bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing Effect of Adding Ketamine Versus Dexmedetomidine to Bupivacaine in Pecs-ⅠⅠ Block on Postoperative Pain Control in Patients Undergoing Breast Surgery
Authors: Hefni Amira F. , Eldeek Abeer M. , Ismael Shereen A. , Shaban Ahmed R.
Published: July 2022

Background:

Pectoralis and serratus plane blocks (Pecs-II block) has successfully demonstrated a good quality of perioperative analgesia for breast surgery.

Objective:

This study aimed to compare the quality of postoperative pain control when adding either ketamine or dexmedetomidine to bupivacaine 0.25% for Pecs-II block.

Methods:

This prospective randomized double-blind study was conducted on 159 female patients with American Society of Anesthesiologist (ASA) physical status class I–III scheduled to have modified radical mastectomy. Patients were randomly assigned into 3 groups. Each group included 53 patients to receive ultrasound guided Pecs-II blocks with either 32 mL of 0.25% bupivacaine added to ketamine hydrochloride 1 mg/kg (BK group), 32 mL of 0.25% bupivacaine added to dexmedetomidine 1 ug/kg (BD group) or 32 mL of 0.25% bupivacaine only (B group).

The primary outcome was the total postoperative morphine consumption for the first 24 hours postoperatively. The time of the first request of analgesia, the pain scores at rest of ipsilateral arm, and the intraoperative fentanyl requirements, were the secondary outcome measures. Any side effects occurred were recorded.

Results:

The total postoperative morphine consumption was significantly lower in patients received bupivacaine with addition of either ketamine (BK group), (10.3±2.6 mg), or dexmedetomidine (BD group), (3.8±0.2 mg) respectively, versus patients received only bupivacaine (B group), (16.9±5.3 mg). Both ketamine (BK group) and dexmedetomidine (BD group) added to bupivacaine significantly prolonged the time to first analgesic request (16.7±4.5 h), (21.6±1.6 h) in both groups respectively compared with patients received bupivacaine alone (B group) (11.5±1.2 h).

The pain score was variable between the 3 groups during the first 24 hours postoperatively. There were no statistically significant differences in perioperative hemodynamics, O2 saturation, sedation scores, or side effects observed between the 3 groups. Patient satisfaction was reported to be the best in patients received dexmedetomidine added to bupivacaine compared to the patients who received ketamine as an additive or those who received bupivacaine alone.

Conclusion:

Adding dexmedetomidine to bupivacaine provides more effective postoperative pain control than adding ketamine during Pecs-II blocks for breast cancer surgery.
Evaluation of Adult Patients Readmitted for Severe Sepsis/Septic Shock Under the BPCI Advanced Program
Authors: Crabtree Pamela A. , Bach Harry , Del Fierro Eivind , Hunter Krystal , Quevada Kristian , Schorr Christa
Published: July 2022

Bundled Payments for Care Improvement-Advanced Program (BPCI-A) is designed to pay a single payment covering services provided during an episode of care. Sepsis is associated with increased readmissions, mortality, and health care costs. The purpose of the study was to evaluate the BPCI program patients with sepsis who were readmitted within 90 days versus not readmitted. This was a retrospective cohort study including 271 (110 readmitted) patients enrolled in the BPCI program with Diagnostic-Related Grouping codes of septicemia or severe sepsis. Skin/soft tissue infection was the most common infection. There was a significant difference between the groups for resource needs at discharge including wound care (25.45% versus 11.18%; P = 0.002) and physical therapy (74.55% versus 57.14%; P = 0.004). Mortality was higher among readmissions, 43.64% versus 26.71% no readmission (P = 0.004). Identifying risk factors for readmission, providing appropriate resources, and follow-up may contribute to improved patient outcomes for patients with sepsis enrolled in the BPCI program.
Clinical Factors Affecting the Recovery of Sensory Impairment After Cerebral Infarction
Authors: Peng Maohan , Wu Bangqi , Wang Xuhui , Ding Yi , Li Yibing , Cheng Xinyue
Published: July 2022

Background:

About 75% of patients with cerebral infarction suffer from sensory impairment in varying degrees. It prolongs the time for patients to resume normal life and work. The aim of this study was to retrospectively investigate the clinical characteristics affecting the recovery of sensory impairment.

Materials and Methods:

This was a retrospective case-control study. Data of inpatients at the First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine were investigated. We collected information on the patients with sensory disturbances after cerebral infarction. Cases were defined according to whether the National Institutes of Health Stroke Scale (NIHSS) and visual analogue scale (VAS) scores improved. A total of 1078 inpatients from January 1, 2019, to December 31, 2021, were screened. Among those, 187 cases included in this study were divided into no improvement and improvement groups. We compared the clinical characteristics affecting the rehabilitation of these patients.

Results:

The number of patients aged between 63 and 73 years in the no improvement group were significantly higher (P<0.05). The incidence of coronary heart disease and thalamus infarction was significantly higher in patients in the no improvement cohort (P<0.05). Furthermore, coronary heart disease [odds ratio=0.466, 95% confidence interval (0.252, 0.863), P=0.015] and thalamic infarction [odds ratio=0.457, 95% confidence interval (0.230, 0.908), P=0.025] were the independent risk factors against the recovery of sensory disturbance after cerebral infarction.

