compounds, we identified putative ligandable non-catalytic pockets in 188 kinases, 42 phosphatases, 26 deubiquitinases, 9 methyltransferases, 7 acetyltransferases, 7 glycosyltransferases, 4 deacetylases, 3 demethylases and 2 glycosidases, including cavities occupied by chemical matter that may serve as starting points for future ProxPharm compounds. This systematic survey confirms that proximity pharmacology is a versatile modality with largely unexplored and promising potential, and reveals novel opportunities to pharmacologically rewire molecular circuitries.
Transcranial alternating current stimulation does not modulate corticospinal activity in humans
Authors: Ibáñez J. , Zicher B. , Brown K. , Rocchi L. , Casolo A. , Del Vecchio A. , Spampinato D. , Vollette C-A. , Rothwell J. C. , Baker S. N. , Farina D. 
Published: January 2022

ABSTRACTTranscranial alternating current stimulation (TACS) is commonly used to synchronise the output of a cortical area to other parts of the nervous system, but evidence for this based on brain recordings in humans is challenging. The brain transmits beta oscillations (~21Hz) to tonically contracted limb muscles linearly and through the fastest corticospinal pathways. Therefore, muscle activity may be used as a proxy measure for the level of beta entrainment in the corticospinal tract due to TACS over motor cortex. Here, we assessed if TACS is able to modulate the neural inputs to muscles, which would provide an indirect evidence for TACS-driven neural entrainment. In the first part of this study, we ran a series of simulations of motor neuron (MN) pools receiving inputs from corticospinal neurons with different levels of beta entrainment. Results indicated that MNs should be highly sensitive to changes in corticospinal beta activity. Then, we ran experiments on healthy human subjects (N=10) in which TACS (at 1mA) was delivered over the motor cortex at 21Hz (beta stimulation), or at 7Hz or 40Hz (control conditions) while the abductor digiti minimi (ADM) or the tibialis anterior muscle (TA) were tonically contracted. Muscle activity was measured using high-density electromyography, which allowed us to decompose the spiking activity of pools of motor units innervating the studied muscles. By analysing motor unit pool activity, we observed that none of the tested TACS conditions could consistently alter the spectral characteristics of the common neural inputs received by the muscles. These results suggest that 1mA-TACS over motor cortex given at frequencies in the beta band does not affect corticospinal beta entrainment.Highlights-TACS is commonly used to entrain the communication between brain regions-It is challenging to find direct evidence supporting TACS-driven neural entrainment-Simulations show that motor neurons are sensitive to corticospinal beta entrainment-Motor unit activity from human muscles does not support TACS-driven entrainment
Transverse and axial resolution of femtosecond laser ablation
Authors: Wang Yao L. , Grooms Noa W. F. , Chung Samuel H. 
Published: January 2022

AbstractFemtosecond lasers are capable of precise ablation that produce surgical dissections in vivo. The transverse and axial resolution of the laser damage inside the bulk are important parameters of ablation. The transverse resolution is routinely quantified, but the axial resolution is more difficult to measure and is less commonly performed. In some in vivo samples, fine dissections can also be difficult to visualize, but in vitro samples may allow clear imaging. Using a 1040-nm, 400-fs pulsed laser, we performed ablation inside agarose and glass, producing clear and persistent damage spots. Near the ablation threshold of both media, we found that the axial resolution is similar to the transverse resolution. We also ablated neuron cell bodies and fibers in C. elegans and demonstrate submicrometer resolution in both the transverse and axial directions, consistent with our results in agarose and glass. Using simple yet rigorous methods, we define the resolution of laser ablation in transparent media along all directions.
Caenorhabditisnematodes colonize ephemeral resource patches in neotropical forests
Authors: Sloat Solomon A. , Noble Luke M. , Paaby Annalise B. , Bernstein Max , Chang Audrey , Kaur Taniya , Yuen John , Tintori Sophia C. , Jackson Jacqueline L. , Martel Arielle , Salome Correa Jose A. , Stevens Lewis , Blaxter Mark , Rockman Matthew V. 
Published: January 2022

ABSTRACTFactors shaping the distribution and abundance of species include life-history traits, population structure, and stochastic colonization-extinction dynamics. Field studies of model species groups help reveal the roles of these factors. Species ofCaenorhabditisnematodes are highly divergent at the sequence level but exhibit highly conserved morphological uniformity, and many of these species live in sympatry on microbe-rich patches of rotten material. Here, we use field experiments and large-scale opportunistic collections to investigate species composition, abundance, and colonization efficiency ofCaenorhabditisin two of the world’s best studied lowland tropical field sites: Barro Colorado Island in Panamá and La Selva in Sarapiquí, Costa Rica. We observed seven species ofCaenorhabditis, four of them known only from these collections. While these localities contain species from many parts of the phylogeny, both localities were dominated by globally distributed androdiecious species. We found thatCaenorhabditiswere able to colonize baits accessible only by phoresy, preferring to colonize baits making direct contact with the ground. We estimate founder numbers per colonization event to be low.
Obesity associated with attenuated tissue immune cell responses in COVID-19
Authors: Guo Shuang A. , Bowyer Georgina S. , Ferdinand John R. , Maes Mailis , Tuong Zewen K. , Gilman Eleanor , Liao Mingfeng , Lindeboom Rik G. H. , Yoshida Masahiro , Worlock Kaylee , Gopee Huda , Stephenson Emily , Lyons Paul A. , Smith Kenneth G.C. , Haniffa Muzlifah , Meyer Kerstin B. , Nikolić Marko Z. , Zhang Zheng , Wunderink Richard G. , Misharin Alexander V. , Dougan Gordon , Navapurkar Vilas , Teichmann Sarah A. , Conway-Morris Andrew , Clatworthy Menna R. 
Published: January 2022

