bluuebunny/crossref_metadata_2025 huggingface dataset:
APPLICATION OF EXCHABODY TECHNOLOGY FOR PAIRING VHHS TO ACHIEVE SYNERGISTIC EFFECTS
Authors: Luo Yi , Zhan Xiaoxiao , Shen Yilong , Sheng Ziyang , Zhu Yin , Huang Mingyue
Published: July 2023

Objective

Single-domain antibodies, such as VHH and nanobody, have shown potential for use in therapy and diagnostics. One application of VHHs is the tethering of two fragments to different epitopes on the same target, which is difficult to achieve with conventional antibodies. Synergistic heterologous VHH dimers have higher affinity, better specificity, and broad applications in developing high-affinity monoclonal antibodies, bispecific antibodies, ADCs, and CAR-Ts. However, finding the best pair of VHHs for these applications requires combinational screening, which is traditionally a time-consuming and costly process.

The objective of this study is to develop a technology that can quickly screen and pair two synergistic VHHs without the need to express tandem VHH dimers.

Methods

The researchers developed proprietary tags and specific dockers that, when stabilized on a solid station, can capture any VHHs that the dockers recognize and pull them together to form a non-covalent dimer. This platform is called ExchaBody technology, and the VHH dimers formed this way are ExchaBodies. The researchers used this technology to conduct a bi-epitope screening campaign, where VHHs were first expressed as monomers with tags and then binned and grouped into different categories. VHHs were then paired with all reasonable combinations using ExchaBody technology, and these ExchaBodies were evaluated for their combined activities.

Results

ExchaBody technology was able to link any two VHHs together within one hour, and the resulting ExchaBodies had bivalent or bifunctional VHH activities. The bi-epitope VHH screening campaign, which would have taken months to complete using traditional methods, was finished within two weeks using ExchaBody technology, saving time and cost. The researchers were able to construct two lead molecules, a bi-specific VHH-Fc fusion protein and a tri-valent VHH molecule, using ExchaBody technology. These lead molecules were found to be superior to their counterparts on the market based on affinity and functional assays.

Conclusion

ExchaBody technology is a bispecific VHH screening and pairing platform that can quickly and cost-effectively create non-covalent, bispecific VHHs (ExchaBodies) without the need to express them. ExchaBodies possess the binding and cellular activities of a covalently linked, bispecific, tandem VHH dimer. This technology has broad applications in developing high-affinity monoclonal antibodies, bispecific antibodies, ADCs, and CAR-Ts.
‘Our Practice Has a Superiority:’ Debt Enforcement, Bills of Exchange, and Credit in Eighteenth-Century Glasgow
Authors: Harris Hunter
Published: July 2023

This article explores the relationship between the Scots law of bills of exchange, debt enforcement procedures, and credit in the eighteenth century. Compared to England, Scots law’s procedures for recovering debts on obligations were faster, cheaper, and more efficient. These legal provisions are under-appreciated in the current literature on bills of exchange. Scots law’s superiority meant that the provision of medium-value credit in urban economies often occurred through written obligations. Using a new archival data set of nearly 300 bills of exchange from Glasgow, this article demonstrates how Glaswegians used those instruments. It finds that elements of the law of obligations traditionally stressed in the literature, namely negotiability, do little to explain the use of credit instruments in Glasgow. Instead, it was Scots law’s quick recovery procedures that account for their patterns of use. The data shows that inland bills did not commonly pass from hand to hand but instead were held as proofs of debt that could quickly be enforced. The advantage of Scots law in this area did not go unnoticed by contemporaries, and unsuccessful attempts at legal reform in the Victorian era sought to introduce the Scottish rules to the English system. This article joins a growing literature in turning scholarly focus away from the negotiable properties of bills, and shows the importance of expedited enforcement procedures for understanding the Scots credit system. It suggests that paying closer attention to procedural law and differences between jurisdictions can advance research agendas on the relationship between law and economic development.
The CXCL12-CXCR4-NLRP3 axis promotes Schwann cell pyroptosis and sciatic nerve demyelination in rats
Authors: Li Wei , Liang Jie , Li Shaohua , Jiang Suli , Song Meiying , Xu Shuo , Wang Luoyang , Meng Haining , Zhai Dongchang , Tang Lei , Yang Yanyan , Zhang Bei
Published: July 2023

Studies have shown that the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is detrimental to the functional recovery of the sciatic nerve, but the regulatory mechanisms of the NLRP3 inflammasome in peripheral nerves are unclear. C-X-C motif chemokine 12 (CXCL12) can bind to C-X-C chemokine receptor type 4 (CXCR4) and participate in a wide range of nerve inflammation by regulating the NLRP3 inflammasome. Based on these, we explore whether CXCL12-CXCR4 axis regulates the NLRP3 inflammasome in the peripheral nerve. We found that CXCR4/CXCL12, NLRP3 inflammasome-related components, pyroptosis-related proteins and inflammatory factors in the sciatic nerve injured rats were markedly increased compared with the sham-operated group. AMD3100, a CXCR4 antagonist, reverses the activation of NLRP3 inflammasome, Schwann cell pyroptosis and sciatic nerve demyelination. We further treated rat Schwann cells with LPS (lipopolysaccharide) and adenosine triphosphate (ATP) to mimic the cellular inflammation model of sciatic nerve injury, and the results were consistent with those in vivo. In addition, both in vivo and in vitro experiments demonstrated that AMD3100 treatment reduced the phosphorylation of nuclear factor κB (NF-κB) and the expression of thioredoxin interacting protein (TXNIP), which contributes to activating NLRP3 inflammasome. Therefore, our findings suggest that, after sciatic nerve injury, CXCL12-CXCR4 axis may promote Schwann cell pyroptosis and sciatic nerve demyelination through activating NLRP3 inflammasome and slow the recovery process of the sciatic nerve.
Exoprotease exploitation and social cheating in a Pseudomonas aeruginosa environmental lysogenic strain with a noncanonical quorum sensing system
Authors: Huelgas-Méndez Daniel , Cazares Daniel , Alcaraz Luis David , Ceapã Corina Diana , Cocotl-Yañez Miguel , Shotaro Toya , Maeda Toshinari , Fernández-Presas Ana María , Tostado-Islas Oswaldo , González-Vadillo Ana Lorena , Limones-Martínez Aldo , Hernandez-Cuevas Carlos Eduardo , González-García Karen , Jiménez-García Luis Felipe , Martínez Reyna-Lara , Santos-López Cristian Sadalis , Husain Fohad Mabood , Khan Altaf , Arshad Mohammed , Kokila Kota , Wood Thomas K , García-Contreras Rodolfo
Published: July 2023

