bluuebunny/crossref_metadata_2025 huggingface dataset:
Shear hardening in frictionless amorphous solids near the jamming transition
Authors: Pan Deng , Meng Fanlong , Jin Yuliang
Published: February 2023

The jamming transition, generally manifested by a rapid increase of rigidity under compression (i.e. compression hardening), is ubiquitous in amorphous materials. Here we study shear hardening in deeply annealed frictionless packings generated by numerical simulations, reporting critical scalings absent in compression hardening. We demonstrate that hardening is a natural consequence of shear-induced memory destruction. Based on an elasticity theory, we reveal two independent microscopic origins of shear hardening: (i) the increase of the interaction bond number and (ii) the emergence of anisotropy and long-range correlations in the orientations of bonds—the latter highlights the essential difference between compression and shear hardening. Through the establishment of physical laws specific to anisotropy, our work completes the criticality and universality of jamming transition, and the elasticity theory of amorphous solids.
Rethinking how and when to report descriptions of behavior change content within interventions: a case study of an ongoing physical activity trial (ready steady 3.0)
Authors: McMahon Siobhan K , Macheledt Kait , Choma Elizabeth A , Lewis Beth A , Guan Weihua , Wyman Jean F , Rothman Alexander J
Published: February 2023

Specifications of what and how much health behavior change (BC) content within research interventions are needed to advance BC science, its implementation, and dissemination. We analyzed the types and dosages of the smallest potentially active BC ingredients and associated behavioral prescriptions intended to be delivered in an ongoing physical activity optimization trial for older adults (Ready Steady 3.0 [RS3]). We defined BC types as behavior change techniques (BCT) and behavioral prescriptions. Our protocol integrated the BCT Taxonomy coding procedures with BCT roles (primary or secondary) and, when relevant, linkages to behavioral prescriptions. Primary BCTs targeted theoretical mechanisms of action, whereas secondary BCTs supported primary BCT delivery. Behavioral prescriptions represented what participants were encouraged to do with each primary BCT in RS3 (ascertain, practice, implement). We assessed dosage parameters of duration, frequency, and amount in each BCT and prescription.

Results provided a catalog of in-depth, multidimensional content specifications with 12 primary BCTs, each supported by 2-7 secondary BCTs, with dosages ranging from 2 to 8 weeks, 1 to 8 contacts, and 5 to 451 minutes. Minutes spent on behavioral prescriptions varied: ascertain (1 to 41), practice (5 to 315), and implement (0 to 38). Results can be organized and summarized in varied ways (e.g., by content component) to strengthen future assessments of RS3 fidelity and intervention refinement.

Results highlight potential benefits of this early, integrated approach to analyzing BC content and frames questions about how such information might be incorporated and disseminated with reporting research outcomes.
Previously unreported X-ray findings associated with distal toe pain in children
Authors: Taniwaki Hiroshi , Shintani Kosuke , Aono Masanari
Published: February 2023

While children undergo skeletal maturation, it is difficult to distinguish between normal variants and abnormalities of the epiphysis and acrophysis on radiological images. Abnormalities in the epiphysis and acrophysis of the toe phalanx have not been reported yet. Here, we describe a series of abnormalities in the epiphysis and acrophysis of the fourth and fifth toe phalanges, including an investigation of their pathogenesis. We evaluated patients suspected of having bone tumors at a local orthopedic clinic because of abnormal findings of the toe phalanx between the distal and middle phalanx on plain radiographs. The site of the lesion, duration of pain until the hospital visit, history of trauma and sports, treatment, and clinical course were investigated. A total of seven patients (five boys and two girls) with a mean age of 10 years (range 9–16) were included. In all cases, a circular erosive radiolucent image was present between the distal and middle phalanx. In two cases, the fourth toe was affected, and in five cases, the fifth toe was affected. Six patients showed improvements with conservative treatment using shoe insoles. In one case, surgical treatment was performed for persistent pain. Histological examination of the fibrous tissue collected from the circular erosive radiolucent area revealed normal bone and slightly degenerated hyaline cartilage. This is the first report on the abnormalities of the epiphysis and acrophysis of the toe phalanx, which is termed as Shintaniwakino disease. A better understanding of this disease may aid in the avoidance of unnecessary treatment.

Level of Evidence: IV.
Motorized Robotic Closed Cervical Traction
Authors: Sherrod Brandon A. , Schwehr Trevor , Waldram Daniel , Adams Andrew , Averett Sterling , Ha Jeewon , Kahle Simon , Mitchell Derek , Polevoi Seth , Dailey Andrew T. , Merryweather Andrew S. , Mazur Marcus D.
Published: February 2023

Study Design.

Biomechanical study

Objective.

To demonstrate that robotic cervical traction can apply closed cervical traction as effectively as manual weight-and-pulley traction in extension spring and cadaveric models.

Summary of Background Data.

Closed cervical traction is used to reduce subaxial cervical spine dislocation injuries and to distract the intervertebral space during cervical spine surgery. Weight-and-pulley cervical traction relies on cumbersome and imprecise technology without any safeguard to prevent over-traction or weights being pulled/released inadvertently.

Methods.

