bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Mesh and Fixation Options with Reoperation Risk after Laparoscopic Groin Hernia Surgery: A Swedish Hernia Registry Study of 25,190 Totally Extraperitoneal and Transabdominal Preperitoneal Repairs
Authors: Novik Bengt , Sandblom Gabriel , Ansorge Christoph , Thorell Anders
Published: April 2022

BACKGROUND

International guidelines concerning mesh and mesh fixation options in laparoscopic totally extraperitoneal (TEP) and transabdominal preperitoneal (TAPP) groin hernia repair are based on studies focusing on either mesh or fixation. We hypothesized that the value of such recommendations is limited by lacking knowledge on how mesh and fixation interact. The current registry-based nationwide cohort study compared different mesh/fixation combinations for relative risks for reoperation after TEP and TAPP groin hernia repair.

STUDY DESIGN

All TEP and TAPP registered in the Swedish Hernia Registry 2005 to 2017 with standard polypropylene (StdPPM) or lightweight (LWM) flat mesh, having tack, fibrin glue, or no fixation, were included. The endpoint was reoperation due to recurrence as of December 31, 2018. Multivariable Cox regression rendered relative risk differences between the exposures, expressed as hazard ratios (HR) with 95% CIs.

RESULTS

Of 25,190 repairs, 924 (3.7%) were later reoperated for recurrence. The lowest, mutually equivalent, reoperation risks were associated with StdPPM without fixation (HR 1), StdPPM with metal tacks (HR 0.8, CI 0.4 to 1.4), StdPPM with fibrin glue (HR 1.1, CI 0.7 to 1.6), and LWM with fibrin glue (HR 1.2, CI 0.97 to 1.6). Except for with fibrin glue, LWM correlated with increased risk, whether affixed with metal (HR 1.7, CI 1.1 to 2.7), or absorbable tacks (HR 2.4, CI 1.8 to 3.1), or deployed without fixation (HR 2.0, CI 1.6 to 2.6).

CONCLUSIONS

With StdPPM, neither mechanical nor glue fixation seemed to improve outcomes. Thus, for this mesh category, we recommend nonfixation. With LWM, we recommend fibrin glue fixation, which was the only LWM alternative on par with nonaffixed StdPPM.
Patient, Surgeon, or Hospital: Explaining Variation in Outcomes after Colectomy
Authors: Bamdad Michaela C , Brown Craig S , Kamdar Neil , Weng Wenjing , Englesbe Michael J , Lussiez Alisha
Published: April 2022

BACKGROUND

Complication rates after colectomy remain high. Previous work has failed to establish the relative contribution of patient comorbidities, surgeon performance, and hospital systems in the development of complications after elective colectomy.

STUDY DESIGN

We identified all patients undergoing elective colectomy between 2012 and 2018 at hospitals participating in the Michigan Surgical Quality Collaborative. The primary outcome was development of a postoperative complication. We used risk- and reliability-adjusted generalized linear mixed models to estimate the degree to which variance in patient-, surgeon-, and hospital-level factors contribute to complications.

RESULTS

A total of 15,755 patients were included in the study. The mean hospital-level complication rate was 15.8% (range, 8.7% to 30.2%). The proportion of variance attributable to the patient level was 35.0%, 2.4% was attributable to the surgeon level, and 1.8% was attributable to the hospital level. The predicted probability of complication for the least comorbid patient was 1.5% (CI 0.7–3.1%) at the highest performing hospital with the highest performing surgeon, and 6.6% (CI 3.2–12.2%) at the lowest performing hospital with the lowest performing surgeon. By contrast, the most comorbid patient in the cohort had a 66.3% (CI 39.5–85.6%) or 89.4% (CI 73.7–96.2%) risk of complication.

CONCLUSIONS

This study demonstrated that variance from measured factors at the patient level contributed more than 8-fold more to the development of complications after colectomy compared with variance at the surgeon and hospital level, highlighting the impact of patient comorbidities on postoperative outcomes. These results underscore the importance of initiatives that optimize patient foundational health to improve surgical care.
Impact of Incorporating Whole Blood into Hemorrhagic Shock Resuscitation: Analysis of 1,377 Consecutive Trauma Patients Receiving Emergency-Release Uncrossmatched Blood Products
Authors: Brill Jason B , Tang Brian , Hatton Gabrielle , Mueck Krislynn M , McCoy C Cameron , Kao Lillian S , Cotton Bryan A
Published: April 2022

BACKGROUND:

Use of whole blood (WB) for trauma resuscitation has seen a resurgence. The purpose of this study was to investigate survival benefit of WB across a diverse population of bleeding trauma patients.

STUDY DESIGN:

A prospective observational cohort study of injured patients receiving emergency-release blood products was performed. All adult trauma patients resuscitated between November 2017 and September 2020 were included. The WB group included patients receiving any group O WB units. The component (COMP) group received no WB units, instead relying on fractionated blood (red blood cells, plasma, and platelets). Univariate and multivariate analyses were performed. Given large observed differences in our regression model, post hoc adjustments with inverse probability of treatment were conducted and a propensity score created. Propensity scoring and Poisson regression supported these findings.