Social cheating is the exploitation of public goods that are costly metabolites, like exoproteases. Exoprotease exploitation in Pseudomonas aeruginosa has been studied in reference strains. Experimental evolution with reference strains during continuous growth in casein has demonstrated that nonexoprotease producers that are lasR mutants are selected while they behave as social cheaters. However, noncanonical quorum-sensing systems exist in P. aeruginosa strains, which are diverse. In this work, the exploitation of exoproteases in the environmental strain ID4365 was evaluated; ID4365 has a nonsense mutation that precludes expression of LasR. ID4365 produces exoproteases under the control of RhlR, and harbors an inducible prophage. As expected, rhlR mutants of ID4365 behave as social cheaters, and exoprotease-deficient individuals accumulate upon continuous growth in casein. Moreover, in all continuous cultures, population collapses occur. However, this also sometimes happens before cheaters dominate. Interestingly, during growth in casein, ID4565’s native prophage is induced, suggesting that the metabolic costs imposed by social cheating may increase its induction, promoting population collapses. Accordingly, lysogenization of the PAO1 lasR mutant with this prophage accelerated its collapse. These findings highlight the influence of temperate phages in social cheating.
Probing cytoplasmic peroxide metabolism in Shewanella oneidensis
Authors: Toporek Yael , Pak David , Snyder Hannah , Shin Hyun-Dong , DiChristina Thomas J
Published: July 2023

The facultative anaerobe Shewanella oneidensis respires an extensive set of electron acceptors and, as a consequence, can leak electrons to produce reactive oxygen species such as hydrogen peroxide (H2O2). However, the effects of respiration on cytoplasmic redox homeostasis are poorly characterized in comparison. In the present study, the H2O2 sensor HyPer-3 was deployed to interrogate cytoplasmic peroxide levels of both wild-type and gene deletion mutants lacking peroxide scavenging enzymes following exposure to H2O2. HyPer-3 signals were validated in the S. oneidensis wild-type strain and exhibited a dynamic range of 0–250 μM H2O2. As reported by the HyPer-3 sensor, the cytoplasm of H2O2-perturbed mutant strains lacking periplasmic glutathione peroxidase (PgpD) and double deletion mutants lacking catalase (KatB) and bifunctional catalase-peroxidases (KatG1 or KatG2) contained high H2O2 concentrations. The high cytoplasmic H2O2 concentrations correlated with impaired H2O2 removal rates displayed by the mutant strains. Results of the present study provide the first in vivo interrogation of the redox environment of the S. oneidensis cytoplasm with HyPer-3 sensors and indicate that proper redox conditions in minimal growth medium are maintained by the concerted action of both well-known (periplasmic PgpD, cytoplasmic KatB and KatG1) and previously overlooked (cytoplasmic KatG2) peroxidases and catalases.
Learning curves of resection and reconstruction procedures in robotic-assisted pancreatoduodenectomy by a single surgeon: a retrospective cohort study of 160 consecutive cases
Authors: Huang Xi-Tai , Wang Xi-Yu , Xie Jin-Zhao , Cai Jian-Peng , Chen Wei , Chen Liu-Hua , Yin Xiao-Yu
Published: July 2023

Background

Robotic-assisted pancreatoduodenectomy (RPD) has been routinely performed in a few of centers worldwide. This study aimed to evaluate the perioperative outcomes and the learning curves of resection and reconstruction procedures in RPD by one single surgeon.

Methods

Consecutive patients undergoing RPD by a single surgeon at the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between July 2016 and October 2022 were included. The perioperative outcomes and learning curves were retrospectively analysed by using cumulative sum (CUSUM) analyses.

Results

One-hundred and sixty patients were included. According to the CUSUM curve, the times of resection and reconstruction procedures were shortened significantly after 30 cases (median, 284 vs 195 min; P < 0.001) and 45 cases (median, 138 vs 120 min; P < 0.001), respectively. The estimated intraoperative blood loss (median, 100 vs 50 mL; P < 0.001) and the incidence of clinically relevant post-operative pancreatic fistula (29.2% vs 12.5%; P = 0.035) decreased significantly after 20 and 120 cases, respectively. There were no significant differences in the total number of lymph nodes examined, post-operative major complications, or post-operative length-of-stay between the two groups.