A prototype robotic traction device was designed and manufactured by the authors with real-time tensile force measurement, ±1-lbs (5 N) force application accuracy, locking/non-backdriveable linear actuators with actuator position sensing, 200-lbs (900 N) maximum force capability, up to 20° of flexion/extension manipulation, <25-lbs (111 N) device weight, and compatibility with Gardner-Wells tongs or Mayfield head clamp. The device was tested using an extension spring model and an intact fresh cadaver specimen to assess applied and desired force over time and radiographic changes in the cervical spine as traction force increased. The cadaver was tested in manual traction initially and then robotic traction in 10-lbs (50 N) increments up to 80-lbs (355 N) to compare methods.

Results.

The prototype device met or exceeded all requirements. In extension spring testing, the device reached the prescribed forces of both 25-lbs (111 N) and 80-lbs (355 N) accurately and maintained the desired weight. In cadaveric testing, radiographic outcomes were equivalent between the prototype and manual weight-and-pulley traction at 80-lbs (355 N; disk space measurements within ±10% for all levels), and the device reached the desired weight within±1-lbs (5 N) of accuracy at each weight interval.

Conclusion.

This preliminary work demonstrates that motorized robotic cervical traction can safely and effectively apply controlled traction forces.
Challenges for anaesthesia for robotic-assisted surgery in the elderly
Authors: Aceto Paola , Galletta Claudia , Cambise Chiara , Punzo Giovanni , Luca Ersilia , Schipa Chiara , Sollazzi Liliana
Published: February 2023

Steep and reverse Trendelenburg positions are often used in robotic-assisted surgery (RAS) to improve surgical access. The elderly are particularly vulnerable to the cardiovascular effect of the combination of pneumoperitoneum and these extreme positions. Falls in both cardiac output (CO) and mean arterial pressure (MAP) caused by pneumoperitoneum are enhanced in reverse Trendelenburg. Hypotension with dangerous cerebral and myocardial hypoperfusion may occur. Caution should be exercised in patients with low cardiac reserve and the degree of peri-operative risk should dictate the level of haemodynamic monitoring employed. The effects of pneumoperitoneum on CO are less pronounced in the standard Trendelenburg position due to gravity, but head-down combined with pneumoperitoneum can increase both MAP and systemic cardiovascular resistance. However, in patients with impaired myocardial contractility, the head-down position may lead to cardiac failure. In addition, the adverse respiratory effects of pneumoperitoneum, which include reduction of pulmonary compliance and functional residual capacity, may be exacerbated by steep Trendelenburg. At the same time, hypercarbia resulting from CO2 insufflation can lead to an increase in stasis of brain blood flow and intracranial pressure with possible repercussions on cognitive functions in the elderly. Another problem is the increase in intra-ocular pressure during steep Trendelenburg, and injury to the optic nerve has been reported after robot-assisted prostatectomy. Finally, strategies to use the lowest possible pneumoperitoneum pressure are considered to reduce possible complications. Moreover, the extreme positions should be limited only to the time strictly necessary for surgery and should be avoided in high-risk patients.
Using eZIS of SPECT to evaluate the therapeutic effect of carotid endarterectomy
Authors: Zhang Zhiting , Sun Danyang , Wang Xuan , Li Wei
Published: February 2023

Objective

Stroke is an acute cerebrovascular disease with high morbidity and mortality. The main causes of ischemic stroke include carotid artery stenosis, and carotid endarterectomy (CEA) can be used to improve the blood flow of the lesion site. Regional cerebral blood flow (rCBF) can be decreased by using single photon emission computed tomography (SPECT). The Easy Z-Score imaging system (eZIS) can display the changes of rCBF as Z-Score. The purpose of this study was to determine whether eZIS of SPECT can be used to evaluate the therapeutic effect of CEA in the treatment of carotid artery stenosis.

Methods

In this study, subjects were divided into the surgery group and the control group. The surgery group included seven patients with unilateral or bilateral internal carotid artery stenosis who received CEA treatment, and the control group included 11 patients who only received conventional drug treatment but did not receive surgery. Cerebral perfusion imaging (CPI) was collected twice before and after the corresponding treatment (within 6 months). rCBF of the lesion site was measured and Z-score was calculated before and after treatment by the eZIS technique.

Results

The postoperative Z-score of the surgery group was 0.54 ± 2.71 compared with that of the preoperative −1.34 ± 2.68 (P = 0.0034; t = 4.687; df = 6), while the z-score of the control group was −0.33 ± 2.58 compared with that of the pretreatment 1.84 ± 2.62 (P = 0.0010; t = 4.618; df = 10).

Conclusion

CEA can effectively improve the blood flow in the lesion area of patients with carotid artery stenosis. eZIS of SPECT can be used to evaluate the therapeutic effect of CEA on carotid artery stenosis visually.
Machine learning approach using 18F-FDG PET-based radiomics in differentiation of lung adenocarcinoma with bronchoalveolar distribution and infection
Authors: Agüloğlu Nurşin , Aksu Ayşegül , Unat Damla S.
Published: February 2023

Objective

In this study, we aimed to evaluate the role of 18F-fluorodeoxyglucose PET/computerized tomography (18F-FDG PET/CT)-based radiomic features in the differentiation of infection and malignancy in consolidating pulmonary lesions and to develop a prediction model based on radiomic features.

Material and methods

The images of 106 patients who underwent 18F-FDG PET/CT of consolidated lesions observed in the lung between January 2015 and July 2020 were evaluated using LIFEx software. The region of interest of the lung lesions was determined and volumetric and textural features were obtained. Clinical and radiomic data were evaluated with machine learning algorithms to build a model.