RESULTS:

Of 1,377 patients receiving emergency release blood products, 840 received WB and 537 remained in the COMP arm. WB patients had higher Injury Severity Score (ISS; 27 vs 20), lower field blood pressure (103 vs 114), and higher arrival lactate (4.2 vs 3.5; all p < 0.05). Postarrival transfusions and complications were similar between groups, except for sepsis, which was lower in the WB arm (25 vs 30%, p = 0.041). Although univariate analysis noted similar survival between WB and COMP (75 vs 76%), logistic regression found WB was independently associated with a 4-fold increased survival (odds ratio [OR] 4.10, p < 0.001). WB patients also had a 60% reduction in overall transfusions (OR 0.38, 95% CI 0.21-0.70). This impact on survival remained regardless of location of transfusion, ISS, or presence of head injury.

CONCLUSION:

In patients experiencing hemorrhagic shock, WB transfusion is associated with both improved survival and decreased overall blood utilization.
Pandemic Operating Room Supply Shortage and Surgical Site Infection: Considerations as We Emerge from the Coronavirus Disease 2019 Pandemic
Authors: Malhotra Gautam K , Tran Thuy , Stewart Camille , Battey Hannah , Tegtmeier Bernard , McNeese Kathy , Flood Annemarie , Melstrom Laleh , Fong Yuman
Published: April 2022

BACKGROUND:

The coronavirus disease 2019 (COVID-19) pandemic created shortages of operating room (OR) supplies, forcing healthcare systems to make concessions regarding “standard” OR attire. At our institution, we were required to reduce shoe covers, reuse face masks, and allow washable head coverings. We determined if these changes affected surgical site infection (SSI) rates.

STUDY DESIGN:

A single institutional study was performed to compare the SSI rates reported to the National Healthcare Safety Network in the 2 years preceding COVID-19 (PRE, January 1, 2018, to December 31, 2020) with the first 12 months after the pandemic (POST, April 1, 2020, to March 31, 2021). We confirmed our findings using propensity score matching and multivariate analysis.

RESULTS:

Elimination of traditional shoe covers, disposable head covers, and single-use face masks was associated with a decreased SSI rate from 5.1% PRE to 2.6% POST (p < 0.001). Furthermore, this was despite a 14% increase in surgical volume and an increase in the number of contaminated/dirty cases (2.2% PRE vs 7.4% POST, p < 0.001). Use of disposable face masks decreased by 4.3-fold during this period from 3.5 million/y PRE to 0.8 million/y POST. Of note, inpatient hand hygiene throughout the hospital increased from 71% PRE to 85% POST (p < 0.001).

CONCLUSIONS:

This analysis has practical applications as we emerge from the pandemic and make decisions regarding OR attire. These data suggest that disposable head covers and shoe covers and frequent changes of face masks are unnecessary, and discontinuation of these practices will have significant cost and environmental implications. These data also reinforce the importance of good hand hygiene for infection prevention.
Survival and Robotic Approach for Pancreaticoduodenectomy: A Propensity Score-Match Study
Authors: Rosemurgy Alexander S , Ross Sharona B , Espeut Abigail , Nguyen Danielle , Crespo Kaitlyn , Syblis Cameron , Vasanthakumar Padma , Sucandy Iswanto
Published: April 2022

BACKGROUND:

Robotic surgery is a burgeoning minimally invasive approach to pancreaticoduodenectomy. This study was undertaken to compare survival after robotic vs “open” pancreaticoduodenectomy for ductal adenocarcinoma using propensity score–matched patients.

STUDY DESIGN:

With institutional review board approval, we prospectively followed 521 patients who underwent robotic (n = 311) or open (n = 210) pancreaticoduodenectomy. Patients who underwent robotic (n = 75) or open (n = 75) pancreaticoduodenectomy were propensity score–matched by age, sex, and American Joint Committee on Cancer stage. Neoadjuvant therapy was rarely administered, and adjuvant therapy was stressed (FOLFIRINOX for patients <70 years of age and gemcitabine + nab-paclitaxel for patients >70 years of age). Data are presented as median (mean ± SD).

RESULTS:

Operative duration was longer and estimated blood loss and length of stay were less with robotic pancreaticoduodenectomy (421 [409 ± 94.0] vs 267 [254 ± 81.2] minutes; 307 [(150 ± 605.3] vs 444 [255 ± 353.1] mL; 7 [5 ± 5.1] vs 11 [8 ± 9.5] days; p < 0.00001 for all). There were no differences in complications (Clavien-Dindo class ≥III, p = 0.30), in-hospital mortality (p = 0.61), or 30-day readmission rates (p = 0.19). Median survival after robotic vs open pancreaticoduodenectomy was 37 vs 24 months (p = 0.08). For propensity score–matched patients, operative duration for robotic pancreaticoduodenectomy was longer (442 [438 ± 117.7] vs 261 [249 ± 67.1] minutes) and estimated blood loss was less (269 [200 ± 296.1] vs 468 [300 ± 394.9] mL), as was length of stay (7 [5 ± 5.1] vs 10 [7 ± 8.6] days; p < 0.00001 for all). There were no differences in complication rates (Clavien-Dindo class ≥ III, p = 0.31) or in-hospital mortality (p = 0.40); 30-day readmissions were fewer after robotic pancreaticoduodenectomy (7% vs 20%, p = 0.03). Median survival for the robotic vs the open approach was 41 vs 17 months (p = 0.02).