Conclusions

Optimization of the resection procedure and the acquisition of visual feedback facilitated the performance of RPD. RPD was a safe and feasible procedure in the selected patients.
Potential Contribution of Ancient Introgression to the Evolution of a Derived Reproductive Strategy in Ricefishes
Authors: Flury Jana M , Meusemann Karen , Martin Sebastian , Hilgers Leon , Spanke Tobias , Böhne Astrid , Herder Fabian , Mokodongan Daniel F , Altmüller Janine , Wowor Daisy , Misof Bernhard , Nolte Arne W , Schwarzer Julia
Published: July 2023

Transitions from no parental care to extensive care are costly and involve major changes in life history, behavior, and morphology. Nevertheless, in Sulawesi ricefishes, pelvic brooding evolved from transfer brooding in two distantly related lineages within the genera Adrianichthys and Oryzias, respectively. Females of pelvic brooding species carry their eggs attached to their belly until the fry hatches. Despite their phylogenetic distance, both pelvic brooding lineages share a set of external morphological traits. A recent study found no direct gene flow between pelvic brooding lineages, suggesting independent evolution of the derived reproductive strategy. Convergent evolution can, however, also rely on repeated sorting of preexisting variation of an admixed ancestral population, especially when subjected to similar external selection pressures. We thus used a multispecies coalescent model and D-statistics to identify gene-tree–species-tree incongruencies, to evaluate the evolution of pelvic brooding with respect to interspecific gene flow not only between pelvic brooding lineages but also between pelvic brooding lineages and other Sulawesi ricefish lineages. We found a general network-like evolution in Sulawesi ricefishes, and as previously reported, we detected no gene flow between the pelvic brooding lineages. Instead, we found hybridization between the ancestor of pelvic brooding Oryzias and the common ancestor of the Oryzias species from the Lake Poso area. We further detected signs of introgression within the confidence interval of a quantitative trait locus associated with pelvic brooding in O. eversi. Our results hint toward a contribution of ancient standing genetic variation to the evolution of pelvic brooding in Oryzias.
A Reinvestigation of Multiple Independent Evolution and Triassic–Jurassic Origins of Multicellular Volvocine Algae
Authors: Ma Xiaoya , Shi Xuan , Wang Qiuping , Zhao Mengru , Zhang Zhenhua , Zhong Bojian
Published: July 2023

The evolution of multicellular organisms is considered to be a major evolutionary transition, profoundly affecting the ecology and evolution of nearly all life on earth. The volvocine algae, a unique clade of chlorophytes with diverse cell morphology, provide an appealing model for investigating the evolution of multicellularity and development. However, the phylogenetic relationship and timescale of the volvocine algae are not fully resolved. Here, we use extensive taxon and gene sampling to reconstruct the phylogeny of the volvocine algae. Our results support that the colonial volvocine algae are not monophyletic group and multicellularity independently evolve at least twice in the volvocine algae, once in Tetrabaenaceae and another in the Goniaceae + Volvocaceae. The simulation analyses suggest that incomplete lineage sorting is a major factor for the tree topology discrepancy, which imply that the multispecies coalescent model better fits the data used in this study. The coalescent-based species tree supports that the Goniaceae is monophyletic and Crucicarteria is the earliest diverging lineage, followed by Hafniomonas and Radicarteria within the Volvocales. By considering the multiple uncertainties in divergence time estimation, the dating analyses indicate that the volvocine algae occurred during the Cryogenian to Ediacaran (696.6–551.1 Ma) and multicellularity in the volvocine algae originated from the Triassic to Jurassic. Our phylogeny and timeline provide an evolutionary framework for studying the evolution of key traits and the origin of multicellularity in the volvocine algae.
Genomic analyses provide insights into the evolution and salinity adaptation of halophyte Tamarix chinensis
Authors: Liu Jian Ning , Fang Hongcheng , Liang Qiang , Dong Yuhui , Wang Changxi , Yan Liping , Ma Xinmei , Zhou Rui , Lang Xinya , Gai Shasha , Wang Lichang , Xu Shengyi , Yang Ke Qiang , Wu Dejun
Published: July 2023

Background

The woody halophyte Tamarix chinensis is a pioneer tree species in the coastal wetland ecosystem of northern China, exhibiting high resistance to salt stress. However, the genetic information underlying salt tolerance in T. chinensis remains to be seen. Here we present a genomic investigation of T. chinensis to elucidate the underlying mechanism of its high resistance to salinity.

Results

Using a combination of PacBio and high-throughput chromosome conformation capture data, a chromosome-level T. chinensis genome was assembled with a size of 1.32 Gb and scaffold N50 of 110.03 Mb. Genome evolution analyses revealed that T. chinensis significantly expanded families of HAT and LIMYB genes. Whole-genome and tandem duplications contributed to the expansion of genes associated with the salinity adaptation of T. chinensis. Transcriptome analyses were performed on root and shoot tissues during salt stress and recovery, and several hub genes responding to salt stress were identified. WRKY33/40, MPK3/4, and XBAT31 were critical in responding to salt stress during early exposure, while WRKY40, ZAT10, AHK4, IRX9, and CESA4/8 were involved in responding to salt stress during late stress and recovery. In addition, PER7/27/57/73 encoding class III peroxidase and MCM3/4/5/7 encoding DNA replication licensing factor maintained up/downregulation during salt stress and recovery stages.