Conclusions:

Patients with thalamus infarction and coronary heart disease may be more inclined to recover poorly from somatosensory deficits.
Physicochemical stability of pemetrexed diarginine at 25 mg/mL in partially-used vials and at 3 and 12 mg/mL diluted in dextrose 5% or in sodium chloride 0.9% in polyolefin bags
Authors: Nisse Yann-Eric , Sobalak Nathalie , Vigneron Jean , Demore Béatrice
Published: July 2022

Introduction:

A new pemetrexed salt, pemetrexed diarginine (PDA), was marketed by Mylan company. The product is a ready-to-dilute 25 mg/mL solution. The manufacturer indicates a 24-hour stability after dilution in dextrose 5% (D5W).

The objectives were to study the stability of: PDA in D5W and 0.9% sodium chloride (0.9% NaCl) polyolefin bags at 3 and 12 mg/mL protected from light (PFL) between 2 to 8°C and at 25°C, and not PFL at room temperature; PDA vials at 25 mg/mL partially used perforated with a plastic spike PFL between 2 to 8°C and at 25°C and not PFL at room temperature.

Methods:

The stability study was performed by high-performance liquid chromatography coupled to a photodiode array detector. The method was validated according to International Council for Harmonisation guideline Q2(R1). Physical stability was evaluated by visual and subvisual inspection. pH values were measured.

Results:

PDA solutions PFL in D5W and in 0.9% NaCl at 3 and 12 mg/mL retained more than 95% of the initial concentration after 7 days at 25°C and after 28 days at 2 to 8°C. PDA ready-to-dilute 25 mg/mL solutions PFL retained more than 95% of the initial concentration after 28 days at 25°C and 2 to 8°C. PDA solutions in D5W and in 0.9% NaCl at 3 mg/mL and 12 mg/mL and PDA ready-to-dilute 25 mg/mL solutions not PFL retained more than 95% of the initial concentration after 7 days at room temperature. All samples had a pH in the range of 8.05 to 8.77. A light colouration, described in SPC, to an intense yellow-brown colouration, appeared depending on concentration and time. No precipitate was observed.

Conclusion:

According to the manufacturer's specifications and to the chemical stability defined as more than 95% of the initial concentration, PDA solutions in D5W and in 0.9% NaCl at 3 and 12 mg/mL and PDA ready-to-dilute 25 mg/mL solutions PFL at 25°C and not PFL at room temperature were stable for 7 days and for 28 days at 2 to 8°C. The absence of a color change as an acceptance criterion for the 25 mg/mL ready-to-dilute solution perforated with a plastic spike leads to a stability of 7 days at 2 to 8°C and 4 days at room temperature allowing the use of the vial for a preparation in advance with an optimal stability.
Social robots in pediatric oncology: opinions of health care providers
Authors: van Bindsbergen Kelly L.A. , van Gorp Marloes , Thomassen Brigitte W. , Merks Johannes H.M. , Grootenhuis Martha A.
Published: July 2022

Background:

We aimed to describe the opinions of health care providers in pediatric oncology regarding social robots and to examine differences in their opinions based on their background characteristics.

Methods:

Health care providers working in pediatric oncology care were approached globally to participate online in a cross-sectional questionnaire study with multiple choice and open-ended questions. Open-ended questions were coded and collapsed into categories by two researchers independently. Frequencies were used to describe the answers. Differences in opinions were studied using logistic regression analyses.

Results:

Health care providers’ (n = 286) first thoughts about social robots were mostly positive (81.0%). They saw value in social robots (83.6%), mostly during hospitalization or procedures and when used for distraction. They were willing to use one (67.8%), but also expected difficulties (67.1%), mainly concerning technical errors. Psychosocial staff members less often saw value in social robots, more often expected difficulties and were less willing to use a social robot than other health care providers (Ps < .05). No other differences were found.

Conclusions:

Social robots may be a promising addition to pediatric oncology care, since health care providers were generally positive about this innovation. However, psychosocial staff members seemed more reluctant. Important potential barriers were defined that should be addressed upon implementation.
Adverse Events in Infants Less Than 6 Months of Age After Ambulatory Surgery and Diagnostic Imaging Requiring Anesthesia
Authors: Uffman Joshua C. , Kim Stephani S. , Quan Loan N. , Shelton Thomas , Beltran Ralph J. , Jatana Kris R. , Chiang Tendy , Tobias Joseph D.
Published: July 2022

Introduction:

AAP guidelines recommend infants less than 6 months of age are monitored for at least 2 hours following surgery. This retrospective study evaluated if adherence to the 2-hour monitoring guideline decreased the risk of adverse events associated with ambulatory procedures in infants younger than 6 months.

Methods:

We queried the hospital’s electronic medical record to identify patients younger than 6 months of age who received anesthetic care from January 2015 to March 2020. Demographic data, intraoperative adverse events, and returns to the emergency department (ED) or urgent care within 7 days were captured for each patient. We calculated the number and frequency for categorical data and median and interquartile range (IQR) for continuous data. Chi-square or Fisher’s exact test were used to compare patients who experienced an adverse event to those that did not.