Results

There was a significant difference in all standardized uptake value (SUV) parameters and 26 texture features between the infection and cancer groups. The features with a correlation coefficient of less than 0.7 among the significant features were determined as SUVmean, GLZLM_SZE, GLZLM_LZE, GLZLM_SZLGE and GLZLM_ZLNU. These five features were analyzed in the Waikato Environment for Knowledge Analysis program to create a model that could distinguish infection and cancer groups, and the model performance was found to be the highest with logistic regression (area under curve, 0.813; accuracy, 75.7%). The sensitivity and specificity values of the model in distinguishing cancer patients were calculated as 80.6 and 70.6%, respectively.

Conclusions

In our study, we created prediction models based on radiomic analysis of 18F-FDG PET/CT images. Texture analysis with machine learning algorithms is a noninvasive method that can be useful in the differentiation of infection and malignancy in consolidating lung lesions in the clinical setting.
Head impact in blind football during the Tokyo Paralympics: Video-based observational study
Authors: Tsutsumi Shogo , Sasadai Junpei , Maeda Noriaki , Shimizu Reia , Suzuki Akira , Fukui Kazuki , Arima Satoshi , Tashiro Tsubasa , Kaneda Kazuki , Yoshimi Mitsuhiro , Mizuta Rami , Ishihara Honoka , Esaki Hinata , Tsuchida Koki , Terada Tomoki , Komiya Makoto , Urabe Yukio
Published: February 2023

Head impacts during blind football are common and have high injury rates; however, their characteristics and impact are still under-reported. We compared head impact characteristics in blind football players with and without falls on all 18 official blind football match videos from the Tokyo 2020 Paralympic games. The rate of head impacts with falls was significantly higher in the preliminary phase, offense phase, and during dribbling. Significant differences in the region of the head impacted were also observed among the impact subjects/objects. The findings in this study would contribute to the development of injury prevention measures to minimize head injuries from head impact in blind football.
68Ga-FAPI-04 PET/CT and 18F-FDG PET/CT in Metastatic Papillary Renal Cell Cancer
Authors: Civan Caner , Isik Emine Goknur , Karadogan Seyfullah , Sanli Yasemin , Kuyumcu Serkan
Published: February 2023

Papillary renal cell cancer is a rare malignancy with limited treatment options in the advanced stage of the disease. We present the case of a 62-year-old man with progressive left-sided papillary renal cell carcinoma who underwent 68Ga-FAPI (fibroblast activated protein inhibitor)-04 and 18F-FDG PET/CT imaging. 68Ga-FAPI-04 PET/CT demonstrated variable FAP expression in all metastatic lesions detected by 18F-FDG PET/CT, including multiple lymph nodes, bone, and thyroid. This case highlights that FAP-targeted imaging can be a promising modality for diagnostic and theranostic use in papillary renal cell carcinoma.
Impact of 18F-Fluciclovine PET/CT Findings on Failure-Free Survival in Biochemical Recurrence of Prostate Cancer Following Salvage Radiation Therapy
Authors: Lawal Ismaheel O. , Marcus Charles , Schuster David M. , Goyal Subir , Adediran Omotayo A. , Dhere Vishal R. , Joshi Shreyas S. , Abiodun-Ojo Olayinka A. , Master Viraj A. , Patel Pretesh R. , Fielder Bridget , Goodman Mark , Shelton Joseph W. , Kucuk Omer , Hershatter Bruce , Halkar Raghuveer K. , Jani Ashesh B.
Published: February 2023

Purpose

We aimed to evaluate the impact of 18F-fluciclovine PET/CT imaging on failure-free survival (FFS) post–salvage radiotherapy (SRT) for prostate cancer (PCa) recurrence.

Methods

Seventy-nine patients were recruited in a phase 2/3 clinical trial to undergo 18F-fluciclovine PET/CT before SRT for PCa. Four patients with extrapelvic disease were excluded. All patients were followed up at regular intervals up to 48 months. Treatment failure was defined as a serum prostate-specific antigen level of ≥0.2 ng/mL above the nadir after SRT, confirmed with an additional measurement, requiring systemic treatment or clinical progression. Failure-free survival was computed and compared between patients grouped according to 18F-fluciclovine PET/CT imaging findings.

Results

Eighty percent (60/75) of patients had a positive finding on 18F-fluciclovine PET/CT, of which 56.7% (34/60) had prostate bed-only uptake, whereas 43.3% (26/60) had pelvic nodal ± bed uptake. Following SRT, disease failure was detected in 36% (27/75) of patients. There was a significant difference in FFS between patients who had a positive versus negative scan (62.3% vs 92.9% [P < 0.001] at 36 months and 59.4% vs 92.9% [P < 0.001] at 48 months). Similarly, there was a significant difference in FFS between patients with uptake in pelvic nodes ± bed versus prostate bed only at 36 months (49.8% vs 70.7%; P = 0.003) and at 48 months (49.8% vs 65.6%; P = 0.040). Failure-free survival was also significantly higher in patients with either negative PET/CT or prostate bed-only disease versus those with pelvic nodal ± prostate bed disease at 36 (78% vs 49.8%, P < 0.001) and 48 months (74.4% vs 49.8%, P < 0.001).