CONCLUSION:

Patients that underwent robotic pancreaticoduodenectomy had longer operations, less estimated blood loss, shorter length of stay, and fewer 30-day readmissions; they lived much longer than patients who underwent open pancreaticoduodenectomy. We believe that robotic pancreaticoduodenectomy provides salutary and survival benefits for reasons yet unknown.
Pseudomonas rustica sp. nov., isolated from bulk tank raw milk at a German dairy farm
Authors: Fiedler Gregor , Gieschler Stefanie , Kabisch Jan , Grimmler Christina , Brinks Erik , Wagner Natalia , Hetzer Birgit , Franz Charles M. A. P. , Böhnlein Christina
Published: April 2022

Here we present the description of a novel

Pseudomonas

species, designated Pseudomonas rustica sp. nov., which was isolated from raw milk samples obtained from Germany. Results of initial 16S rRNA gene sequence analysis assigned the strain into the genus

Pseudomonas

and showed

Pseudomonas helmanticensis

,

Pseudomonas neuropathica

and

Pseudomonas atagonensis

to be its closest relatives. Further studies including sequence analysis of the rpoB gene, multi-gene phylogenetic tree reconstruction, whole-genome sequence comparisons, cellular fatty acid analysis and chemotaxonomic characterization showed a clear separation from the known

Pseudomonas

species. Isolate MBT-4T was closely related to

Pseudomonas helmanticensis

, 'Pseudomonas crudilactis' and

Pseudomonas neuropathica

with average nucleotide identities based on blast values of 88.8, 88.8 and 88.6%, respectively. Therefore, the strain can be classified into the

Pseudomonas koreensis

subgroup of the

Pseudomonas fluorescens

group. The G+C content of strain MBT-4T was 58.9 mol%. The strain was catalase- and oxidase-positive, while the β-galactosidase reaction was negative. Growth occurred between 4 and 30 °C and at pH values from pH 6.0 to 8.0. In conclusion, strain MBT-4T belongs to a novel species, for which the name Pseudomonas rustica sp. nov. is proposed. The type strain is MBT-4T (=DSM 112348T=LMG 32241T) and strain MBT-17 is also a representative of this species.
Virulence gene mutations as a differentiator of clinical phenotypes: insights from community-acquired uropathogenic Escherichia coli
Authors: Yadav Manisha , Pundir Swati , Kumari Rajesh , Kumar Arvind , Venugopal Shwetha J. , Panigrahy Rajashree , Tak Vibhor , Chunchanur Sneha K. , Gautam Hitender , Kapil Arti , Das Bimal , Sood Seema , Salve Harshal Ramesh , Malhotra Sumit , Kant Shashi , Hari Pankaj , Chaudhuri Susmita , Mohapatra Sarita
Published: April 2022

Uropathogenic

Escherichia coli

(UPEC) remains an important cause of urinary tract infection during pregnancy. Multiple molecular virulence determinants and antibiotic resistant genes facilitate its pathogenesis and virulence phenotype. Hence it is hypothesized that there will be considerable variation in genes among the isolates from symptomatic as well as asymptomatic bacteriuria (ABU) during pregnancy. The aim of this study was to decipher the genetic variation among the two phenotypes. Six different UPEC isolates collected from urine specimens of consecutive pregnant females (five, symptomatic bacteriuria and one, ABU) were tested for their growth kinetics, and biofilm formation. A total of 87 virulence determinants and 56 antibiotic resistance genes were investigated using whole-genome sequencing, to identify putative drives of virulence phenotype. In this analysis, we identified eight different types of fully functional toxin antitoxin (TA) systems [HipAB, YefM-YoeB, YeeU-YeeV (CbtA), YhaV-PrlF, ChpBS, HigAB, YgiUT and HicAB] in the isolates from symptomatic bacteriuria; whereas partially functional TA system with mutations were observed in the asymptomatic one. Isolates of both the groups showed equivalent growth characteristics and biofilm-formation ability. Genes for an iron transport system (Efe UOB system, Fhu system except FhuA) were observed functional among all symptomatic and asymptomatic isolates, however functional mutations were observed in the latter group. Gene YidE was observed predominantly associated with the biofilm formation along with few other genes (BssR, BssS, YjgK, etc.). This study outlines putative critical relevance of specific variations in the genes for the TA system, biofilm formation, cell adhesion and colonization among UPEC isolates from symptomatic and asymptomatic bacteriuria among pregnant women. Further functional genomic study in the same cohort is warranted to establish the pathogenic role of these genes.
Substance P and adenosine signaling pathways regulate exosomal sorting of miR-21 in colonic epithelial cells
Authors: Wani Sameena , Law Ivy Ka Man , Bugwadia Amy K. , Hoffman Jill M. , Pothoulakis Charalabos
Published: April 2022

Background & Aims

MicroRNAs (miRNAs) are transported in body fluids within exosomes, and exosomal-miRNA sorting is highly selective. In colonic epithelial cells (CECs), Substance P-neurokinin-1-receptor (SP/NK1R) signaling regulates miR-21 sorting into secreted exosomes. Here, we studied the molecular mechanisms driving miR-21 sorting into colonic epithelial exosomes (CEEs) under SP-stimulation.

Methods

We performed studies with human colonic epithelial NCM460 cells overexpressing neurokinin-1-receptor (NCM460-NK1R) and in intestinal-epithelial-specific NK1R knockout mice. SP-regulated gene targets were validated by real-time polymerase chain reaction (RT-PCR) and immunoblotting. Small non-coding RNAs (sncRNAs) were isolated from NCM460-NK1R cells and secreted exosomes, and 3′-end adenylated and 3′-end uridylated fractions were separated. Cellular and exosomal sncRNA fractions were processed for miR-21 and miR-1307-3p expression and 3′-end adenylation to uridylation (A/U) ratios using RT-PCR. Pharmacological inhibition studies in NCM460-NK1R cells were performed in the presence of the Adenosine A2B receptor (ADORA2B) antagonist, PSB-1115, followed by RT-PCR and immunoblotting. Mass spectrometry validated in silico interacting partners of miR-21 in CECs.

