bluuebunny/crossref_metadata_2025 huggingface dataset:
Posterior Ankle Impingement Syndrome Clinical Features Are Not Associated With Imaging Findings in Elite Ballet Dancers and Athletes
Authors: Baillie Peta , Ferrar Katia , Cook Jill , Smith Peter , Lam Jason , Mayes Susan
Published: February 2022

Objective:

To assess the association between clinical features and magnetic resonance imaging (MRI) findings in posterior ankle impingement syndrome (PAIS) and to compare the prevalence of imaging findings between participants with and without a clinical diagnosis of PAIS.

Design:

Case-control study.

Setting:

Elite ballet and sport.

Participants:

Eighty-two male (54%) and female participants comprising ballet dancers (n = 43), cricket fast bowlers (n = 24), and football (soccer) players (n = 15).

Independent Variables:

Clinical: posterior ankle pain on body chart, passive plantarflexion pain provocation test. Patient-reported outcome measures: Oslo Sports Trauma Research Center Overuse Injury Questionnaire, Foot and Ankle Ability Measure Sports subscale.

Main Outcome Measures:

Imaging findings including posterior ankle bone marrow edema, os trigonum (± bone marrow edema, and increased signal at synchondrosis), Stieda process (± bone marrow edema), talocrural and subtalar joint effusion–synovitis size, flexor hallucis longus tendinopathy, and tenosynovitis identified as present or absent on 3.0-Tesla MRI.

Results:

Imaging findings were not associated with posterior ankle pain or a positive ankle plantarflexion pain provocation test. Imaging findings were not associated with patient-reported outcome measures. Imaging findings did not differ between PAIS-positive and PAIS-negative groups. Os trigonum and Stieda process were prevalent despite clinical status.

Conclusions:

The lack of association between imaging findings and clinical features questions the role of imaging in PAIS. Clinicians should rely primarily on clinical assessment in the diagnosis and management of patients with PAIS.
Performance and long-term consistency of five Galliform 68Ge/68Ga generators used for clinical Ga-68 preparations over a 4 year period
Authors: Sammartano Antonino , Migliari Silvia , Scarlattei Maura , Baldari Giorgio , Serreli Giulio , Lazzara Chiara , Garau Ludovico , Ghetti Caterina , Ruffini Livia
Published: February 2022

Background

Gallium-68 is a positron emitter for PET applications that can be produced without cyclotron by a germanium (Ge-68) chloride/gallium (Ga-68) chloride generator. Short half-life (67.71 min) of Ga-68, matching pharmacokinetic properties of small biomolecules, facilitates isotope utilization in compounding radiopharmaceuticals for PET imaging. The increasing cost of good manufacturing practice-compliant generators has strengthened the need for radionuclide efficient use by planning specific radiopharmaceutical sessions during the week, careful maintenance of the generator and achievement of high labeling yield and radiochemical purity (RCP) of the radiolabeled molecules.

Methods

The aim of this study was to evaluate the annual performance of five consecutive 68Ge/68Ga generators used for small-scale preparations of 68Ga-radiopharmaceuticals. To assess the long-term efficiency of isotope production we measured the weekly elution yield. To assess process efficiency we measured elution yield, labeling yield and RCP of four radiopharmaceutical preparations (68Ga-DOTATOC, 68Ga-PSMA-HBED-CC, 68Ga-PENTIXAFOR and 68Ga-DOTATATE).

Results

The annual mean elution yield of the generators was 74.7%, higher than that indicated by the manufacturer, and it never went below 65%. The Ge-68 level in the final products was under the detection limits in all the produced batches (mean value 0.0000048%). The RCP of radiopharmaceuticals determined by high-performance liquid chromatography was 98 ± 0.22%. The mean yield of radiolabelling was 64.68, 68.71, 57 and 63.68% for 68Ga-DOTATOC, 68Ga-PSMA-HBED-CC, 68GaPENTIXAFOR and 68Ga-DOTATATE.