CONCLUSIONS

Findings on pre-SRT 18F-fluciclovine PET/CT imaging, even when acted upon to optimize the treatment decisions and treatment planning, are predictive of post-SRT FFS in men who experience PCa recurrence after radical prostatectomy. A negative 18F-fluciclovine PET/CT is most predictive of a lower risk of failure, whereas the presence of pelvic nodal recurrence portends a higher risk of SRT failure.
Somatostatin Receptor-Directed PET/CT for Therapeutic Decision-Making and Disease Control in Patients Affected With Small Cell Lung Cancer
Authors: Serfling Sebastian E. , Hartrampf Philipp E. , Zhi Yingjun , Higuchi Takahiro , Kosmala Aleksander , Serfling Julia , Schirbel Andreas , Hörning Anna , Buck Andreas K. , Weich Alexander , Werner Rudolf A.
Published: February 2023

Background

Somatostatin receptor (SSTR)–targeted PET/CT is used for patients affected with small cell lung cancer (SCLC), but the clinical impact has not been elucidated yet. We aimed to determine whether SSTR PET/CT can trigger relevant therapeutic management changes in patients with SCLC and whether those modifications achieve disease control and are associated with prolonged survival.

Methods

One hundred patients with SCLC received SSTR PET/CT. In a retrospective setting, we evaluated the diagnostic performance of PET versus CT and compared therapies before and after PET/CT to determine the impact of molecular imaging on treatment decision. We also determined the rate of disease control after therapeutic modifications and assessed survival in patients with and without changes in the therapeutic regimen.

Results

Relative to CT, SSTR PET alone was superior for assessing bone lesions in 19 of 39 instances (49%). Treatment was modified in 59 of 100 (59%) after SSTR PET/CT. Forty of 59 (74.6%) received systemic treatment after hybrid imaging, with the remaining 15 of 59 (25.4%) scheduled for nonsystemic therapy. In the latter group, 13 of 15 (86.7%) received local radiation therapy or active surveillance (2/15 [13.3%]). Individuals scheduled for systemic treatment after imaging received peptide receptor radionuclide therapy (PRRT) in 28 of 44 (63.6%), followed by chemotherapy in 10 of 44 (22.7%), change in chemotherapy regimen in 3 of 44 (6.8%), and initiation of tyrosine kinase inhibitor in the remaining 3 of 44 (6.8%). Among patients with modified treatment, follow-up was available in 53 subjects, and disease control was achieved in 14 of 53 (26.4%). However, neither change to systemic treatment (155 days; hazard ratio, 0.94; 95% confidence interval, 0.53–1.67) nor change to nonsystemic treatment (210 days; hazard ratio, 0.67; 95% confidence interval, 0.34–1.34) led to a prolonged survival when compared with subjects with no change (171 days, P ≥ 0.22, respectively).

Conclusions

In patients with SCLC, SSTR-targeted hybrid imaging provides complementary information on the disease status. PET/CT led to management changes in 59% (mainly PRRT), achieving disease control in >26%. The high fraction of patients scheduled for PRRT may lay the foundation for combination strategies to achieve synergistic antitumor effects, for example, by combining PRRT plus recently introduced RNA polymerase II inhibitors.
Somatostatin Receptor PET Imaging in Diffuse Pancreatic Neuroendocrine Tumor
Authors: Zhao Qian , Dong Aisheng , He Tianlin , Zuo Changjing
Published: February 2023

Somatostatin receptor imaging findings of pancreatic neuroendocrine tumor with diffuse involvement of the pancreas are rarely reported. We present somatostatin receptor PET imaging findings in 3 cases of diffuse pancreatic neuroendocrine tumor. One case showed diffuse swelling and diffusely intense activity of the pancreas with multiple metastases in the peripancreatic lymph nodes and liver. The other 2 cases showed diffusely intense activity of the pancreas without metastasis. The pancreatic tumor extended into the duodenum in all the 3 cases. Familiarity with this rare pattern of radiotracer uptake in pancreatic neuroendocrine tumor may be helpful for the diagnosis.
Durvalumab and PET-Directed Chemoradiation in Locally Advanced Esophageal Adenocarcinoma
Authors: Cowzer Darren , Wu Abraham Jing-Ching , Sihag Smita , Walch Henry S. , Park Bernard J. , Jones David R. , Gu Ping , Maron Steven B. , Sugarman Ryan , Chalasani Sree Bhavani , Shcherba Marina , Capanu Marinela , Chou Joanne F. , Choe Jennie K. , Nosov Anton , Adusumilli Prasad S. , Yeh Randy , Tang Laura H. , Ilson David H. , Janjigian Yelena Y. , Molena Daniela , Ku Geoffrey Y.
Published: February 2023

Objective:

To determine the safety and efficacy of adding the anti-PD-L1 antibody durvalumab to induction FOLFOX and preoperative chemotherapy in locally advanced esophageal adenocarcinoma.

Background:

Neoadjuvant induction FOLFOX followed by positron emission tomography (PET) directed chemoradiation has demonstrated improved survival for esophageal adenocarcinoma. There is clear benefit now for the addition of immune checkpoint inhibitors both in early and advanced stage disease. Given these results we investigated the safety and efficacy of adding durvalumab to induction FOLFOX and preoperative chemoradiotherapy.

Methods:

Patients with locally advanced resectable esophageal/gastroesophageal junction adenocarcinoma received PET-directed chemoradiation with durvalumab before esophagectomy. Patients who had R0 resections received adjuvant durvalumab 1500 mg every 4 weeks for 6 treatments. The primary endpoint of the study was pathologic complete response.