Results:

One thousand one hundred seventy-seven patients who had 1,261 unique anesthetic encounters were analyzed. Forty-four adverse events were identified, 20 (1.6%) before discharge, including 3 unplanned admissions, and 24 (1.9%) returns to the ED/UC within 7 days postoperatively. We did not observe differences in postoperative recovery time in patients who experienced an adverse event and those who did not (88 min vs. 77 min, respectively, P = 0.078). None of the ED/UC returns would have been avoided by a longer PACU stay.

Conclusions:

With the appropriate patient selection, once physiological discharge readiness is met, adherence to a strict 2-hour time-based discharge criteria does not increase safety for infants younger than 6 months of age after ambulatory procedures.
Attitudes and behaviors toward using outcome measures in clinical practice: Findings of a blended education program
Authors: Rapaport Malena Sofia , Negri Cara , Pousett Brittany Mae , Mathis Shannon
Published: July 2022

Background:

Outcome measures (OMs) are important in healthcare, but there are barriers to their use. A blended education program was designed to teach orthotic and prosthetic professionals a standard practice of collecting and using OMs in their facility. This study used a single group pretest and post-test mixed methods survey to evaluate the effects of a blended education program for orthotic and prosthetic professionals to incorporate OMs into routine clinical practice.

Methods:

Fifteen learners (seven practitioners, four technicians, and four administrative staff) completed online education and in-person training. Learners’ attitudes toward knowledge of confidence administering and rate of adoption of OMs into clinical practice were assessed before the start of the program, immediately upon completion, and four months after completion. Performance indicators were accessed through electronic medical records (EMRs).

Results:

Participants' attitudes toward OMs were overwhelmingly positive and remained positive (P = .64). Practitioners’ posteducation knowledge scores on the standardized use of OMs increased significantly (P = .046) as did their confidence administering OMs (F = 8.47, P = .007). Practitioners’ reported using OMs significantly more 4 months after the program (F = 19.7, P < .001), and they doubled the number of times OMs were collected each month resulting in a 3000% increase and a 500 data points recorded in the electronic medical record at the end of the 4 months.

Conclusions:

This education program had a significant and positive lasting impact on practitioners’ knowledge of confidence and use of OMs demonstrating an overall change in everyday clinical practice and clinic operations.
Deep Learning-Enhanced Parallel Imaging and Simultaneous Multislice Acceleration Reconstruction in Knee MRI
Authors: Kim MinWoo , Lee Sang-Min , Park Chankue , Lee Dongeon , Kim Kang Soo , Jeong Hee Seok , Kim Shinyoung , Choi Min-Hyeok , Nickel Dominik
Published: July 2022

Objectives

This study aimed to examine various combinations of parallel imaging (PI) and simultaneous multislice (SMS) acceleration imaging using deep learning (DL)-enhanced and conventional reconstruction. The study also aimed at comparing the diagnostic performance of the various combinations in internal knee derangement and provided a quantitative evaluation of image sharpness and noise using edge rise distance (ERD) and noise power (NP), respectively.

Materials and Methods

The data from adult patients who underwent knee magnetic resonance imaging using various DL-enhanced acquisitions between June 2021 and January 2022 were retrospectively analyzed. The participants underwent conventional 2-fold PI and DL protocols with 4- to 8-fold acceleration imaging (P2S2 [2-fold PI with 2-fold SMS], P3S2, and P4S2). Three readers evaluated the internal knee derangement and the overall image quality. The diagnostic performance was calculated using consensus reading as a standard reference, and we conducted comparative evaluations. We calculated the ERD and NP for quantitative evaluations of image sharpness and noise, respectively. Interreader and intermethod agreements were calculated using Fleiss κ.

Results

A total of 33 patients (mean age, 49 ± 19 years; 20 women) were included in this study. The diagnostic performance for internal knee derangement and the overall image quality were similar among the evaluated protocols. The NP values were significantly lower using the DL protocols than with conventional imaging (P < 0.001), whereas the ERD values were similar among these methods (P > 0.12). Interreader and intermethod agreements were moderate-to-excellent (κ = 0.574–0.838) and good-to-excellent (κ = 0.755–1.000), respectively. In addition, the mean acquisition time was reduced by 47% when using DL with P2S2, by 62% with P3S2, and by 71% with P4S2, compared with conventional P2 imaging (2 minutes and 55 seconds).

Conclusions

The combined use of DL-enhanced 8-fold acceleration imaging (4-fold PI with 2-fold SMS) showed comparable performance with conventional 2-fold PI for the evaluation of internal knee derangement, with a 71% reduction in acquisition time.
High-Accuracy Nodal Staging of Head and Neck Cancer With USPIO-Enhanced MRI
Authors: Driessen Daphne A.J.J. , Zámecnik Patrik , Dijkema Tim , Pegge Sjoert A.H. , van Engen-van Grunsven Adriana C.H. , Takes Robert P. , Kaanders Johannes H.A.M. , Scheenen Tom W.J.
Published: July 2022

Objectives

Ultrasmall superparamagnetic iron oxide (USPIO)–enhanced magnetic resonance imaging (MRI) is a potential diagnostic tool for lymph node assessment in patients with head and neck cancer. Validation by radiologic-pathologic correlation is essential before the method is evaluated in clinical studies. In this study, MRI signal intensity patterns of lymph nodes are correlated to their histopathology to develop a new USPIO-enhanced MRI reading algorithm that can be used for nodal assessment in head and neck cancer patients.