Conclusion

The ability to prepare in the hospital radiopharmacy high-purity and pharmaceutically acceptable 68Ga-radiolabeled probes on a routine basis facilitates patient access to precision imaging for clinical and research aims.
Perianal Crohn Disease Is More Common in Children and Is Associated With Complicated Disease Course Despite Higher Utilization of Biologics
Authors: Atia Ohad , Focht Gili , Lujan Rona , Ledder Oren , Greenfeld Shira , Kariv Revital , Dotan Iris , Yanai Henit , Gabay Hagit , Balicer Ran , Haklai Ziona , Nevo Daniel , Turner Dan
Published: February 2022

Background and Objectives:

Both perianal and pediatric‐onset Crohn disease (CD) disease are associated with complicated disease course and higher drug utilization. we aimed to explore the differences between pediatric and adult‐onset perianal CD and their disease course.

Methods:

We included all patients with newly diagnosed CD from 2005 to 2019 at two Israeli Health Maintenance Organizations, covering 78% of the population. A combination of ICD‐9 codes, radiology and procedures was used to define fistulizing perianal CD (PCD) and its severity according to the association with simple and complex perianal disease.

Results:

A total of 12,905 patients were included (2186 [17%] pediatric‐onset, 10,719 [83%] adults), with a median follow‐up of 7.8 years. PCD was diagnosed in 1530 (12%) patients, with higher incidence in children (308 [14%] children vs 1222 adults [11%]; P < 0.001). Children had higher incidence of severe PCD (141/308 [47%] vs 433/1222 [35%]; P < 0.001). At 5 years, children with PCD were more likely than adults to be treated with biologics (212 [69%] vs 515 [42%]; odds ratio [OR] 2.6 [95% confidence interval (CI) 1.6–4.0]; P < 0.001) and immunomodulators (238 [74%] vs 643 [53%]; OR 2.8 [95% CI 2.1–3.6]; P < 0.001). PCD in children was still associated with poorer disease outcomes as shown for surgeries (36 [12%] vs 93 [8%]; P = 0.02) and steroid‐dependency (52 [17%] vs 156 [13%]; P < 0.001). Multivariable modeling indicated that the severity of PCD is a stronger predictor of disease course than age.

Conclusion:

PCD is more common in pediatric‐onset CD and is associated with higher drug utilization and worse disease outcomes, in large due to higher rate of severe PCD in children.
Spanish National Registry of Paediatric Coeliac Disease
Authors: Pérez Solís David , Cilleruelo Pascual Ma Luz , Ochoa Sangrador Carlos , García Burriel Jose Ignacio , Sánchez‐Valverde Visus Félix , Eizaguirre Arocena Francisco Javier , Garcia Calatayud Salvador , Martinez‐Ojinaga Nodal Eva , Donat Aliaga Ester , Barrio Torres Josefa , Castillejo de Villasante Gemma , Miranda Cid Ma del Carmen , Torres Peral Ricardo , Vecino Lopez Raquel , Juste Ruiz Mercedes , Armas Ramos Honorio , Barros Garcia Patricia , Leis Trabazo Rosaura , Solaguren Alberdi Rosa , Salazar Quero José Carlos , Garcia Romero Ruth , Ortigosa del Clastillo Luis , Peña Quintana Luis , Urruzuno Telleria Pedro , Codoñer Franch Pilar , Garcia Casales Zuriñe , Masiques Mas Maria Lluïsa , Galicia Poblet Gonzalo , Martinez Costa Cecilia , Balmaseda Serrano Elena , Polanco Allué Isabel , Ribes Koninck Carmen , Román Riechmann Enriqueta ,   Coeliac Disease Working Group of the Spanish Gastroenterology, Hepatology, Paediatric Nutrition Society (SEGHNP)
Published: February 2022

Objectives:

Over the last several decades, there has been a tendency towards a predominance of less symptomatic forms of coeliac disease (CD) and an increase in the patient age at diagnosis. This study aimed to assess the clinical presentation and diagnostic process of paediatric CD in Spain.

Methods:

A nationwide prospective, observational, multicentre registry of new paediatric CD cases was conducted from January 2011 to June 2017. The data regarding demographic variables, type of birth, breast‐feeding history, family history of CD, symptoms, height and weight, associated conditions, serological markers, human leukocyte antigen (HLA) phenotype, and histopathological findings were collected.