AbstractObesity is common and associated with more severe COVID-19, proposed to be in part related to an adipokine-driven pro-inflammatory state. Here we analysed single cell transcriptomes from bronchiolar lavage in three adult cohorts, comparing obese (Ob, body mass index (BMI) >30m2) and non-obese (N-Ob, BMI <30m2). Surprisingly, we found that Ob subjects had attenuated lung immune/inflammatory responses in SARS-CoV-2 infection, with decreased expression of interferon (IFN)α, IFNγ and tumour necrosis factor (TNF) alpha response gene signatures in almost all lung epithelial and immune cell subsets, and lower expression of IFNG and TNF in specific lung immune cells. Analysis of peripheral blood immune cells in an independent adult cohort showed a similar, but less marked, reduction in type I IFN and IFNγ response genes, as well as decreased serum IFNα, in Ob patients with SARS-CoV-2. Nasal immune cells from Ob children with COVID-19 also showed reduced enrichment of IFNα and IFNγ response genes. Altogether, these findings show blunted tissue immune responses in Ob COVID-19 patients, with clinical implications.
Meiosis in the human pathogen Aspergillus fumigatus has the highest known number of crossovers
Authors: Auxier Ben , Becker Frank , Nijland Reindert , Debets Alfons J. M. , van den Heuvel Joost , Snelders Eveline 
Published: January 2022

AbstractEvidence from both population genetics and a laboratory sexual cycle indicate that sex is common in the fungus Aspergillus fumigatus. However, the impact of sexual reproduction has remained unclear. Here, we show that meiosis in A. fumigatus involves the highest known recombination rate, producing ~29 crossovers per chromosome. This represents the highest known crossover rate for any Eukaryotic species. We validate this recombination rate by mapping resistance to acriflavine, a common genetic marker. We further show that this recombination rate can produce the commonly encountered TR34/L98H azole-resistant cyp51A haplotype in each sexual event, facilitating its rapid and global spread. Understanding the consequences of this unparalleled crossover rate will not only enrich our genetic understanding of this emergent human pathogen, but of meiosis in general.One-Sentence SummaryGenetic exchange between chromosomes during sex in Aspergillus fumigatus is higher than in any other known organism.
The C terminus of the mycobacterium ESX-1 secretion system substrate ESAT-6 is required for phagosomal membrane damage and virulence
Authors: Osman Morwan M. , Shanahan Jonathan K. , Chu Frances , Takaki Kevin K. , Pinckert Malte L. , Pagán Antonio J. , Brosch Roland , Conrad William H. , Ramakrishnan Lalita 
Published: January 2022

AbstractMycobacterium tuberculosisand its close relativeMycobacterium marinuminfect macrophages and induce the formation of granulomas, organized macrophage-rich immune aggregates. These mycobacterial pathogens can accelerate and co-opt granuloma formation for their benefit, using the specialized secretion system ESX-1, a key virulence determinant. ESX-1-mediated virulence is attributed to the damage it causes to the membranes of macrophage phagosomal compartments, within which the bacteria reside. This phagosomal damage, in turn, has been attributed to the membranolytic activity of ESAT-6, the major secreted substrate of ESX-1. However, mutations that perturb ESAT- 6’s membranolytic activity often result in global impairment of ESX-1 secretion. This has precluded an understanding of the causal and mechanistic relationships between ESAT-6 membranolysis and ESX-1-mediated virulence. Here, we identify two conserved residues in the unstructured C-terminal tail of ESAT-6 required for phagosomal damage, granuloma formation and virulence. Importantly, these ESAT-6 mutants have near- normal levels of secretion, far higher than the minimal threshold we establish is needed for ESX-1-mediated virulence early in infection. Unexpectedly, these loss-of-function ESAT-6 mutants retain the ability to lyse acidified liposomes. Thus, ESAT-6’s virulence functionsin vivocan be uncoupled from thisin vitrosurrogate assay. These uncoupling mutants highlight an enigmatic functional domain of ESAT-6 and provide key tools to investigate the mechanism of phagosomal damage and virulence.Significance StatementTuberculosis (TB), an ancient disease of humanity, continues to be a major cause of worldwide death. The causative agent of TB,Mycobacterium tuberculosis, and its close pathogenic relativeMycobacterium marinum, initially infect, evade, and exploit macrophages, a major host defense against invading pathogens. Within macrophages, mycobacteria reside within host membrane-bound compartments called phagosomes.Mycobacterium-induced damage of the phagosomal membranes is integral to pathogenesis, and this activity has been attributed the specialized mycobacterial secretion system ESX-1, and particularly to ESAT-6, its major secreted protein. Here, we show that the integrity of the unstructured ESAT-6 C-terminus is required for macrophage phagosomal damage, granuloma formation, and virulence.