Results

In CECs, miR-21 is predominantly polyuridylated under SP-stimulation and preferentially sorted to CEEs. SP/NK1R signaling activation upregulates extracellular adenosine (ADO) signaling via ADORA2B concomitant with reduced ADO uptake via epithelial-specific equilibrative nucleoside transporter-2 (ENT-2). Mass spectrometry and immunoblotting revealed upregulation of TUT7 in SP-stimulated CEEs. Knockdown of TUT7 decreased both TUT7 and miR-21 content in these exosomes. Pharmacological inhibition of ADORA2B in CECs resulted in decreased TUT7 and miR-21 in CEEs, regardless of SP stimulation.

Conclusions

SP/NK1R coupling in CECs activates ADORA2B and its downstream signaling cascade which mediates TUT7/miR-21 interaction and subsequent miR-21 polyuridylation and exosomal export.

Synopsis

Substance P-neurokinin-1 receptor signaling regulates terminal uridyl transferase7-mediated predominant 3’-end polyuridylation and exosomal recruitment of miR-21 in human colonic epithelial NCM460 cells overexpressing NK-1R via activation of Adenosine A2B receptor and its downstream signaling cascade. Because Adenosine A2B receptor signaling is involved in IBD pathogenesis, it could therefore be exploited as a pharmacological target for the therapeutic benefits in IBD.
Performance in Fundamentals of Laparoscopic Surgery (FLS): Does it Reflect Global Rating Scales in Objective Structured Assessment of Technical Skills (OSATS) in Porcine Laparoscopic Surgery?
Authors: Tiong Ho Yee , So Wei Zheng , Teoh Jeremy Yuen-Chun , Isotani Shuji , Zhu Gang , Ong Teng Aik , Chan Eddie Shu-Yin , Chu Peggy Sau-Kwan , Kijvikai Kittinut , Liu Ming , Lojanapiwat Bannakji , Wong Michael , Ng Anthony Chi-Fai
Published: April 2022

Background

To correlate the utility of Fundamentals of Laparoscopic Surgery (FLS) manual skills program with the Objective Structured Assessment of Technical Skills (OSATS) global rating scale in evaluating operative performance.

Materials and Methods

The Asian Urological Surgery Training and Educational Group (AUSTEG) Laparoscopic Upper Tract Surgery Course (LUTSC) implemented and validated the FLS program for its usage in laparoscopic surgical training. Delegates’ basic laparoscopic skills were assessed using three different training models (Peg Transfer, Precision Cutting and Intra-corporeal Suturing). They also performed live porcine laparoscopic surgery at the same workshop. Live surgery skills were assessed by blinded faculty using the OSATS rating scale.

Results

From 2016 to 2019, a total of 81 certified urologists participated in the course, with a median of 5 years’ experience post residency. Although differences in task timings did not reach statistical significance, those with more surgical experience were visibly faster at completing the peg transfer and intra-corporeal suturing FLS tasks. However, they took longer to complete the precision cutting task than participants with less experience. Overall OSATS scores correlated weakly with all three FLS tasks (Peg Transfer Time: R = -0.331, R2 = 0.110; Precision Cutting Time: R = - 0.240, R2 = 0.058; Suturing with Intra-corporeal Knot Time: R = -0.451, R2 = 0.203).

Conclusion

FLS task parameters did not correlate strongly with OSATS globing rating scale performance. Although the FLS task models demonstrated strong validity, it is important to assimilate the inconsistencies when benchmarking technical proficiency against real-life operative competence, as evaluated by FLS and OSATS respectively.
A mixed cross-sectional and case-control study approach to investigate the risk-factors of Noma/Cancrum oris in Ethiopia
Authors: Gebretsadik Heron Gezahegn , de Kiev Laurent Cleenewerck
Published: April 2022

Introduction

Noma is a polymicrobial gangrenous facial disease affecting people living in the most impoverished areas of low- and middle-income countries. If left untreated, the disease is fatal or else severely disfigure people with the condition. The compromised immune system, poor oral hygiene, measle infection, diarrheal disease, inaccessibility to health education and proper medical care, and lack of a balanced diet and good sanitary facilities are found to be some of the predisposing factors for the development and progression of the disease. Furthermore, debilitating diseases like malaria and measles were considered as significant precursors to Noma.

Materials and Method

A mix of cross-sectional and case-control study approaches was conducted to assess the risk factors of Noma in Ethiopia. The raw data of the cases were obtained from Yekatik 12 Hospital, Facing Africa, and the Harar project Ethiopia. Three controls were selected per single case. The Odd ratio (ORs) and Chi-square test were calculated to rule out the statistical significance of the association observed between the factors and the disease.

Results

A total of 64 cases were selected for the case-control study. Considering the 1:3 case to control ratio, 192 matching controls were identified. Malaria, helminths, measle, diarrheal diseases, and living with domestic animals were found to be risk factors for Noma with a respective p-value < 0.01. Contrarily, the analysis has identified vaccination (p < 0.01) as a protective factor.