Conclusions

The results presented here reveal the genetic mechanisms underlying salt adaptation in T. chinensis, thus providing important genomic resources for evolutionary studies on tamarisk and plant salt tolerance genetic improvement.
Sulfur oxidizing bacteria in agro ecosystem and its role in plant productivity—a review
Authors: Ranadev Praveen , Revanna Ashwin , Bagyaraj Davis Joseph , Shinde Ambika H
Published: July 2023

Sulfur (S) deficiency is becoming more common in agro-ecosystems worldwide due to factors such as agronomic practices, high biomass production, reduced sulfur emissions, and the use of non-sulfur fertilizers. This review explores the natural occurrence and commercial exploitation of sulfur pools in nature, the mineralization and immobilization of sulfur, the physiological role of sulfur in plants, and its deficiency symptoms. Additionally, the organic and inorganic forms of sulfur in soil, their transformations, and the process of microbiological oxidation of sulfur are discussed. The review also addresses the diversity of sulfur-oxidizing bacteria (SOB) and the various biochemical mechanisms involved in their role in plant productivity and soil reclamation. The measurement of S oxidation rate in soil and the variables that influence the process are also examined. Typically, the rate of oxidation of added elemental S is around 40%–51%, which is available for plant uptake. These characteristics of SOB demonstrate their potential as bioinoculants for increasing plant growth, indicating their use as biofertilizers for sustainable crop production in agro-ecosystems.
Examining standardized consumer-generated social determinants of health and resilience data supported by Omaha System terminology
Authors: Austin Robin R , Rajamani Sripriya , Jantraporn Ratchada , Pirsch Anna , Martin Karen S
Published: July 2023

Nursing terminologies like the Omaha System are foundational in realizing the vision of formal representation of social determinants of health (SDOH) data and whole-person health across biological, behavioral, social, and environmental domains. This study objective was to examine standardized consumer-generated SDOH data and resilience (strengths) using the MyStrengths+MyHealth (MSMH) app built using Omaha System. Overall, 19 SDOH concepts were analyzed including 19 Strengths, 175 Challenges, and 76 Needs with additional analysis around Income Challenges. Data from 919 participants presented an average of 11(SD = 6.1) Strengths, 21(SD = 15.8) Challenges, and 15(SD = 14.9) Needs. Participants with at least one Income Challenge (n = 573) had significantly (P < .001) less Strengths [9.4(6.4)], more Challenges [27.4(15.5)], and more Needs [15.1(14.9)] compared to without an Income Challenge (n = 337) Strengths [13.4(4.5)], Challenges [10.5(8.9)], and Needs [5.1(10.0)]. This standards-based approach to examining consumer-generated SDOH and resilience data presents a great opportunity in understanding 360-degree whole-person health as a step towards addressing health inequities.
Modelling UX Ori star eclipses based on spectral observations with the Nordic Optical Telescope − I. RR Tau
Authors: Grinin V P , Tambovtseva L V , Djupvik A A , Gahm G , Grenman T , Weber H , Bengtsson H , De Angelis H , Duszanowicz G , Heinonen D , Holmberg G , Karlsson T , Larsson M , Warell J , Wikander T
Published: July 2023

Based on observations obtained with the Nordic Optical Telescope (NOT) we investigate the spectral variability of the Herbig Ae star RR Tau. This star belongs to the UX Ori family, characterized by very deep fadings caused by the screening of the star with opaque fragments (clouds) of the protoplanetary discs. At the moments of such minima one observes strong spectral variability due to the fact that the dust cloud occults, for an observer, not only the star but also a part of the region where the emission spectrum originates. We calculated a series of obscuration models to interpret the observed variability of the H α line parameters. We consider two main obscuration scenarios: (1) the dust screen rises vertically above the circumstellar disc, and (2) the screen intersects the line-of-sight moving azimuthally with the disc. In both cases, the model of the emission region consists of a compact magnetosphere and a magnetocentrifugal disc wind. Comparison with observations shows that the first scenario explains well the variability of the radiation flux, the equivalent width, as well as the asymmetry of the H α line during eclipses, while the second scenario explains them only partly. This permits us to suggest that in the case of RR Tau, the main causes of the eclipses are either a structured disc wind, or the charged dust lifted along the field lines of the poloidal component of the magnetic field of the circumstellar disc.
Probing the variations in the timing of the Sun’s polar magnetic field reversals through observations and surface flux transport simulations
Authors: Golubeva Elena M , Biswas Akash , Khlystova Anna I , Kumar Pawan , Karak Bidya Binay
Published: July 2023

The polar field reversal is a crucial process in the cyclic evolution of the large-scale magnetic field of the Sun. Various important characteristics of a solar cycle, such as its duration and strength, and also the cycle predictability, are determined by the polar field reversal time. While the regular measurements of solar magnetic field have been accumulated for more than half a century, there is no consensus in the heliophysics community concerning the interpretation of the Sun’s polar field measurements and especially the determination of polar field reversal time. There exists a severe problem of non-reproducibility in the reported results even from studies of the same observational data set, and this causes an obstacle to make more accurate forecasts of solar cycle. Here, we analyze the solar magnetograms from four instruments for the last four cycles, to provide a more correct interpretation of the polar field observations and to find more accurate time of the reversals. We show the absence of triple (multiple) reversals in Cycles 21–24, significant variations in the time interval between reversals in the hemispheres and in the time interval between a reversal and a cycle beginning. In order to understand the origin of the reversal time variation, we perform Surface Flux Transport (SFT) simulations and find out that the presence of the ‘anomalous’ bipolar magnetic regions (BMRs) in different phases of a cycle can cause cycle-to-cycle variations of the reversal time within the similar range found in observations.
The role of magnetic fields in the formation of the filamentary infrared dark cloud G11.11–0.12
Authors: Chen Zhiwei , Sefako Ramotholo , Yang Yang , Jiang Zhibo , Su Yang , Zhang Shaobo , Zhou Xin
Published: July 2023