Results:

In total, 4838 cases (61% girls) from 73 centres were registered. The median age at diagnosis was 4 years. Gastrointestinal symptoms were detected in 71.4% of the patients, and diarrhoea was the most frequent symptom (45.9%). The most common clinical presentation was the classical form (65.1%) whereas 9.8% ofthe patients were asymptomatic. There was a trend towards an increase in the age at diagnosis, proportion of asymptomatic CD cases, and usage of anti‐deamidated gliadin peptide antibodies and HLA typing for CD diagnosis. There was, however, a decreasing trend in the proportion of patients undergoing biopsies. Some of these significant trend changes may reflect the effects of the 2012 ESPGHAN diagnosis guidelines.

Conclusions:

Paediatric CD in Spain is evolving in the same direction as in the rest of Europe, although classical CD remains the most common presentation form, and the age at diagnosis remains relatively low.
Preload Dependence Fails to Predict Hemodynamic Instability During a Fluid Removal Challenge in Children*
Authors: Jacquet-Lagrèze Matthias , Acker Amélie , Hentzen Julie , Didier Capucine , De Lamer Sabine , Chardonnal Laurent , Bouhamri Noureddine , Portran Philippe , Schweizer Rémi , Lilot Marc , Fellahi Jean-Luc
Published: February 2022

OBJECTIVES:

Fluid overload increases morbidity and mortality in PICU patients. Active fluid removal improves the prognosis but may worsen organ dysfunction. Preload dependence in adults does predict hemodynamic instability induced by a fluid removal challenge (FRC). We sought to investigate the diagnostic accuracy of dynamic and static markers of preload in predicting hemodynamic instability and reduction of stroke volume during an FRC in children. We followed the Standards for Reporting of Diagnostic Accuracy statement to design conduct and report this study.

DESIGN:

Prospective noninterventional cohort study.

SETTINGS:

From June 2017 to April 2019 in a pediatric cardiac ICU in a tertiary hospital.

PATIENTS:

Patients 8 years old or younger, with symptoms of fluid overload after cardiac surgery, were studied.

INTERVENTIONS:

We confirmed preload dependence by echocardiography before and during a calibrated abdominal compression test. We then performed a challenge to remove 10-mL/kg fluid in less than 120 minutes with an infusion of diuretics. Hemodynamic instability was defined as a decrease of 10% of mean arterial pressure.

MEASUREMENT AND MAIN RESULTS:

We compared patients showing hemodynamic instability with patients remaining stable, and we built receiver operative characteristic (ROC) curves. Among 58 patients studied, 10 showed hemodynamic instability. The area under the ROC curve was 0.55 for the preload dependence test (95% CI, 0.34–0.75). Using a threshold of 10% increase in stroke volume index (SVi) during calibrated abdominal compression, the specificity was 0.30 (95% CI, 0.00–0.60) and the sensitivity was 0.77 (95% CI, 0.65–0.88). Mean arterial pressure variation and SVi variation were not correlated during fluid removal; r = 0.19; 95% CI –0.07 to 0.43; p = 0.139.

CONCLUSIONS:

Preload dependence is not accurate to predict hemodynamic instability during an FRC. Our data do not support a reduction in intravascular volume being mainly responsible for the reduction in arterial pressure during an FRC in children.
Racial and Ethnic Differences in Inpatient Palliative Care for Pediatric Stem Cell Transplant Patients*
Authors: McKee Maya N. , Palama Brett K. , Hall Matt , LaBelle James L. , Bohr Nicole L. , Hoehn K. Sarah
Published: February 2022

OBJECTIVES:

Racial/ethnic disparities in utilizing inpatient palliative care services are well documented in the adult literature. However, the impact of racial/ethnic disparities in the context of pediatric palliative care is less well understood even in high-acuity patient populations such as stem cell transplant patients. We investigated racial/ethnic differences in the utilization of inpatient palliative care consultations (IPCCs) for pediatric stem cell transplant patients.

STUDY DESIGN:

A retrospective cohort study was conducted using the Pediatric Health Information System database. A generalized linear mixed effects model was developed to assess demographic and clinical characteristics associated with the likelihood of receiving IPCC.

SETTING:

Thirty-eight tertiary pediatric hospitals in the United States.