Discussion

Noma/face of poverty is mostly preventable by providing proper nutrition, sanitary and water facilities, awareness about the disease, oral health education, and vaccinations. Poverty-related diseases such as malaria, helminths infection, measle, diarrheal diseases, and unfavorable living conditions were identified to be the risk factor for Noma. As such the disease is truly preventable. Prevention of the disease can be achieved through promoting overall awareness of the disease, poverty reduction, improved nutrition, and promotion of exclusive breastfeeding in the first 3-6 months of life. Furthermore, optimum prenatal care, timely immunizations against common childhood diseases, initiating vaccination, and improving the social living conditions are the other preventive mechanisms. Moreover, long-lasting economic development should be considered to effectively and sustainably prevent the disease.
Trait anxiety is associated with hidden state inference during aversive reversal learning
Authors: Zika Ondrej , Wiech Katja , Reinecke Andrea , Browning Michael , Schuck Nicolas W.
Published: April 2022

Updating beliefs in changing environments can be driven by gradually adapting expectations or by relying on inferred hidden states (i.e., contexts), and changes therein. Previous work suggests that increased reliance on context could underly fear relapse phenomena that hinder clinical treatment of anxiety disorders. We test whether trait anxiety variations in a healthy population influence how much individuals rely on hidden-state inference. In a Pavlovian learning task, participants observed cues that predicted an upcoming electrical shock with repeatedly changing probability, and were asked to provide expectancy ratings on every trial. We show that trait anxiety is associated with steeper expectation switches after contingency reversals and reduced oddball learning. Furthermore, trait anxiety is related to better fit of a state inference compared to a gradual learning model when contingency changes are large. Our findings support previous work suggesting hidden-state inference as a mechanism behind anxiety-related to fear relapse phenomena.
Functional coupling of the mesencephalic locomotor region and V2a reticulospinal neurons driving forward locomotion
Authors: Carbo-Tano Martin , Lapoix Mathilde , Jia Xinyu , Auclair François , Dubuc Réjean , Wyart Claire
Published: April 2022

Locomotion in vertebrates relies on high brain centers converging onto the mesencephalic locomotor region (MLR). How the MLR recruits brainstem reticulospinal neurons (RSNs) to initiate locomotion is incompletely understood due to the challenge of recording these cells in vivo. To tackle this question, we leveraged the transparency and genetic accessibility of larval zebrafish. In this model organism, we uncovered the locus of the MLR as a small region dorsal to the locus coeruleus containing glutamatergic and cholinergic neurons. MLR stimulations reliably elicited forward bouts of controlled duration and speed. We find that the MLR elicits forward locomotion by recruiting V2a RSNs in the pontine and retropontine regions, and gradually in the medulla. Remarkably, recruited V2a RSNs in the medulla act as maintain cells encoding speed of forward locomotion. Altogether, our study reveals that the MLR recruits genetically-identified reticulospinal neurons in the medulla to control the kinematics of exploration.
Bmal1-knockout mice exhibit reduced cocaine-seeking behaviour and cognitive impairments
Authors: Castro-Zavala Adriana , Alegre-Zurano Laia , Cantacorps Lídia , Gallego-Landin Ines , Welz Patrick-S. , Benitah Salvador A. , Valverde Olga
Published: April 2022

Brain and Muscle Arnt-like Protein 1 (BMAL1) is an essential component of the molecular clock underlying circadian rhythmicity. Recently, its function has also been associated with alterations in mood, and reward processing. We investigated the behavioural and neurobiological impact ofBmal1gene deletion in mice, as well as how these alterations affect rewarding effects of cocaine. Additionally, key clock genes and components of the dopamine system were assessed in several brain areas. Our results evidence behavioural alterations inBmal1-KOmice including changes in locomotor activity with impaired habituation to environments as well as short term memory and social recognition impairments. In addition,Bmal1-KOmice experienced reduced cocaine-induced sensitization and rewarding effects of cocaine as well as reduced cocaine-seeking behaviour. Furthermore,Bmal1deletion influenced the expression of other clock-related genes in the mPFC and striatum as well as alterations in the expression of dopaminergic elements. Overall, the present article offers a novel and extensive characterization ofBmal1-KOanimals. We suggest that reduced cocaine’s rewarding effects in these mutant mice might be related toBmal1role as an expression regulator of MAO and TH, two essential enzymes involved in dopamine metabolism.
An open-source, ready-to-use and validated ripple detector plugin for the Open Ephys GUI
Authors: de Sousa Bruno Monteiro , de Oliveira Eliezyer Fermino , da Silva Beraldo Ikaro Jesus , Polanczyk Rafaela Schuttenberg , Leite João Pereira , Aguiar Cleiton Lopes
Published: April 2022

Sharp wave-ripples (SWRs, 100-250 Hz) are oscillatory events extracellularly recorded in the CA1 subfield of the hippocampus during sleep and quiet wakefulness. SWRs are thought to be involved in the dialogue between the hippocampus and cortical regions to promote memory consolidation during sleep and memory-guided decision making. Many studies employed closed-loop strategies to either detect and abolish SWRs within the hippocampus or manipulate other relevant areas upon ripple detection. However, the code and schematics necessary to replicate the detection system are not always available, which hinders the reproducibility of experiments among different research groups. Furthermore, information about performance is not usually reported. Here, we present the development and validation of an open-source, real-time ripple detection plugin integrated into the Open Ephys GUI. It contains a built-in movement detector based on accelerometer or electromyogram data that prevents false ripple events (due to chewing, grooming, or moving, for instance) from triggering the stimulation/manipulation device. To determine the accuracy of the detection algorithm, we first carried out simulations in Matlab with synthetic and real ripple recordings. Using a specific combination of detection parameters (amplitude threshold of 5 standard deviations above the mean, time threshold of 10 ms, and RMS block size of 7 samples), we obtained a 97% true positive rate and 2.48 false positives per minute on the real data. Next, an Open Ephys plugin based on the same detection algorithm was developed, and a closed-loop system was set up to evaluate the round trip (ripple onset-to-stimulation) latency over synthetic data. The lowest latency obtained was 34.5 ± 0.5 ms. Besides contributing to increased reproducibility, we anticipate that the developed ripple detector plugin will be helpful for many closed-loop applications in the field of systems neuroscience.
Communication-Efficient Cluster Scalable Genomics Data Processing Using Apache Arrow Flight
Authors: Ahmad Tanveer , Ma Chengxin , Al-Ars Zaid , Hofstee H. Peter
Published: April 2022