We report on the near-infrared polarimetric observations of G11.11–0.12 (hereafter G11) obtained with SIRPOL on the 1.4 m IRSF telescope. The starlight polarisation of the background stars reveals the on-sky component of magnetic fields in G11, and these are consistent with the field orientation observed from polarised dust emission at $850\, \mu$m. The magnetic fields in G11 are perpendicular to the filament, and are independent of the filament’s orientation relative to the Galactic plane. The field strength in the envelope of G11 is in the range $50-100\, \mu$G, derived from two methods. The analyses of the magnetic fields and gas velocity dispersion indicate that the envelope of G11 is supersonic but sub-Alfvénic. The critical mass-to-flux ratio in the envelope of G11 is close to 1 and increases to ≳ 1 on the spine of G11. The relative weights on the importance of magnetic fields, turbulence and gravity indicate that gravity dominates the dynamical state of G11, but with significant contribution from magnetic fields. The field strength, |B|, increases slower than the gas density, n, from the envelope to the spine of G11, characterized by |B|∝n0.3. The observed strength and orientation of magnetic fields in G11 imply that supersonic and sub-Alfvénic gas flow is channelled by the strong magnetic fields and is assembled into filaments perpendicular to the magnetic fields. The formation of low-mass stars is enhanced in the filaments with high column density, in agreement with the excess of low-mass protostars detected in the densest regions of G11.
CSDE1 promotes miR-451 biogenesis
Authors: Kakumani Pavan Kumar , Ko Yunkoo , Ramakrishna Sushmitha , Christopher Grace , Dodgson Maria , Shrinet Jatin , Harvey Louis-Mathieu , Shin Chanseok , Simard Martin J
Published: July 2023

MicroRNAs are sequentially processed by RNase III enzymes Drosha and Dicer. miR-451 is a highly conserved miRNA in vertebrates which bypasses Dicer processing and instead relies on AGO2 for its maturation. miR-451 is highly expressed in erythrocytes and regulates the differentiation of erythroblasts into mature red blood cells. However, the mechanistic details underlying miR-451 biogenesis in erythrocytes remains obscure. Here, we report that the RNA binding protein CSDE1 which is required for the development of erythroblasts into erythrocytes, controls the expression of miR-451 in erythroleukemia cells. CSDE1 binds miR-451 and regulates AGO2 processing of pre-miR-451 through its N-terminal domains. CSDE1 further interacts with PARN and promotes the trimming of intermediate miR-451 to the mature length. Together, our results demonstrate that CSDE1 promotes biogenesis of miR-451 in erythroid progenitors.
Analysis of recommended thresholds for medical evaluation in cases of radionuclide intakes
Authors: Reis Arlene , Sampaio Camilla , Sousa Wanderson , Aguiar Laís
Published: July 2023

Literature presents different thresholds for evaluation intended for screening people who may need additional medical assistance in cases of radionuclide intakes. There are thresholds based on the committed effective dose (CED), as well as thresholds based on the relative biological effectiveness-weighted absorbed dose (ADT) in the bone marrow and lungs. As in some emergency exposure scenarios with radionuclide intakes the risk for stochastic effects may be low whereas the threshold for deterministic effects may be exceeded, the aim of this analysis was to evaluate and to present the most appropriated threshold for each exposure scenario of interest. The results show that even adopting CED of 100 mSv as threshold for medical evaluation, it is important to screen for tissue reactions because in some scenarios the adopted threshold for deterministic effects is reached whilst the CED is below the adopted threshold value for stochastic effects.
The Impact of Physical Therapy After Lumbar Fusion Surgery
Authors: Heard Jeremy C. , Lee Yunsoo A. , Lambrechts Mark , Brush Parker , Issa Tariq Z. , Kanhere Arun , Bodner John , Purtill Caroline , Reddy Yashas C. , Patil Sanath , Somers Sydney , D’Antonio Nicholas D. , Mangan John J. , Canseco Jose A. , Woods Barrett R. , Kaye Ian D. , Rihn Jeff A. , Hilibrand Alan S. , Vaccaro Alexander R. , Kepler Christopher K. , Schroeder Gregory D.
Published: July 2023

Study Design:

Retrospective Cohort.

Objective:

To determine if outcomes varied between patients based on physical therapy (PT) attendance after lumbar fusion surgery.

Summary of Background Data:

The literature has been mixed regarding the efficacy of postoperative PT to improve disability and back pain, as measured by patient-reported outcome measures. Given the prevalence of PT referrals and lack of high-quality evidence, there is a need for additional studies investigating the efficacy of PT after lumbar fusion surgery to aid in developing robust clinical guidelines.

Methods:

We retrospectively identified patients receiving lumbar fusion surgery by current procedural terminology codes and separated them into 2 groups based on whether PT was prescribed. Electronic medical records were reviewed for patient and surgical characteristics, PT utilization, and surgical outcomes. Patient-reported outcome measures (PROMs) were identified and compared preoperatively, at 90 days postoperatively and one year postoperatively.