Results:

We enrolled 36 patients, 33 of whom completed all preoperative treatment and underwent surgery. Preoperative treatment was well tolerated, with no delays to surgery nor new safety signals. Pathologic complete response was identified in 8 [22% (1-sided 90% lower bound: 13.3%)] patients with major pathologic response in 22 [61% (1-sided 90% lower bound: 50%)] patients. Twelve and 24-month overall survival was 92% and 85%, respectively.

Conclusions:

The addition of durvalumab to induction FOLFOX and PET-directed chemoradiotherapy before surgery is safe, with a high rate of pathologic response, as well as encouraging survival data.
The RAST-NP Pilot
Authors: Woodard Benjamin , Dixon Jane
Published: February 2023

With more new graduate primary care nurse practitioners (NPs) practicing in remote locales than ever before, their preparation for performing emergency procedural skills (EPSs) is critical for safe and effective care. Emergency procedural skills are not uniformly taught in primary care academic programs but are easily imparted via additional training and practice. The purpose of this project was to develop and pilot an expert panel–validated training program specifically for NPs bound for remote practice and to evaluate how the participants rated their self-efficacy in performing specific EPSs before and after completing the training, called the Remote Advanced Skills Training for NPs (RAST-NP). A diverse expert panel rated EPSs to determine skills to be included in a pilot training program. After achieving consensus on skills to be taught, a hybrid online-in-person curriculum was developed using standards from the International Nursing Association for Clinical Simulation and Learning. This training was conducted for more than 2 days and delivered to a class of 15 primary care NP students in their final year of education. All participants completed a pre- and postparticipation survey to assess their self-efficacy using a validated questionnaire, modified to address the EPSs taught. The participants reported higher confidence following training on all EPSs taught, as indicated by an increase in difference in mean scores from 1 to 6.15 on an 11-point scale. For each EPS, the difference was statistically significant by both a paired t test and a Whitney–Mann U test with probability of 0.01 or less. Results indicate that the methods utilized (i.e., psychomotor practice) increased confidence in NP students, and they also suggest that the amount of time spent practicing skills is associated with interval increases in confidence. A combination of didactic and psychomotor methods was uniformly effective at increasing confidence, and thereby self-efficacy, and higher success is associated with more time practicing the kinesthetic skills in situ.
Reducing Adult Transgender Barriers to Care in the Emergency Department
Authors: Goszkowicz Kelly , Davis Philip
Published: February 2023

The Research to Practice column is intended to improve the research critique skills of the advanced practice registered nurse (APRN) and the emergency department (ED) registered nurse (RN) and to assist with translating research into practice. In this column, we review a recent qualitative research study by M. Allison, S. Marshall, G. Stewart, M. Joiner, C. Nash, and M. Stewart (2021) titled “Experiences of Transgender and Gender Nonbinary Patients in the Emergency Department and Recommendations for Health Care Policy, Education, and Practice” with discussion of how their findings can be applied to inform providers how to deliver appropriate care of transgender patients within the ED.
Scombroid Poisoning
Authors: Gonzalez Juan Manuel , Ortega Johis , McGhee Stephen , Nadeau Catherine , Crenshaw Nichole
Published: February 2023

Scombroid poisoning is a common fish-borne disease in clinical settings. Fish that has not been adequately stored after catching can allow bacteria to proliferate, which causes the conversion of histidine to histamine. Once histamine has formed, freezing or cooking the fish will not remove the histamine content. Once the fish is consumed, histamine is released, causing toxicity to the patient with symptoms including cutaneous, gastrointestinal, and anaphylactoid. Emergency nurse practitioners should identify, appropriately diagnose, and treat individuals with scombroid poisoning and avoid misdiagnosing it as fish allergy.
Impact of Fasting Status and Circadian Variation on the Pharmacokinetics of Mycophenolate Mofetil and the Glucuronide Metabolite in Renal Transplant Recipients
Authors: Drevland Ole Martin , Robertsen Ida , Theie Gustavsen Marte , Kveim Hanne Kamilla , Herberg Hovd Markus , Midtvedt Karsten , Åsberg Anders
Published: February 2023

Background.

Mycophenolate mofetil (MMF) is an immunosuppressive prodrug often used to prevent allograft rejection following solid organ transplantation. After oral administration, MMF is rapidly hydrolyzed to the active metabolite mycophenolate acid (MPA), which is inactivated by glucuronosyltransferase to the mycophenolic acid glucuronide metabolite (MPAG). The aim was 2-fold: to investigate the impact of circadian variation and fasting versus nonfasting status on MPA and MPAG pharmacokinetics in renal transplant recipients (RTRs).

Methods.

RTRs with stable graft function treated with tacrolimus, prednisolone, and MMF (750 mg BID) were included in this open, nonrandomized study. Two 12-h pharmacokinetic investigations were conducted in succession following morning and evening doses, both in a fasting and in a real-life nonfasting condition.

Results.

A total of 30 (22 men) RTRs performed one 24-h investigation, and 16 repeated the investigation within 1 mo. In a real-life nonfasting state, MPA area under the curve (AUC)0–12 and C
0 failed to meet the bioequivalence criteria. Following the evening dose, mean MPA AUC12–24 was 16% lower (P < 0.001) compared with AUC0–12, and a shorter T
max was observed (P = 0.09). Under fasting conditions, MPA AUC12–24 was 13% lower than AUC0–12, and the absorption rate was slower after the evening dose (P < 0.05). MPAG displayed circadian variation only under real-life conditions with lower AUC0–12 following the evening dose (P < 0.001).