Current cluster scaled genomics data processing solutions rely on big data frameworks like Apache Spark, Hadoop and HDFS for data scheduling, processing and storage. These frameworks come with additional computation and memory overheads by default. It has been observed that scaling genomics dataset processing beyond 32 nodes is not efficient on such frameworks.

To overcome the inefficiencies of big data frameworks for processing genomics data on clusters, we introduce a low-overhead and highly scalable solution on a SLURM based HPC batch system. This solution uses Apache Arrow as in-memory columnar data format to store genomics data efficiently and Arrow Flight as a network protocol to move and schedule this data across the HPC nodes with low communication overhead.

As a use case, we use NGS short reads DNA sequencing data for pre-processing and variant calling applications. This solution outperforms existing Apache Spark based big data solutions in term of both computation time (2x) and lower communication overhead (more than 20-60% depending on cluster size). Our solution has similar performance to MPI-based HPC solutions, with the added advantage of easy programmability and transparent big data scalability. The whole solution is Python and shell script based, which makes it flexible to update and integrate alternative variant callers. Our solution is publicly available on GitHub at https://github.com/abs-tudelft/time-to-fly-high/genomics.
Brain-heart interactions are optimized across the respiratory cycle via interoceptive attention
Authors: Zaccaro Andrea , Perrucci Mauro Gianni , Parrotta Eleonora , Costantini Marcello , Ferri Francesca
Published: April 2022

Respiration and heartbeat continuously interact within the living organism at many different levels, representing two of the main oscillatory rhythms of the body and providing major sources of interoceptive information to the brain. Despite the modulatory effect of respiration on exteroception and cognition has been recently established in humans, its role in shaping interoceptive perception has been scarcely investigated so far.

In two independent studies, we investigated the effect of spontaneous breathing on cardiac interoception by assessing the Heartbeat Evoked Potential (HEP) in healthy humans. In Study 1, we compared HEP activity for heartbeats occurred during inhalation and exhalation in 40 volunteers at rest. We found higher HEP amplitude during exhalation, compared to inhalation, over fronto-centro-parietal areas. This suggests increased brain-heart interactions and improved cortical processing of the heartbeats during exhalation. In Study 2, we tested the respiratory phase-dependent modulation of HEP activity in 20 volunteers during Exteroceptive and Interoceptive conditions of the Heartbeat Detection (HBD) task. In these conditions, participants were requested to tap at each heartbeat, either listened to or felt, respectively. Results showed higher HEP activity and higher detection accuracy at exhalation than inhalation in the Interoceptive condition only. These effects were positively correlated, suggesting a link between optimization of both cortical processing of cardiac signals and perception of heartbeats across the respiratory cycle. Direct comparisons of Interoceptive and Exteroceptive conditions confirmed stronger respiratory phase-dependent modulation of HEP and accuracy when attention was directed towards the interoceptive stimuli.

Overall, we provide data showing that respiration shapes cardiac interoception at the neurophysiological and behavioural levels. Specifically, exhalation may allow attentional shift towards the internal bodily states.
Cue-driven motor planning facilitates express visuomotor responses in human arm muscles
Authors: Contemori Samuele , Loeb Gerald E. , Corneil Brian D. , Wallis Guy , Carroll Timothy J.
Published: April 2022

Humans can produce “express” (∼100ms) arm muscle responses that are inflexibly locked in time and space to the presentation of a visual target, consistent with subcortical visuomotor transformations via the tecto-reticulo-spinal pathway. These express visuomotor responses are sensitive to explicit cue-driven expectations, but it is unclear at what stage of sensory-to-motor transformation such modulation occurs. Here, we recorded electromyographic activity from shoulder muscles as participants reached toward one of four virtual targets whose physical location was partially predictable from a symbolic cue. In an experiment in which targets could be veridically reached, express responses were inclusive of the biomechanical requirements for reaching the cued locations and not systematically modulated by cue validity. In a second experiment, movements were restricted to the horizontal plane so that the participants could perform only rightward or leftward reaches, irrespective of target position on the vertical axis. Express muscle responses were almost identical for targets that were validly cued in the horizontal direction, regardless of cue validity in the vertical dimension. Together, these findings suggest that the cue-induced enhancements of express responses are dominated by effects at the level of motor plans and not solely via facilitation of early visuospatial target processing. Notably, direct cortico-tectal and cortico-reticular projections exist that are well-placed to modulate pre-stimulus motor preparation state in subcortical circuits. Our results appear to reflect a neural mechanism by which contextually relevant motor plans can be stored within subcortical visuomotor nodes and rapidly released in response to compatible visual inputs.