Materials and Methods

Ten head and neck cancer patients underwent in vivo USPIO-enhanced MRI before neck dissection. An ex vivo MRI of the neck dissection specimen was performed for precise coregistration of in vivo MRI with histopathology. Normal clinical histopathological workup was extended with meticulous matching of all lymph nodes regarded as potentially metastatic based on their in vivo MRI signal intensity pattern. On the basis of histopathology of resected nodes, in vivo MRI signal characteristics were defined separating benign from malignant lymph nodes.

Results

Fifteen of 34 node-to-node correlated lymph nodes with remaining signal intensity on T2*-weighted MRI were histopathologically metastatic and 19 were benign. Radiological analysis revealed that metastatic lymph nodes showed equal or higher MRI signal intensity when compared with lipid tissue on T2*-weighted MGRE sequence (15/16 lymph nodes; 94%), whereas healthy lymph nodes showed lower (17/19 lymph nodes; 89%) or complete attenuation of signal intensity (273/279; 98%) when compared with lipid tissue on T2*-weighted MGRE. Histopathology of all resected specimens identified 392 lymph nodes. Six lymph nodes with (micro)metastases were missed with in vivo MRI. Whether these 6 lymph nodes were correlated to a nonmalignant lymph node on in vivo MRI or could not be detected at all is unclear.

Conclusions

We developed a new reading algorithm to differentiate benign from malignant lymph nodes in head and neck cancer patients on the basis of their appearance on high-resolution T2*-weighted USPIO-enhanced MRI. Next steps involve validation of our reading algorithm to further improve the accuracy of neck lymph node staging with USPIO-enhanced MRI in prospective clinical studies with larger number of patients.
Active search signatures in a free-viewing task exploiting concurrent EEG and eye movements recordings
Authors: Care Damián , da Fonseca María , Ison Matias J. , Kamienkowski Juan E.
Published: July 2022

Tasks we often perform in our everyday lives, such as reading or looking for a friend in the crowd, are seemingly straightforward but they actually require the orchestrated activity of several cognitive processes. Free-viewing visual search requires a plan to move our gaze on the different items, identifying them, and deciding on whether to continue with the search. Little is known about the electrophysiological signatures of these processes in free-viewing since there are technical challenges associated with eye movement artifacts. Here we aimed to study how category information, as well as ecologically-relevant variables such as the task performed, influence brain activity in a free-viewing paradigm. Participants were asked to observe/search from an array of faces and objects embedded in random noise. We concurrently recorded EEG and eye movements and applied a deconvolution analysis approach to estimate the contribution of the different elements embedded in the task. Consistent with classical fixed-gaze experiments and a handful of free-viewing studies, we found a robust categorical effect around 150 ms in occipital and occipitotemporal electrodes. We also report a task effect, more negative in posterior central electrodes in visual search compared to exploration, starting at around 80 ms. We also found significant effects of trial progression, and an interaction with the task effect. Overall, these results generalise the characterisation of early visual face processing to a wider range of experiments and show how a suitable analysis approach allows to discern among multiple neural contributions to the signal, preserving key attributes of real-world tasks.
Single nuclei RNAseq analysis of HD mouse models and human brain reveals impaired oligodendrocyte maturation and potential role for thiamine metabolism
Authors: Lim Ryan G. , Al-Dalahmah Osama , Wu Jie , Gold Maxwell P. , Reidling Jack C. , Tang Guomei , Adam Miriam , Dansu David , Park Hye-Jin , Casaccia Patricia , Miramontes Ricardo , Reyes-Ortiz Andrea M. , Lau Alice , Khan Fatima , Paryani Fahad , Tang Alice , Ofori Kenneth , Miyoshi Emily , Michael Neethu , Geller Nicolette , Flowers Xena E. , Vonsattel Jean Paul , Davidson Shawn , Menon Vilas , Swarup Vivek , Fraenkel Ernest , Goldman James E. , Thompson Leslie M.
Published: July 2022

The complexity of affected brain regions and cell types is a challenge for Huntington’s disease (HD) treatment. Here we used single nucleus RNA sequencing (snRNAseq) to investigate mechanism of pathology in the cortex and striatum from R6/2 mice at 8 and 12w and in three regions of human HD post-mortem tissue. We identified cell type-specific and cell agnostic signatures and found changes suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) were arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 were negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells showed decreased accessibility of sites regulated by OL maturation genes. Glucose and lipid metabolism were implicated in abnormal cell maturation and PRKCE and Thiamine Pyrophosphokinase 1 were identified as central genes. High dose thiamine/biotin treatment of R6/1 HD mice to target thiamine metabolism not only restored OL maturation, but also rescued pathology in neurons. These findings reveal insights into HD OL pathology that spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.
The suppressive potential of a gene drive in populations of invasive social wasps is currently limited
Authors: Meiborg Adriaan B. , Faber Nicky R. , Taylor Benjamin A. , Harpur Brock A. , Gorjanc Gregor
Published: July 2022