PATIENTS:

Pediatric patients undergoing stem cell transplantation for any indication from January 2017 to December 2019.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

Of the 1,193 inpatient encounters studied, 12% (n = 143) included a palliative care consult. IPCC rates varied across hospitals with a median rate of 5.97% (interquartile range, 0.00–20.71). In multivariable analyses, Hispanic/Latinx patients were 59% less likely to receive IPCC compared with non-Hispanic White patients (odds ratio [OR], 0.41; 95% CI, 0.21–0.78). This difference persisted after adjusting for all other sociodemographic and clinical factors. In terms of the other clinical characteristics, having a malignant condition and mechanical ventilation were associated with significantly increased odds of receiving IPCC for the entire cohort (OR Malignancy: 1.93; 95% CI: 1.07-3.51; OR Mechanical Ventilation: 2.37; 95% CI: 1.36-4.13). The remainder of the variables were not found to be significantly associated with IPCC.

CONCLUSIONS:

Racial and ethnic differences exist in the likelihood of receiving palliative care consultations among hospitalized pediatric stem cell transplant recipients. Evaluating the impact of systemic racism and social determinants on palliative care medicine as well as standardizing early integration of IPCC may potentially mitigate disparities in this population.
Should Pharmacists Lead Medication Reconciliation in Critical Care? A One-Stem Interventional Study in an Egyptian Intensive Care Unit
Authors: El Hadidi Seif , Hamdi Mohamed , Sabry Nirmeen
Published: February 2022

Objectives

The main objective was to compare physician-obtained medication histories to the practice of medication reconciliation undertaken by a pharmacist in the intensive care unit (ICU).

Methods

A one-stem interventional study involving 500 adults 18 years and older admitted to the ICU (50 beds) of an Egyptian Joint Commission International–accredited reference hospital was conducted. The primary outcome measure was the proportion of ICU patients with missing medications in the cohorts of physician versus pharmacist-led medication reconciliation. The secondary outcome measure was the percentage of patients who had at least one clinical condition or adverse event (AE) that was left untreated during hospitalization of the 2 arms of patients after reconciliation.

Results

A total of 500 patients received reconciliation. Medication discrepancies in the cohort of physician-led reconciliation were greater than that of the pharmacist (26.1% versus 2.6%, P = 0.001). The most common discrepancy was indication with no medication, which was found to be greater in the physician-led cohort of patients than that of the pharmacist cohort (25.2% versus 2.6%, P = 0.001). Untreated AEs in the former cohort were present in 9.1% of cases versus 1.5% in the pharmacist-led reconciliation cohort (P = 0.001).

Conclusions

The present study revealed that pharmacist-led medication reconciliation in ICU has dramatically decreased medication discrepancies and AEs in adults with acute ICU admissions.
Spectral dynamic causal modeling of mindfulness, mind-wandering, and resting-state in the triple network using fMRI
Authors: Kim Hyun-Chul , Lee Jong-Hwan
Published: February 2022

Objective

Functional connectivity in intrinsic brain networks, namely, the triple network, which includes the salience network, default mode network (DMN) and central executive network (CEN), has been suggested as prominent, major networks involved in human cognition and mental state–mindfulness, mind-wandering and resting-state. Despite the established roles of functional connections within and between intrinsic networks, there has been limited research on the effective connectivity of mindfulness, mind-wandering and resting-state using the triple network, as well as on their direct comparisons.

Methods

We employed spectral dynamic causal modeling to compare effective connectivity patterns across mindfulness (i.e. attention focused on physical sensations of breathing), mind-wandering (i.e. connecting thoughts) and resting-state (i.e. relaxing while remaining calm and awake) conditions using functional MRI data of healthy subjects who underwent ambulatory training by practicing mindfulness and mind-wandering (N = 59).

Results

When comparing mindfulness and mindwandering conditions, our analysis results revealed that salience network and CEN interacted depending on mindfulness or mind-wandering. When mindfulness or mind-wandering was compared to resting-state, mindfulness increased the effective connectivity from the left CEN to salience network through DMN, whereas mindwandering increased the effective connectivity from the DMN to right CEN.