NEW & NOTEWORTHY

Express arm muscle responses to suddenly appearing visual targets for reaching rapid have been attributed to the tecto-reticulo-spinal pathway in humans. We demonstrate that symbolic cues before target presentation can modulate such express arm muscle responses compatibly with the biomechanics of the cued reaching direction and the cue validity. This implies cortically mediated modulation of one or more sensorimotor transformation nodes of the subcortical express pathway.
Machine Learning Classification Reveals Robust Morphometric Biomarker of Glial and Neuronal Arbors
Authors: Akram Masood A. , Wei Qi , Ascoli Giorgio A.
Published: April 2022

Neurons and glia are the two main cell classes in the nervous systems of most animals. Although functionally distinct, neurons and glia are both characterized by multiple branching arbors stemming from the cell bodies. Glial processes are generally known to form smaller trees than neuronal dendrites. However, the full extent of morphological differences between neurons and glia in multiple species and brain regions has not yet been characterized, nor is it known whether these cells can be reliably distinguished based on geometric features alone. Here, we show that multiple supervised learning algorithms (K-nearest neighbor, random forest, and support vector machine) deployed on a large database of morphological reconstructions can systematically classify neuronal and glial arbors with nearly perfect accuracy and precision. Moreover, we report multiple morphometric properties, both size-related and size-independent, that differ substantially between these cell types. In particular, we newly identify an individual morphometric measurement, Average Branch Euclidean Length (ABEL) that can robustly separate neurons from glia across multiple animal models, a broad diversity of experimental conditions, and anatomical areas, with the notable exception of the cerebellum. We discuss the practical utility and physiological interpretation of this discovery.
Nonlinear Parameter and State Estimation Approach in End-stage Kidney Disease Patients
Authors: Abohtyra Rammah M. , Vincent Tyrone L.
Published: April 2022

Background

Blood and fluid volume management in End-stage Kidney Disease (ESKD) patients plays an essential role in dialysis therapy to replace kidney function. Reliable knowledge of blood and fluid volumes before and during dialysis could be used to improve treatment outcomes significantly.

Objective

This study aims to develop an estimation approach providing predictable information on blood and fluid volumes before and during a regular dialysis routine.

Methods

A new approach is developed to estimate blood volume, fluid overload, and vascular refilling parameters from dialysis data. The method utilizes a nonlinear fluid volume model, an optimization technique, and the Unscented Kalman Filter (UKF) incorporated with data. This method does not rely on restricted ultrafiltration (UF) and dilution protocols and uses the Fisher information matrix to quantify error estimation.

Results

Accurate estimations for blood volumes (5.9±0.07L and 4.8±0.03L) and interstitial fluid volumes (18.81±0.15L and 12.19±0.03) were calculated from dialysis data consisting of constant and stepwise UF profiles. We demonstrated that by implementing the estimated parameters into the model, a precise prediction of the measured hematocrit (HCT) can be achieved during the treatment.

Conclusion

We showed that the result does not depend highly on initial conditions and can be accurately estimated from a short data segment. A new method, applicable to the current dialysis routine, is now available for ESKD patients to be implemented within the dialysis machines.
The mobilome associated with Gram-negative bloodstream infections: A large-scale observational hybrid sequencing based study
Authors: Lipworth Samuel , Matlock Willam , Shaw Liam , Vihta Karina-Doris , Rodger Gillian , Chau Kevin , Barker Leanne , George Sophie , Kavanagh James , Davies Timothy , Vaughan Alison , Andersson Monique , Jeffery Katie , Oakley Sarah , Morgan Marcus , Hopkins Susan , Peto Timothy , Crook Derrick , Walker A. Sarah , Stoesser Nicole
Published: April 2022

Plasmids carry genes conferring antimicrobial resistance (AMR), and other clinically important traits; their ability to move within and between species may provide the machinery for rapid dissemination of such genes. Existing studies using complete plasmid assemblies, which are essential for reliable inference, have been small and/or limited to those carrying particularly antimicrobial resistance genes (ARGs). In this study, we sequenced 1,880 complete plasmids from 738 isolates from bloodstream infections (BSI) in 2009 (194 isolates) and 2018 (368 isolates) in Oxfordshire, UK, plus a stratified selection from intervening years (176 isolates). We demonstrate that plasmids are largely, but not entirely, constrained to host species, although there is substantial overlap between species of plasmid gene-repertoire. Most ARGs are carried by a relatively small number of plasmid groups with biological features that are predictable. Plasmids carrying ARGs (including those encoding carbapenemases) share a putative ‘backbone’ of core genes with those carrying no such genes. These findings suggest that future surveillance should, in addition to tracking plasmids currently associated with clinically important genes, focus on identifying and monitoring the dissemination of high-risk plasmid groups with the potential to rapidly acquire and disseminate these genes.
Delayed dynamics of migratory response to CTLA-4 blockade reveals a mechanistic view on potential T cells reinvigoration following immune checkpoint blockade
Authors: Safaeifard Fateme , Shariatpanahi Seyed Peyman , Golieai Bahram , Aref Amir R. , Foroughmand-Araabi Mohammad-Hadi , Goliaei Sama , Rüegg Curzio
Published: April 2022

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) receptors, two clinically relevant targets for immunotherapy of cancer, are negative regulators of in immune cell activation and migration. However, optimizing therapeutic outcomes still requires fundamental research to reach a comprehensive insight into the coherent function of immune regulators.

Here, we investigated the statistical dynamics of T cells migration as a measure of the functional response to these pathways in an experimental setup of immune checkpoint blockade. For this purpose, we used a previously developed 3-dimensional organotypic culture of patient-derived tumor spheroids.