Social insects are very successful invasive species, and the continued increase of global trade and transportation has exacerbated this problem. The yellow-legged hornet, Vespa velutina nigrithorax (henceforth Asian hornet), is drastically expanding its range in Western Europe. As an apex insect predator, this hornet poses a serious threat to the honey bee industry and endemic pollinators. Current suppression methods have proven too inefficient and expensive to limit its spread. Gene drives might be an effective tool to control this species, but their use has not yet been thoroughly investigated in social insects. Here, we built a model that matches the hornet’s life history and modelled the effect of different gene drive scenarios on an established invasive population. To test the broader applicability and sensitivity of the model, we also incorporated the invasive European paper wasp Polistes dominula. We find that although a gene drive can spread through a social wasp population, it can only do so under stringent gene drive-specific conditions. The main issue is that the large number of offspring that social wasp colonies produce guarantees that, even with very limited formation of resistance alleles, such alleles will quickly spread and rescue the population. Furthermore, we find that only a gene drive targeting female fertility is promising for population control due to the haplodiploidy of social insects. Nevertheless, continued improvements in gene drive technology may make it a promising method for the control of invasive social insects.
Prediction of mammalian tissue-specific CLOCK-BMAL1 binding to E-box motifs
Authors: Marri Daniel , Filipovic David , Kana Omar , Tischkau Shelley , Bhattacharya Sudin
Published: July 2022

The mammalian circadian clock is based on a core intracellular gene regulatory network, coordinated by communication between the central nervous system and peripheral tissues like the liver. Transcriptional and translational feedback loops underlie the molecular mechanism of circadian oscillation and generate its 24 h periodicity. The Brain and muscle Arnt-like protein-1 (Bmal1) forms a heterodimer with Circadian Locomotor Output Cycles Kaput (Clock) that binds to E-box gene regulatory elements, activating transcription of clock genes. In this work we aimed to develop a predictive model of genome-wide CLOCK-BMAL1 binding to E-box motifs. We found over-representation of the canonical E-box motif CACGTG in BMAL1-bound regions in accessible chromatin of the mouse liver, heart and kidney. We developed three different tissue-specific machine learning models based on DNA sequence, DNA sequence plus DNA shape, and DNA sequence and shape plus histone modifications. Combining DNA sequence with DNA shape and histone modification features yielded improved transcription factor binding site prediction. Further, we identified the genomic and epigenomic features that best correlate to the binding of BMAL1 to DNA. The DNA shape features Electrostatic Potential, Minor Groove Width and Propeller Twist together with the histone modifications H3K27ac, H3K4me1, H3K36me3, and H3K4me3 were the features most highly predictive of DNA binding by BMAL1 across all three tissues.
Neural Population Dynamics of Computing with Synaptic Modulations
Authors: Aitken Kyle , Mihalas Stefan
Published: July 2022

In addition to long-time scale rewiring, synapses in the brain are subject to significant modulation that occurs at much shorter time scales and allows them to process short-term information. Despite this, models of the brain like recurrent neural networks (RNNs) often have their weights frozen after training, relying on an internal state stored in neuron activity to process temporal information. Although networks with dynamical synapses have been explored previously, often said dynamics are added to networks that also have recurrent connections and thus the short-time scale computational capabilities of synapse modulation alone remain unclear. In this work, we analyze the dynamics of a network that relies solely on synaptic modulations to process short-time scale information, the multi-plasticity network (MPN). We thoroughly examine the neural population dynamics of the MPN trained on integration-based tasks and compare it to known RNN dynamics, findings the two to have fundamentally different behavior and attractor structure. We find said differences in dynamics allow the MPN to outperform its RNN counterparts on several neuroscience-relevant tasks. Of note, the MPN has a significantly simpler attractor structure that allows it to be more flexible in training and sequential-learning settings. Lastly, how the dynamics change for MPNs trained on contextual and continuous integration tasks is also investigated.
Retrieving fMRI data in real-time: difficulties and pitfalls
Authors: Lührs Michael , Poser Benedikt A , Auer Tibor , Goebel Rainer
Published: July 2022

One of the significant challenges in real-time fMRI environments is to ensure that the functional images are exported in real-time. The prerequired ability to reconstruct these images immediately after the acquisition has already been resolved in 2004. Nowadays, more sophisticated sequences allow for higher resolution and faster repetition times and thereby challenging the ability to export this data in real-time. In this article, we tackle the potentially arising problem of sending the reconstructed data from the MRI to an external PC to perform the real-time fMRI analysis. We show that depending on the implementation of the data transfer, long delays can occur that can differ drastically in time and how often they occur. In addition, we propose a solution for SIEMENS MRI devices which was tested and applied already on multiple MRI devices including 3T and 7T machines on different vendor software versions. This new technique can be used as a blueprint that can be directly applied to other manufacturers. We also provide the source code of the described solution and show that the delay in the data transfer can be significantly reduced to a tolerable level using our proposed procedure. Finally, we integrate measurement options for the data transfer times to improve quality measures in real-time fMRI environments (e.g., clinical) that can implement the proposed solution. Efforts should be taken by the real-time community and MRI manufacturers to employ a standardized real-time export e.g., similar to the lab streaming layer which is used as a standard export method in EEG environments.
Quantification of Receptor Binding from Response Data Obtained at Different Receptor Levels: A Simple Individual Sigmoid Fitting and a Unified SABRE Approach
Authors: Buchwald Peter
Published: July 2022