Results:

The two groups had similar patient characteristics and comorbidities and demonstrated no significant differences between readmission, complication, and revision rates after surgery. Patients that attended PT had significantly more fused levels (1.41 ± 0.64 vs. 1.32 ± 0.54, P=0.027), longer operative durations (234 ± 96.4 vs. 215 ± 86.1 min, P=0.012), and longer postoperative hospital stays (3.35 ± 1.68 vs. 3.00 ± 1.49 days, P=0.004). All groups improved similarly by Oswestry Disability Index, short form-12 physical and mental health subsets, and back and leg pain by Visual Analog Scale at 90-day and 1-year follow-up.

Conclusion:

Our data suggest that physical therapy does not significantly impact PROMs after lumbar fusion surgery. Given the lack of data suggesting clear benefit of PT after lumbar fusion, surgeons should consider more strict criteria when recommending physical therapy to their patients after lumbar fusion surgery.

Level of Evidence:

Level—Ⅲ
Differential Roles of Interleukin-6 in Severe Acute Respiratory Syndrome-Coronavirus-2 Infection and Cardiometabolic Diseases
Authors: Ren Jingjing , Wang Xiao-Qi , Nakao Tetsushi , Libby Peter , Shi Guo-Ping
Published: July 2023

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection can lead to a cytokine storm, unleashed in part by pyroptosis of virus-infected macrophages and monocytes. Interleukin-6 (IL-6) has emerged as a key participant in this ominous complication of coronavirus disease 2019 (COVID-19). IL-6 antagonists have improved outcomes in patients with COVID-19 in some, but not all, studies. IL-6 signaling involves at least 3 distinct pathways, including classic-signaling, trans-signaling, and trans-presentation depending on the localization of IL-6 receptor and its binding partner glycoprotein gp130. IL-6 has become a therapeutic target in COVID-19, cardiovascular diseases, and other inflammatory conditions. However, the efficacy of inhibition of IL-6 signaling in metabolic diseases, such as obesity and diabetes, may depend in part on cell type-dependent actions of IL-6 in controlling lipid metabolism, glucose uptake, and insulin sensitivity owing to complexities that remain to be elucidated. The present review sought to summarize and discuss the current understanding of how and whether targeting IL-6 signaling ameliorates outcomes following SARS-CoV-2 infection and associated clinical complications, focusing predominantly on metabolic and cardiovascular diseases.
Fatal Severe Cytokine Release Syndrome Post-haploidentical Stem Cell Transplant With Post-transplant Cyclophosphamide in an Infant With Severe Combined Immunodeficiency and Disseminated Bacille Calmette-Guérin Infection
Authors: Arora Sunisha , Upasana K. , Thakkar Dhwanee , Yadav Anjali , Rastogi Neha , Yadav Satya P.
Published: July 2023

Introduction:

Severe Combined Immunodeficiency (SCID) is a primary immunodeficiency disorder characterized by absent or dysfunctional T lymphocytes, leading to defective cellular and humoral immunity requiring urgent hematopoietic stem cell transplantation (HSCT). We report a case of SCID with disseminated Bacille Calmette-Guérin (BCG) infection who developed cytokine release syndrome (CRS) and possible Immune reconstitution inflammatory syndrome (IRIS) after Haploidentical HSCT with post-transplant cyclophosphamide.

Methods:

Data were retrospectively retrieved from electronic medical records.

Result:

A 5-month-old male infant was referred with fever, cough, and generalized maculopapular rash for 15 days, and had pallor without hepatosplenomegaly or lymphadenopathy. He had a history of previous male sibling death at 6 months of age due to pneumonia. Investigations: hemoglobin: 4.7 g/dL, TLC-6.37×103/uL, absolute lymphocytes: 0.98×103/uL, platelets: 319×103/uL, bilateral patchy opacities in both lung fields, and low immunoglobulin levels. Lymphocyte subset analysis revealed T−, B+, NK− SCID. Genetic analysis showed a hemizygous mutation in IL2RG (c.314A>G). The child received intravenous (IV) antibiotics, antifungal, antitubercular drugs, irradiated blood products, and IV immunoglobulins. Urgent haploidentical HSCT from the mother was planned. Conditioning was Fludarabine-40 mg/m2/d for 4 days, cyclophosphamide: 14.5 mg/kg/d for 2 days. He received peripheral blood hematopoietic stem cells with CD34− 15×106 cells/kg and CD3− 805×106 cells/kg. Within 2 hours of stem cell infusion, he developed respiratory distress, fever, shock, and flaring of rash. Methylprednisolone was started in view of CRS. On day+2, he had sudden desaturation and bradycardia needing mechanical ventilation and inotropes. His inflammatory markers were elevated (Ferritin: 3640 ng/mL, IL-6:5000 pg/mL, CRP:255 mg/L). In view of high-grade CRS, he received an injection of tocilizumab 8 mg/kg on day +2 and day +4. He received post-transplant cyclophosphamide 5 mg/kg on day +3. The endotracheal secretion GeneXpert was positive for Mycobacterium supporting the diagnosis of disseminated tuberculosis. Our patient had disseminated BCG infection which could also be contributory in the initiation of IRIS as the mother was immunized with the BCG vaccine in childhood so she must be having cytotoxic T cells specific for BCG, which were transferred to the infant with peripheral blood stem cell product. He succumbed to severe acute respiratory distress syndrome and multiorgan dysfunction on day +5 post-transplant.