Conclusions.

Both MPA and MPAG showed circadian variation with somewhat lower systemic exposures following the evening dose with limited clinical relevance in the dosing of MMF in RTRs. Fasting status affects MMF absorption rate differently, but with similar results in systemic exposure.
Encounter rates prime interactions between microorganisms
Authors: Słomka Jonasz , Alcolombri Uria , Carrara Francesco , Foffi Riccardo , Peaudecerf François J. , Zbinden Matti , Stocker Roman
Published: February 2023

Properties of microbial communities emerge from the interactions between microorganisms and between microorganisms and their environment. At the scale of the organisms, microbial interactions are multi-step processes that are initiated by cell–cell or cell–resource encounters. Quantification and rational design of microbial interactions thus require quantification of encounter rates. Encounter rates can often be quantified through encounter kernels—mathematical formulae that capture the dependence of encounter rates on cell phenotypes, such as cell size, shape, density or motility, and environmental conditions, such as turbulence intensity or viscosity. While encounter kernels have been studied for over a century, they are often not sufficiently considered in descriptions of microbial populations. Furthermore, formulae for kernels are known only in a small number of canonical encounter scenarios. Yet, encounter kernels can guide experimental efforts to control microbial interactions by elucidating how encounter rates depend on key phenotypic and environmental variables. Encounter kernels also provide physically grounded estimates for parameters that are used in ecological models of microbial populations. We illustrate this encounter-oriented perspective on microbial interactions by reviewing traditional and recently identified kernels describing encounters between microorganisms and between microorganisms and resources in aquatic systems.
Time-varying effects are common in genetic control of gestational duration
Authors: Juodakis Julius , Ytterberg Karin , Flatley Christopher , Sole-Navais Pol , Jacobsson Bo
Published: February 2023

Preterm birth is a major burden to neonatal health worldwide, determined in part by genetics. Recently, studies discovered several genes associated with this trait or its continuous equivalent – gestational duration. However, their effect timing, and thus clinical importance, is still unclear. Here, we use genotyping data of 31,000 births from the Norwegian Mother, Father and Child cohort (MoBa) to investigate different models of the genetic pregnancy “clock”. We conduct genome-wide association studies using gestational duration or preterm birth, replicating known maternal associations and finding one new foetal variant. We illustrate how the interpretation of these results is complicated by the loss of power when dichotomizing. Using flexible survival models, we resolve this complexity and find that many of the known loci have time-varying effects, often stronger early in pregnancy. The overall polygenic control of birth timing appears to be shared in the term and preterm, but not very preterm periods, and exploratory results suggest involvement of the major histocompatibility complex genes in the latter. These findings show that the known gestational duration loci are clinically relevant, and should help design further experimental studies.
A comparative study on the impact of fiveDesmodiumspecies on soil microbiome reveals enrichment of selected bacterial and fungal taxa
Authors: David Aneth Bella , Mwaikono Kilaza Samson , Midega Charles , Magingo Francis , Alsanius Beatrix W. , Drinkwater Laurie E. , Dekker Teun , Lyantagaye Sylvester
Published: February 2023

Introduction

SeveralDesmodiumspp. are used as intercrops in push-pull pest management systems to repel insect herbivores. In addition,Desmodiumsuppresses the parasitic weedStriga, and diversifies the soil microbiome with negative impacts on fungi. We investigated the impact of a 2-year cropping of fiveDesmodiumspecies on soil microbiome populations.

Methodology

Total DNA was obtained from root zone soil samples collected from a two-years-old common garden experiment with replicated plots of fiveDesmodiumspp. at the international centre for insect physiology and ecology (ICIPE), Mbita, Kenya. Subsequently, 16S and ITS DNA sequencing were performed and the data was analysed by using QIIME2 and Calypso.

Results

Our findings show significant differences in composition and abundance of specific microbial taxa among theDesmodiumplots and the bulk soil, with a stronger shift observed for fungal community profiles than bacteria. There was, however, no significant difference in overall diversity, richness and evenness of microbial communities among theDesmodiumplots and the bulk soil. Similarly, beta diversity analysis did not reveal a significant association of variation to specificDesmodiumspp. plots.

Discussion and conclusion

This is the first study to compare impact and association of whole soil microbiomes to differentDesmodiumspecies. Whereas long-termDesmodiumcropping clearly shifts whole microbiome communities, no significant difference in overall diversity and richness of microbial populations was observed among the studied plots. However, there was a divergence of individual taxa reflected on their increased abundance in association to specificDesmodiumspp., pointing towards potential impact on ecosystem services. These findings indicate that significant shifts in whole microbial populations due toDesmodiumspp. and thus potentially provision of associated ecosystem services require longer cultivation periods to solidify. Future studies should focus on techniques that monitor real-time changes in microbial populations such as RNA-seq to ascertain live and dead microbes, and thus infer ecological services.
Clinical severity prediction of COVID-19 admitted patients in Spain: SEMI and REDISSEC cohorts
Authors: Martínez-García Mario , García-Gutierrez Susana , Barreñada Taleb Lasai , Armañanzas Rubén , Inza Inaki , Lozano Jose A.
Published: February 2023