Methods that allow quantification of receptor binding (occupancy) by measuring response (effect) data only are of interest as they can be used to allow characterization of binding properties (e.g., dissociation constant, Kd) without having to perform explicit ligand binding experiments that require different setups (e.g., use of labeled ligands). However, since response depends not just on the binding affinity-determined receptor occupancy, but also on receptor activation, which is affected by ligand efficacy (plus constitutive activity, if present), and downstream pathway amplification, this requires the acquisition and fitting of multiple concentration-response data. Here, two alternative methods, which both are straightforward to implement using nonlinear regression software, are described to fit such multiple responses measured at different receptor levels that can be obtained, for example, by partial irreversible receptor inactivation (i.e., Furchgott method) or different expression levels. One is a simple method via straightforward fitting of each response with sigmoid functions and estimation of Kd from the obtained Emax and EC50 values as Kd=(Emax·EC’50−E’max·EC50)/(Emax−E’max). This is less error-prone than the original Furchgott method of double-reciprocal fit and simpler than alternatives that require concentration interpolations, thus, should allow more widespread use of this so-far underutilized approach to estimate binding properties. Relative efficacies can then be compared using Emax·Kd/EC50 values. The other is a complex method that uses the SABRE receptor model to obtain a unified fit of the multiple concentration-response curves with a single set of parameters that include binding affinity Kd, efficacy ε, amplification γ, and Hill coefficient n. Illustrations with simulated and experimental data are presented including with activity data of three muscarinic agonists measured in rabbit myocardium.
Electrical Signaling in Cochlear Efferents is Driven by an Intrinsic Neuronal Oscillator
Authors: Hong Hui , Trussell Laurence O
Published: July 2022

Efferent neurons are believed to play essential roles in maintaining auditory function. The lateral olivocochlear (LOC) neurons, which project from the brainstem to the inner ear where they release multiple transmitters including peptides, catecholamines and acetylcholine, are the most numerous yet least understood elements of efferent control of the cochlea. Usingin vitrocalcium imaging and patch-clamp recordings, we found that LOC neurons in juvenile and young adult mice exhibited extremely slow waves of activity (~0.1 Hz). These seconds-long bursts of Na+spikes were driven by an intrinsic oscillator dependent on L-type Ca2+channels, and were not observed in prehearing mice, suggesting an age-dependent mechanism underlying the intrinsic oscillator. Using optogenetic approaches, we identified both ascending (cochlear nucleus) and descending (auditory cortex) sources of synaptic excitation, as well as the synaptic receptors used for such excitation. Additionally, we identified potent inhibition originating in the glycinergic medial nucleus of trapezoid body (MNTB). Conductance-clamp experiments revealed an unusual mechanism of electrical signaling in LOC neurons, in which synaptic excitation and inhibition served to switch on and off the intrinsically generated spike burst mechanism, allowing for prolonged periods of activity or silence controlled by brief synaptic events. Protracted bursts of action potentials may be essential for effective exocytosis of the diverse transmitters released by LOC fibers in the cochlea.

Significance Statement

The lateral olivocochlear (LOC) neurons, being the most abundant auditory efferent control of the ear, remained largely unexplored. Here we reported that LOC neurons displayed patterned electrical activity at an unusually slow pace (~0.1 Hz), mediated by a calcium-dependent intrinsic oscillator. This is surprising given the speed and precision were believed to be the currency of signaling in the lower auditory system. Optogenetic experiments determined the glutamatergic and glycinergic sources of synaptic inputs to these neurons, while conductance-clamp experiments revealed that synaptic activity acts like switches for turning on or off prolonged spike activity driven by the intrinsic oscillator. This extended spike activity may be essential for effective exocytosis of the diverse transmitters released by LOC fibers in the cochlea.
A prebiotic diet modulates microglial states and motor deficits in α-synuclein overexpressing mice
Authors: Abdel-Haq Reem , Schlachetzki Johannes C.M. , Boktor Joseph C. , Cantu-Jungles Thaisa M. , Thron Taren , Zhang Mengying , Bostick John W. , Khazaei Tahmineh , Chilakala Sujatha , Morais Livia H. , Humphrey Greg , Keshavarzian Ali , Katz Jonathan E. , Thomson Matt , Knight Rob , Gradinaru Viviana , Hamaker Bruce R. , Glass Christopher K. , Mazmanian Sarkis K.
Published: July 2022