Conclusions:

In haploidentical HSCT of SCID, post-transplant course can be complicated by CRS and IRIS as these patients are inefficient in mounting any response to infused donor lymphocytes resulting in their unregulated growth.
International Survey of the Management of Disseminated Intravascular Coagulation Among Pediatric and Neonatal Health Care Practitioners
Authors: Solh Ziad , Rajagopal Revathi , Thachil Jecko , Chan Anthony KC , Monagle Paul
Published: July 2023

The International Society of Thrombosis and Hemostasis (ISTH) provides objective disseminated intravascular coagulation (DIC) measurement through diagnostic criteria validated in adults. The applicability of these criteria in pediatric and neonatal DIC is controversial and unvalidated. Primary objective: to evaluate current practice in pediatric and neonatal DIC management among different specialties. Secondary objective: to understand the potential impact of developmental hemostasis on DIC laboratory evaluation. We performed a multicenter survey between January and September 2016. The questionnaire was distributed internationally through professional societies. In all, 211 responses were received, of which 160 were full responses and 51 were partial. Overall, 85% of respondents practiced in tertiary academic centers; 70% practiced in pediatric-only hospitals. The majority of respondents (42%) used their personal clinical experience in the management of DIC. Sixty percent of respondents treated DIC until the resolution of both clinical and laboratory parameters. Laboratory investigations were monitored in the majority of DIC cases without thrombosis or bleeding (80%); age-specific reference ranges for tests were lacking in 20% of pediatric-only hospitals and 35% of combined pediatric/adult hospitals. Adherence to standardized DIC guidelines was poor but varied by geographical location. This survey reveals variable practices among pediatricians in the management of DIC. Further studies are needed to validate the DIC diagnostic criteria in children.
Capecitabine-induced Gastrointestinal Injury Shows a Graft-Versus-Host Disease (GVHD)-like Pattern
Authors: Ojukwu Kenechukwu , Cox Brian K. , Larson Brent K. , Guindi Maha , Waters Kevin M. , Hutchings Danielle A.
Published: July 2023

Capecitabine is a commonly used oral chemotherapeutic agent. Gastrointestinal (GI) side effects are clinically well-known, however, the histopathologic changes have not been comprehensively studied. This study describes the largest case series (8 patients) characterizing the histopathology of capecitabine-induced GI injury. All patients were adults (median age: 64.5 y, range: 61 to 76 y) and there was gender parity. Patients were receiving treatment for malignancies of the colorectum (n=5), breast (n=1), pancreas (n=1), and appendix (n=1). All had GI symptoms, including 7 with diarrhea and abdominal pain and 1 with melena. Five of 8 (63%) showed graft-versus-host disease (GVHD)-like histologic changes in small intestinal and/or colonic biopsies characterized by crypt disarray and dropout, crypt atrophy, dilated crypts lined by attenuated epithelium, and increased crypt apoptosis. Neuroendocrine cell aggregates were present in 4 of 5 cases. Four of 5 showed patchy prominence in lamina propria eosinophils. One patient receiving concomitant radiation therapy had a small intestinal biopsy showing regenerative changes. Two patients had histologically unremarkable biopsies. On follow-up, capecitabine was discontinued or dose-reduced in all patients. Three of 5 patients with a GVHD-like pattern had clinical improvement, whereas 2 died shortly after biopsy. One with regenerative changes also had radiation dose reduction and improved clinically. Two with unremarkable biopsies improved symptomatically. In summary, capecitabine-related GI injury shows a GVHD-like pattern. Knowledge of this is important to confirm the diagnosis as patients typically improve with dose reduction or discontinuation of the drug.
Variation in Early Pediatric Intensive Care Management Strategies and Duration of Invasive Mechanical Ventilation for Acute Viral Bronchiolitis in the United Kingdom: A Retrospective Multicenter Cohort Study*
Authors: Miranda Mariana , Ray Samiran , Boot Elizabeth , Inwald David , Meena Daleep , Kumar Ramesh , Davies Patrick , Rivero-Bosch Maria , Sturgess Philippa , Weeks Charlotte , Holliday Kathryn , Cuevas-Asturias Sofia , Donnelly Peter , Elsaoudi Ahmed , Lillie Jon , Nadel Simon , Tibby Shane , Mitting Rebecca
Published: July 2023

OBJECTIVES:

Management of mechanically ventilated patients with bronchiolitis is not standardized and duration of mechanical ventilation has been shown to vary widely between centers. The aim of this study was to examine practice in a large number of U.K. PICUs with a view to identify if early management choices relating to fluid prescription, sedative agent use, and endotracheal tube (ETT) placement were associated with differences in duration of invasive mechanical ventilation (IMV).

DESIGN:

Retrospective multicenter cohort study. Primary outcome was duration of IMV. A hierarchical gamma generalized linear model was used to test for associations between practice variables (sedative and neuromuscular blocking agents, route of endotracheal intubation at 24 hr and fluid balance at 48 hr) and duration of IMV after adjustment for known confounders.

SETTING:

Thirteen U.K. PICUs. Duration of 2 months between November and December 2019.

PATIENTS:

Three hundred fifty infants receiving IMV for bronchiolitis. Excluded were patients receiving long-term ventilation, extracorporeal life support, or who died before separation from IMV.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

After adjustment for confounders, several variables were associated with an increase in the geometric mean duration of IMV (expressed as a percentage) including: nasal ETT use, 16% (95% CI, 1–32%); neuromuscular blockade use, 39% (95% CI, 21–61%); and fluid balance at 48 hr, 13% per 100 mL/kg positive fluid balance (95% CI, –1% to 28%). The association of sedative use varied with class of agent. The use of an alpha-2 agonist alone was associated with a reduction in duration of IMV by 19% in relation to no sedative agent (95% CI, –31 to –5%), whereas benzodiazepine uses alone or with alpha-2 agonist in combination were similar to using neither agent.