This report addresses, from a machine learning perspective, a multi-class classification problem to predict the first deterioration level of a COVID-19 positive patient at the time of hospital admission. Socio-demographic features, laboratory tests and other measures are taken into account to learn the models. Our output is divided into 4 categories ranging from healthy patients, followed by patients requiring some form of ventilation (divided in 2 cate-gories) and finally patients expected to die. The study is conducted thanks to data provided bySociedad Española de Medicina Interna(SEMI) andRed de Investigación en Servicios de Salud de Enfermedades Crónicas(REDISSEC). Results show that logistic regression is the best method for identifying patients with clinical deterioration.
TheE. colipathobiont LF82 encodes a unique variant of σ70that results in specific gene expression changes and altered phenotypes
Authors: Arroyo-Mendoza Melissa , Proctor Alexandra , Correa-Medina Abraham , Brand Meghan Wymore , Rosas Virginia , Wannemuehler Michael J. , Phillips Gregory J. , Hinton Deborah M.
Published: February 2023

LF82, an adherent invasiveEscherichia colipathobiont, is associated with ileal Crohn’s disease, an inflammatory bowel disease of unknown etiology. Although LF82 contains no virulence genes, it carries several genetic differences, including single nucleotide polymorphisms (SNPs), that distinguish it from nonpathogenicE. coli. We have identified and investigated an extremely rare SNP that is within the highly conservedrpoDgene, encoding σ70, the primary sigma factor for RNA polymerase. We demonstrate that this single residue change (D445V) results in specific transcriptome and phenotypic changes that are consistent with multiple phenotypes observed in LF82, including increased antibiotic resistance and biofilm formation, modulation of motility, and increased capacity for methionine biosynthesis. Our work demonstrates that a single residue change within the bacterial primary sigma factor can lead to multiple alterations in gene expression and phenotypic changes, suggesting an underrecognized mechanism by which pathobionts and other strain variants with new phenotypes can emerge.
Testing the predictive performance of comparative extinction risk models to support the global amphibian assessment
Authors: Lucas P.M. , Di Marco M. , Cazalis V. , Luedtke J. , Neam K. , Brown M.H. , Langhammer P. , Mancini G. , Santini L.
Published: February 2023

Assessing the extinction risk of species through the IUCN Red List is key to guiding conservation policies and reducing biodiversity loss. This process is resource-demanding, however, and requires a continuous update which becomes increasingly difficult as new species are added to the IUCN Red List. The use of automatic methods, such as comparative analyses to predict species extinction risk, can be an efficient alternative to maintaining up to date assessments. Using amphibians as a study group, we predict which species were more likely to change status, in order to suggest species that should be prioritized for reassessment. We used species traits, environmental variables, and proxies of climate and land-use change as predictors of the IUCN Red List category of species. We produced an ensemble prediction of IUCN Red List categories by combining four different model algorithms: Cumulative Link Models (CLM), phylogenetic Generalized Least Squares (PGLS), Random Forests (RF), Neural Networks (NN). By comparing IUCN Red List categories with the ensemble prediction, and accounting for uncertainty among model algorithms, we identified species that should be prioritized for future reassessments due to high prediction versus observation mismatch. We found that CLM and RF performed better than PGLS and NN, but there was not a clear best algorithm. The most important predicting variables across models were species range size, climate change, and landuse change. We propose ensemble modelling of extinction risk as a promising tool for prioritizing species for reassessment while accounting for inherent models’ uncertainty.
Inflammation induces bitter taste oversensitization via epigenetic changes inTas2rgene clusters
Authors: Lin Cailu , Jyotaki Masafumi , Quinlan John , Feng Shan , Zhou Minliang , Jiang Peihua , Matsumoto Ichiro , Huang Liquan , Ninomiya Yuzo , Margolskee Robert F. , Reed Danielle R. , Wang Hong
Published: February 2023

T2R bitter receptors, encoded byTas2rgenes, are not only critical for bitter taste signal transduction but also important for defense against bacteria and parasites. However, little is known about whether and howTas2rgene expression are regulated. Here we show that, in an inflammation model mimicking bacterial infection, the expression of manyTas2rsare significantly up-regulated and mice displayed markedly increased neural and behavioral responses to bitter compounds. Using single-cell assays for transposase-accessible chromatin with sequencing (scATAC-seq), we found that the chromatin accessibility ofTas2rswas highly cell type specific and inflammation increased the accessibility of manyTas2rs. scATAC-seq also revealed substantial chromatin remodeling in immune response genes in taste tissue stem cells, suggesting potential long-term effects. Together, our results suggest an epigenetic mechanism connecting inflammation,Tas2rgene regulation, and altered bitter taste, which may explain heightened bitter taste that can occur with infections and cancer treatments.
BAG3 regulates the specificity of the recognition of specific MAPT species by NBR1 and SQSTM1
Authors: Lin Heng , Sandkuhler Sarah , Dunlea Colleen , King Darron H , Johnson Gail V. W.
Published: February 2023