Parkinson’s disease (PD) is a movement disorder characterized by neuroinflammation, α-synuclein pathology, and neurodegeneration. Most cases of PD are non-hereditary, suggesting a strong role for environmental factors, and it has been speculated that disease may originate in peripheral tissues such as the gastrointestinal (GI) tract before affecting the brain. The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, though mechanisms of gut-brain interactions remain incompletely defined. Intestinal bacteria ferment dietary fibers into short-chain fatty acids, with fecal levels of these molecules differing between PD and healthy controls and in mouse models. Among other effects, dietary microbial metabolites can modulate activation of microglia, brain-resident immune cells implicated in PD. We therefore investigated whether a fiber-rich diet influences microglial function in α-synuclein overexpressing (ASO) mice, a preclinical model with PD-like symptoms and pathology. Feeding a prebiotic high-fiber diet attenuates motor deficits and reduces α-synuclein aggregation in the substantia nigra of mice. Concomitantly, the gut microbiome of ASO mice adopts a profile correlated with health upon prebiotic treatment, which also reduces microglial activation. Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum uncovers increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to wild-type counterparts on standard diets. However, prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of protective disease-associated macrophage (DAM) subsets of microglia. Notably, depletion of microglia using a CSF1R inhibitor eliminates the beneficial effects of prebiotics by restoring motor deficits to ASO mice despite feeding a prebiotic diet. These studies uncover a novel microglia-dependent interaction between diet and motor symptoms in mice, findings that may have implications for neuroinflammation and PD.
Induced CD45 Proximity Potentiates Natural Killer Cell Receptor Antagonism
Authors: Ren Junming , Jo Yeara , Picton Lora K. , Su Leon L. , Raulet David H , Garcia K. Christopher
Published: July 2022

Natural Killer (NK) cells are a major subset of innate immune cells that are essential for host defense against pathogens and cancer. Two main classes of inhibitory NK receptors (NKR), KIR and CD94/NKG2A, play a key role in suppressing NK activity upon engagement with tumor cells or virus infected cells, limiting their antitumor and antiviral activity. Here, we find that single-chain mouse NKR antagonists linked to a VHH that binds the cell surface phosphatase CD45 potentiate NK and T activity to a greater extent than NKR blocking antibodies alone in vitro. We also uncovered crosstalk between mouse NKG2A and Ly49 that collectively inhibit NK cell activation, such that CD45-NKG2A and CD45-Ly49 bispecific molecules show synergistic effects in their ability to enhance NK cell activation. The basis of the activity enhancement by CD45 ligation may reflect greater antagonism of inhibitory signaling from engagement of MHC I on target cells, combined with other mechanisms, including avidity effects, tonic signaling, antagonism of weak inhibition from engagement of MHC I on non-target cells and possibly CD45 segregation within the NK cell-target cell synapse. These engineered ligands uncover a mechanism for enhancing the activity of mouse NK and T cells that merits evaluation in the context of human NKR antagonist cancer immunotherapies.
Modelling of immune response in chronic myeloid leukemia patients suggests potential for treatment reduction prior to cessation
Authors: Karg Elena , Baldow Christoph , Zerjatke Thomas , Clark Richard E , Roeder Ingo , Fassoni Artur C. , Glauche Ingmar
Published: July 2022

Tyrosine kinase inhibitors (TKI) are highly efficient drugs to combat Chronic Myeloid Leukemia (CML). While long-term drug administration is associated with side effects and high economic costs, current efforts focus on the discontinuation of TKI therapy for well-responding patients. The DESTINY trial showed that TKI dose reduction prior to cessation can lead to an increased number of patients achieving sustained treatment free remission (TFR). However, there has been no systematic investigation to evaluate how dose reduction regimens can further improve the success of TKI stop trials.

Here, we apply an established mathematical model of CML therapy to investigate different TKI dose reduction schemes prior to therapy cessation and evaluate them with respect to the total amount of drug used and the expected TFR success. Our analysis is based on a cohort of 72 patients from the DESTINY trial for which we obtained individual model fits.

Our systematic analysis confirms clinical findings that the overall time of TKI treatment is a major determinant of TFR success, while highlighting that lower dose TKI treatment for the same duration is equally sufficient for many patients. Applying the model to an unstratified cohort of CML patients in deep remission our results suggest that a stepwise dose reduction prior to TKI cessation can increase the success rate of TFR, while substantially reducing the amount of administered TKI.

Our findings illustrate the potential of dose reduction schemes prior to treatment cessation and suggest corresponding and clinically testable strategies that are applicable to many CML patients.

Discontinuation of tyrosine kinase inhibitor (TKI) treatment is emerging as the main therapy goal for patients suffering from Chronic Myeloid Leukemia, although it is not clear how dose reduction regimens can improve the achievement of treatment free remission (TFR). Our systematic analysis uses mathematical models of leukemia-immune interaction to show that a stepwise dose reduction prior to TKI cessation can potentially increase the success rate of TFR, while substantially reducing the amount of total administered TKI.
Evidence of selection in UCP1 gene region suggests local adaptation to irradiance rather than cold temperatures in savanna monkeys (Chlorocebus spp.)
Authors: Gagnon Christian M. , Svardal Hannes , Jasinska Anna J. , Cramer Jennifer Danzy , Freimer Nelson B. , Grobler J. Paul , Turner Trudy R. , Schmitt Christopher A.
Published: July 2022