CONCLUSIONS:

Early management strategies for bronchiolitis were associated with the duration of IMV across U.K. centers after adjustment for confounders. Future work should prospectively assess the impact of fluid restriction, route of endotracheal intubation, and alpha-2 agonist use on duration of IMV in infants with bronchiolitis, with the aim of reducing seasonal bed pressure.
A Multiclass Radiomics Method–Based WHO Severity Scale for Improving COVID-19 Patient Assessment and Disease Characterization From CT Scans
Authors: Henao John Anderson Garcia , Depotter Arno , Bower Danielle V. , Bajercius Herkus , Todorova Plamena Teodosieva , Saint-James Hugo , de Mortanges Aurélie Pahud , Barroso Maria Cecilia , He Jianchun , Yang Junlin , You Chenyu , Staib Lawrence H. , Gange Christopher , Ledda Roberta Eufrasia , Caminiti Caterina , Silva Mario , Cortopassi Isabel Oliva , Dela Cruz Charles S. , Hautz Wolf , Bonel Harald M. , Sverzellati Nicola , Duncan James S. , Reyes Mauricio , Poellinger Alexander
Published: July 2023

Objectives

The aim of this study was to evaluate the severity of COVID-19 patients' disease by comparing a multiclass lung lesion model to a single-class lung lesion model and radiologists' assessments in chest computed tomography scans.

Materials and Methods

The proposed method, AssessNet-19, was developed in 2 stages in this retrospective study. Four COVID-19–induced tissue lesions were manually segmented to train a 2D-U-Net network for a multiclass segmentation task followed by extensive extraction of radiomic features from the lung lesions. LASSO regression was used to reduce the feature set, and the XGBoost algorithm was trained to classify disease severity based on the World Health Organization Clinical Progression Scale. The model was evaluated using 2 multicenter cohorts: a development cohort of 145 COVID-19–positive patients from 3 centers to train and test the severity prediction model using manually segmented lung lesions. In addition, an evaluation set of 90 COVID-19–positive patients was collected from 2 centers to evaluate AssessNet-19 in a fully automated fashion.

Results

AssessNet-19 achieved an F1-score of 0.76 ± 0.02 for severity classification in the evaluation set, which was superior to the 3 expert thoracic radiologists (F1 = 0.63 ± 0.02) and the single-class lesion segmentation model (F1 = 0.64 ± 0.02). In addition, AssessNet-19 automated multiclass lesion segmentation obtained a mean Dice score of 0.70 for ground-glass opacity, 0.68 for consolidation, 0.65 for pleural effusion, and 0.30 for band-like structures compared with ground truth. Moreover, it achieved a high agreement with radiologists for quantifying disease extent with Cohen κ of 0.94, 0.92, and 0.95.

Conclusions

A novel artificial intelligence multiclass radiomics model including 4 lung lesions to assess disease severity based on the World Health Organization Clinical Progression Scale more accurately determines the severity of COVID-19 patients than a single-class model and radiologists' assessment.
Highly Sensitive 3-Tesla Real Inversion Recovery MRI Detects Leptomeningeal Contrast Enhancement in Chronic Active Multiple Sclerosis
Authors: Okar Serhat Vahip , Dieckhaus Henry , Beck Erin S. , Gaitán María I. , Norato Gina , Pham Dzung L. , Absinta Martina , Cortese Irene CM , Fletcher Anita , Jacobson Steven , Nair Govind , Reich Daniel S.
Published: July 2023

Background

Leptomeningeal contrast enhancement (LME) on T2-weighted Fluid-Attenuated Inversion Recovery (T2-FLAIR) MRI is a reported marker of leptomeningeal inflammation, which is known to be associated with progression of multiple sclerosis (MS). However, this MRI approach, as typically implemented on clinical 3-tesla (T) systems, detects only a few enhancing foci in ~25% of patients and has thus been criticized as poorly sensitive.

Purpose

To compare an optimized 3D real-reconstruction inversion recovery (Real-IR) MRI sequence on a clinical 3 T scanner to T2-FLAIR for prevalence, characteristics, and clinical/radiological correlations of LME.

Materials and Methods

We obtained 3D T2-FLAIR and Real-IR scans before and after administration of standard-dose gadobutrol in 177 scans of 154 participants (98 women, 64%; mean ± SD age: 49 ± 12 years), including 124 with an MS-spectrum diagnosis, 21 with other neurological and/or inflammatory disorders, and 9 without neurological history. We calculated contrast-to-noise ratios (CNR) in 20 representative LME foci and determined association of LME with cortical lesions identified at 7 T (n = 19), paramagnetic rim lesions (PRL) at 3 T (n = 105), and clinical/demographic data.

Results

We observed focal LME in 73% of participants on Real-IR (70% in established MS, 33% in healthy volunteers, P < 0.0001), compared to 33% on T2-FLAIR (34% vs. 11%, P = 0.0002). Real-IR showed 3.7-fold more LME foci than T2-FLAIR (P = 0.001), including all T2-FLAIR foci. LME CNR was 2.5-fold higher by Real-IR (P < 0.0001). The major determinant of LME status was age. Although LME was not associated with cortical lesions, the number of PRL was associated with the number of LME foci on both T2-FLAIR (P = 0.003) and Real-IR (P = 0.0003) after adjusting for age, sex, and white matter lesion volume.

Conclusions

Real-IR a promising tool to detect, characterize, and understand the significance of LME in MS. The association between PRL and LME highlights a possible role of the leptomeninges in sustaining chronic inflammation.