Experiment-based dynamical modeling remarked distinct characteristics of the receptors regulation followed through with the modification of their proportions in the immune modulation. We demonstrated that time-delayed kinetics of PD-1 activation just overrides its relatively more efficient cell-level function which potentially makes an operative contribution to the functional dominance of CTLA-4 in the tumor microenvironment. Simulation results showed good agreement with data for tumor cells reduction and active immune cells count observed in each experiment.

These analyses propose a new mechanistic view on relative immunogenicity of PD-1 and CTLA-4 inhibitors manifested in literature and point the possible inherent obstacles in checkpoint inhibition-based immunotherapy of cancer to address in the future.

Significance

Ex vivo monitoring of temporal response to PD-1 and CTLA-4 in the closure of T cell movement dynamics and elucidating their feasible commitment to the kinetic constraints at cell-level resolution. Delayed dynamics of migratory response to CTLA-4 inhibition revealed a mechanistic view on potential T cell reinvigoration following immune checkpoint blockade.
Methacrylic acid-based biomaterials promote peripheral innervation in the subcutaneous space of mice
Authors: Androschuk Alaura M. , Tam Theresa H. , Mahou Redouan , Lo Cheun , Salter Michael W. , Sefton Michael V.
Published: April 2022

Peripheral nerve innervation is essential for regulating tissue repair and regeneration. MAA-based biomaterials have been previously shown to promote angiogenesis. Here we show a new role for MAA-based biomaterials in promoting terminal axon nerve growth. Our results demonstrate that MAA-based biomaterials promote peripheral nerve growth in an Igf-1 and Shh dependent manner. The resulting nerves increased the sensitivity of treated mice paws to nociception. iDISCO clearing showed that MAA increased the presence of peripheral nerve structures in whole explants. MAA was also able to increase the expression of key neuronal markers and growth factors in a peripheral neuropathy model, the diabetic db/db mouse, suggesting that MAA-based biomaterials may be relevant to treatment of peripheral neuropathy. Moreover, in a peripheral neuropathy model, MAA was able to up-regulate the expression of growth factors for an extended duration suggesting MAA may prevent degeneration through an effect on factors that promote survival. As all tissues are innervated, MAA-based biomaterials could have broad applications in the promoting regeneration and preventing degeneration of peripheral nerves.

HIGHLIGHTS

Methacrylic acid-based biomaterials promote axon growth in-situ without exogenous growth factors or cells

Methacrylic acid-based biomaterial induced terminal axon growth displays nociception, an indicator of functional outgrowth

Methacrylic acid-based biomaterials terminal axon growth is Igf-1 and Shh driven
CCR4 and CCR7 differentially regulate thymocyte localization with distinct outcomes for central tolerance
Authors: Li Yu , Tipan Pablo Guaman , Selden Hilary J. , Srinivasan Jayashree , Hale Laura P. , Ehrlich Lauren I.R.
Published: April 2022

Central tolerance ensures autoreactive T cells are eliminated or diverted to the regulatory T cell lineage, thus preventing autoimmunity. To undergo central tolerance, thymocytes must enter the medulla to test their TCRs for autoreactivity against the diverse self-antigens displayed by antigen presenting cells (APCs). While CCR7 is known to promote thymocyte medullary entry and negative selection, our previous studies implicate CCR4 in these processes, raising the question of whether CCR4 and CCR7 play distinct or redundant roles in central tolerance. Here, synchronized positive selection assays, 2-photon timelapse microscopy, and quantification of TCR-signaled apoptotic thymocytes, demonstrate that CCR4 and CCR7 promote medullary accumulation and central tolerance of distinct post-positive selection thymocyte subsets. CCR4 is upregulated within hours of positive selection signaling and promotes medullary entry and clonal deletion of immature post-positive selection thymocytes. In contrast, CCR7 is expressed several days later and is required for medullary localization and negative selection of mature thymocytes. In addition, CCR4 and CCR7 differentially enforce self-tolerance, with CCR4 enforcing tolerance to self-antigens presented by activated APCs, which express CCR4 ligands. Our findings show that CCR7 expression is not synonymous with medullary localization and support a revised model of central tolerance in which CCR4 and CCR7 promote early and late stages of negative selection, respectively, via interactions with distinct APC subsets.
Engineering Proprioceptive Implants via Surgical and Regenerative Approaches: Preliminary Interpretations
Authors: Das Siddhartha , Sarma H.D. , Bellare Jayesh
Published: April 2022

The periodontal ligaments are a group of specialized connective tissue fibres with vascular and neural elements that essentially attach a tooth to the alveolar bone. Endosseous dental implant replacing a lost tooth, gets ankylosed to the alveolar bone without intervening periodontal fibres (osseointegration). Hence, proprioception, one of the most important function of periodontal ligament is not elicited by commercial dental implants currently in use. To salvage the flaw, in our proof-of-principle trial in rabbits, biodegradable nanofibres were coiled around the additive manufactured (AM) customized titanium implants. Further, human dental pulp stem cells (DPSCs), adult mesenchymal stem cells of neuro-ectodermal origin, were seeded on the nanofibrous coated, orthotopically placed 3D-printed titanium implants and were induced to differentiate into neural cell lineages. The invivo anchoring mechanism of these biodegradable neuro-supportive scaffold coated implants could probably be “proprioceptive osseointegration” instead of defaults events leading to normal “osseointegration” and could exhibit features similar to periodontium, having possible anastomosis between the severed nerve terminals present in the wall of the extraction socket relaying to/from brain and newly differentiated neural cells present in the regenerated neo-tissue complex, gradually replacing the biodegradable scaffold and may eventually results in the development of proprioceptive osseointegrated root-form endosseous dental implants in near future.