Autophagy receptors are essential for the recognition and clearance of specific cargos by selective autophagy, which is essential for maintaining MAPT proteostasis. Previous studies have implicated different autophagy receptors in directing distinct species of MAPT to autophagy, but the underlying mechanisms have not been fully investigated. Here we examine how the autophagy receptors NBR1 and SQSTM1 differentially engage specific forms of MAPT and facilitate their clearance. In primary neurons depletion of NBR1, unlike depletion of SQSTM1, significantly increased phosphorylated MAPT levels. The specificity of the interactions were confirmed using in vitro binding assays with purified proteins. We provide direct evidence that NBR1 preferentially binds to monomeric MAPT, while SQSTM1 interacts predominantly with oligomeric MAPT, and that the co-chaperone BAG3 regulates the specificity of these interactions. Using an in vitro pulldown assay, we show that SQSTM1 only binds to monomeric MAPT when BAG3 is absent and fails to bind when BAG3 is present. The opposite is true of NBR1; its binding to monomeric MAPT was dependent on the presence of BAG3. Interestingly, in Alzheimer’s disease brain the association of NBR1 with BAG3 was significantly decreased. In a mouse model, ablation of BAG3 in neural cells disrupted the association of NBR1 with phosphorylated MAPT and lead to increased levels of phosphorylated and oligomeric MAPT. Overall, our results uncover a novel role for BAG3 in regulating the specificity of selective autophagy receptors in targeting different species of MAPT and provide compelling evidence that BAG3 plays a key role in maintaining MAPT proteostasis.

Highlights

First direct evidence of the district role of NBR1 and SQSTM1 in binding with monomeric and oligomeric MAPT, respectively.

Demonstration of a novel mechanism by which BAG3 regulates the specificity of the recognition of monomeric MAPT by NBR1 and oligomeric MAPT by SQSTM1.

Conditional knockout of BAG3 in the brain disrupted the association of NBR1 with phosphorylated MAPT and lead to increased levels of phosphorylated and oligomeric MAPT.
Self-stabilization mechanism encoded by a bacterial toxin facilitates reproductive parasitism
Authors: Harumoto Toshiyuki
Published: February 2023

A wide variety of bacterial endosymbionts in insects are associated with reproductive parasitism, whereby they interfere with host reproductive systems to spread within populations. Recent successes in identifying bacterial factors responsible for reproductive parasitism have highlighted the common appearance of deubiquitinase domains, although their functional roles remain unknown. For example,Spiroplasmasymbionts inDrosophilaselectively kill male progeny with a male-killing toxin Spaid that encodes an OTU deubiquitinase domain. Here I show that without the function of OTU, the male-killing activity of Spaid is attenuated, though not eliminated, since it is polyubiquitinated and degraded through the host ubiquitin-proteasome pathway. Furthermore, I find that Spaid utilizes its OTU domain to deubiquitinate itself in an intermolecular manner. Collectively, the deubiquitinase domain of Spaid serves as a self-stabilization mechanism to facilitate male killing in flies, optimizing a molecular strategy of endosymbionts that enables the efficient manipulation of the host at low-cost.
Extracellular proteases are an essential public good supportingBacillus subtilisgrowth through exogenous protein degradation
Authors: Rosazza Thibault , Eigentler Lukas , Earl Chris , Davidson Fordyce , Stanley-Wall Nicola
Published: February 2023

Bacteria encounter polymeric nutrient sources that need to be processed to support growth.Bacillus subtilisis a bacterium known for its adaptability and resilience within the rhizosphere and broader soil environment. Here we explore the role that a suite of extracellular proteases plays in supporting growth ofB. subtiliswhen an extracellular heterologous protein (BSA) provides an abundant, but polymeric, food source. We confirm the essential role of extracellular proteases in this context and note the influence of the polymeric nutrient concentration on the yield of growth, but not on the relative level of extracellular proteases. We demonstrate the collective action of the extracellular proteases in supportingB. subtilisgrowth and evidence their use as a shared public good. Furthermore, we show thatB. subtilisis subjected to a public good dilemma, but only in the context of using a polymeric food source. Using mathematical simulations, we uncover that this dilemma is driven by therelativecost of producing the public good. Collectively, our findings reveal howB. subtiliscan survive in environments that vary significantly in terms of immediate nutrient accessibility. This information should inform steps to improve its efficacy as a biofertilizer in agricultural settings.
Ts-Biotag, a multimodal reporter of Tie2 expression, labels microglia in a model of neuro injury
Authors: Brodsky Jennifer , Tashi Zeinab , Christopher Sharon K. , Cerna Gabriella , Gohsman Simone , Bartelle Benjamin B.
Published: February 2023

The Ts-Biotag transgenic mouse reports the expression of receptor tyrosine kinase Tie2, a known marker of angiogenic states for both vascular endothelial cells and macrophages. We demonstrate Ts-Biotag labeling and Tie2 expression in a neural injury model to find the majority of labeling occurs in the myeloid derived and brain resident cell type, microglia. Additionally the ligand of Tie2, Ang1, is dynamically expressed, first in astrocytes then neural progenitor during wound signaling and healing. These results offer a Tie2 specific, in vivo view of a neuroimmune response to injury, suggesting a microglia/neural progenitor intercellular interaction guides recovery from a brain lesion.

Graphical Abstract

The Ts-Biotag mouse reports expression of Tie2 for any imaging modality compatible with avidinated agents. Mice were given a transcranial cryo-injury and Ts-Biotag activity was followed for 7 days with MRI and histology, showing local and systemic Ts-Biotag labeling. Histology of WT and labeled bone marrow chimeras showed the protein Tie2 expressed in microglia, which assembled at the border of the lesion 1-2d post injury before invading by day 7. The main ligand of Tie2, Ang1, was first expressed systemically by astrocytes, then by neural progenitor cells proximal to and within the lesion. These results elucidate an axis of intercellular signaling involved in the resolution of inflammation and partial healing of a CNS injury.