The genus Chlorocebus is widely distributed throughout sub-Saharan Africa, and in the last 300 thousand years expanded from equatorial Africa into the southernmost latitudes of the continent. In these new environments, colder climate was a likely driver of natural selection. We investigated population-level genetic variation in the mitochondrial uncoupling protein 1 (UCP1) gene region – implicated in non-shivering thermogenesis within brown/beige adipocytes – in 73 wild savanna monkeys from three taxa representing this southern expansion (C. pygerythrus hilgerti, C. cynosuros, C. p. pygerythrus) ranging from Kenya to South Africa. We found 17 SNPs with extended haplotype homozygosity consistent with positive selective sweeps, 10 of which show no significant LD with each other. Phylogenetic generalized least squares modeling with ecological covariates suggest that most derived allele frequencies are significantly associated with solar irradiance and winter precipitation, rather than overall low temperatures. This selection and association with irradiance appears to be driven by a population isolate in the southern coastal belt of South Africa. We suggest that sunbathing behaviors common to savanna monkeys, in combination with strength of solar irradiance, may mediate adaptations to thermal stress via non-shivering thermogenesis among savanna monkeys. The variants we discovered all lie in non-coding regions, some with previously documented regulatory functions, calling for further validation and research.
Adaptive duplication and functional diversification of Protein kinase R contribute to the uniqueness of bat-virus interactions
Authors: Jacquet Stéphanie , Culbertson Michelle , Zang Chi , El Filali Adil , De La Myre Mory Clément , Pons Jean-Baptiste , Filippi-Codaccioni Ondine , Lauterbur M. Elise , Ngoubangoye Barthélémy , Duhayer Jeanne , Verez Clément , Park Chorong , Dahoui Clara , Carey Clayton M. , Brennan Greg , Enard David , Cimarelli Andrea , Rothenburg Stefan , Elde Nels C. , Pontier Dominique , Etienne Lucie
Published: July 2022

Several bat species act as asymptomatic reservoirs for many viruses that are instead highly pathogenic in other mammals. Here, we have characterized the functional diversification of the Protein kinase R (PKR), a major antiviral innate defense system. Our data indicate that PKR has evolved under positive selection and has undergone repeated genomic duplications in bats, in contrast to all studied mammals that possess a single copy of the gene. Functional testing of the relationship between PKR and poxvirus antagonists revealed how an evolutionary conflict with ancient pathogenic poxviruses has shaped a specific bat host-virus interface. More importantly, we determined that duplicated PKRs of the Myotis species have undergone functional diversification allowing them to collectively escape from and enhance control of DNA and RNA viruses. These findings suggest that viral-driven adaptations in PKR contribute to modern virus-bat interactions and may account for bat specific immunity.
Linking impulsivity to activity levels in pre-supplementary motor area during sequential gambling
Authors: Lohse Allan , Løkkegaard Annemette , Siebner Hartwig R. , Meder David
Published: July 2022

Impulsivity refers to the tendency to act prematurely or without forethought, and excessive impulsivity is a key problem in many neuropsychiatric disorders. Since the pre-supplementary motor area (preSMA) has been implicated in inhibitory control, this region may also contribute to impulsivity. Here, we examined whether functional recruitment of preSMA may contribute to risky choice behavior (state impulsivity) during sequential gambling and its relation to self-reported trait impulsivity. To this end, we performed task-based functional MRI (fMRI) after low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of the preSMA. We expected low-frequency rTMS to modulate task-related engagement of the preSMA and hereby, tune the tendency to make risky choices. 24 healthy volunteers (12 females, 19-52 years) received real or sham rTMS on separate days in counterbalanced order. Thereafter, participants performed a sequential gambling task with concurrently increasing stakes and risk during whole-brain fMRI. In the sham-rTMS session, self-reported trait impulsivity scaled positively with state impulsivity (riskier choice behavior) during gambling. The higher the trait-impulsivity, the lower was the task-related increase in preSMA activity with increasingly risky choices. Following real-rTMS, low-impulsivity participants increased their preference for risky choices, while the opposite was true for high-impulsivity participants resulting in an overall decoupling of trait impulsivity and state impulsivity during gambling. This rTMS-induced behavioral shift was mirrored in the rTMS-induced change in preSMA activation. These results provide converging evidence for a causal link between the level of task-related preSMA activity and the propensity for impulsive risk-taking behavior in the context of sequential gambling.

Significance statement

Impulsivity is a personal trait characterized by a tendency to act prematurely or without forethought, and excessive impulsivity is a key problem in many neuropsychiatric disorders. The pre-supplementary motor area (preSMA) has been implicated in inhibitory control. Here, we provide evidence that this region contributes to the implementation of general impulsive tendencies (trait impulsivity) into actual behavior (state impulsivity). When healthy volunteers performed a sequential gambling task, their choice behavior (i.e., state impulsivity) correlated positively with their impulsivity score (i.e, trait impulsivity). Additionally, participants with lower trait impulsivity showed a stronger increase in task-related activity of the preSMA with increasing risk. Both of these relationships were uncoupled after perturbing the preSMA with repetitive transcranial stimulation (rTMS).