Conclusion

To the best of our knowledge, this is the first study to examine possible differences in effective connectivity patterns among mindfulness, mind-wandering and resting-state using the triple network. We believe that our findings will provide deeper insights into the neural substrates of mindfulness compared to mind-wandering and resting-state.
The level of liver and renal function biomarker abnormalities among hospitalized COVID-19 patients in Ethiopia
Authors: Tsegay Yakob Gebregziabher , Bitew Molalegne , Workneh Tigist , Atlaw Assegdew , Aragaw Mintsnot , Gemechu Mesay , Brhane Nega
Published: February 2022

Background

COVID-19 pandemic is unprecedented public health emergency and added burden to developing countries. The pandemic cause multi organ failures (MOF) predominantly affects lung, cardiac, renal and liver organs as severity of the disease exacerbates. That is the rationale to execute this study with the aim to determine the magnitude of abnormal organ function test parameters and its association between markers of organ failure and disease severity in patients infected with COVID-19 admitted at Millennium COVID-19 Care Center (CCC).

Methods

A cross-sectional study was conducted among COVID-19 patients admitted at Millennium COVID-19 Care and Treatment Center (MCCTC) from May 2021 up to Oct 2021. In this study 500 participant’s information were collected from the laboratory database of Millennium COVID-19 care center. Data were analyzed using SPSS version 25. P-value <0.05 was considered significantly associated.

Result

The median age of the 500 study participants was 55.6±7.7 years, and from these 67.6% of patients were males. Liver function parameters Aspartae transferase (AST),) alanine aminotransferase (ALT) and Alakaline phosphatase (ALP) the mean value of overall patients were elevated and three of these parameters were highly elevated among critical patients (56.9±57.7, 58.5±6, and 114.6±6) respectively. All study participants had an elevated Creatinine. 66.8% males, 65% Intensive care unit (ICU), had an elevated serum value of ALT and AST respectively. Troponin was found elevated among males (54%) and 59% among ICU (critical) patients.

Conclusion

Liver and renal function test biomarkers such as creatine kinase muscle-brain isoenzymes (CK-MB), troponin, AST, ALT and Creatinine serum value was found elevated among ICU than non ICU patients. Organ function biomarkers are a candidate for predicting COVID-19 disease severity in order to guide clinical care.
Pan-cancer detection and typing by mining patterns in large genome-wide cell-free DNA sequencing datasets
Authors: Che Huiwen , Jatsenko Tatjana , Lenaerts Liesbeth , Dehaspe Luc , Vancoillie Leen , Brison Nathalie , Parijs Ilse , Van Den Bogaert Kris , Fischerova Daniela , Heremans Ruben , Landolfo Chiara , Testa Antonia Carla , Vanderstichele Adriaan , Liekens Lore , Pomella Valentina , Wozniak Agnieszka , Dooms Christophe , Wauters Els , Hatse Sigrid , Punie Kevin , Neven Patrick , Wildiers Hans , Tejpar Sabine , Lambrechts Diether , Coosemans An , Timmerman Dirk , Vandenberghe Peter , Amant Frédéric , Vermeesch Joris Robert
Published: February 2022

Background

Cell-free DNA (cfDNA) analysis holds great promise for non-invasive cancer screening, diagnosis and monitoring. We hypothesized that mining the patterns of big datasets of shallow whole genome sequencing cfDNA from cancer patients could improve cancer detection.

Methods

By applying unsupervised clustering and supervised machine learning on large shallow whole-genome sequencing cfDNA datasets from healthy individuals (n=367), patients with different hematological (n=238) and solid malignancies (n=320), we identify cfDNA signatures that enable cancer detection and typing.

Results

Unsupervised clustering revealed cancer-type-specific sub-grouping. Classification using supervised machine learning model yielded an overall accuracy of 81.62% in discriminating malignant from control samples. The accuracy of disease type prediction was 85% and 70% for the hematological and solid cancers, respectively. We demonstrate the clinical utility of our approach by classifying benign from invasive and borderline adnexal masses with an AUC of 0.8656 and 0.7388, respectively.

Conclusions

This approach provides a generic and cost-effective strategy for non-invasive pan-cancer detection.
No evidence of progressive pro-inflammatory cytokine storm in brain dead organ donors - A time course analysis using clinical samples
Authors: Bera Kasia D , Tabak Joel , Ploeg Rutger J
Published: February 2022

Organ donation after brain death (DBD) is an important source of transplanted organs as chronic undersupply means many patients die whilst awaiting a transplant. Improving organ quality and graft survival is key to reducing waiting lists. The interval between brain death confirmation and organ procurement offers an opportunity to reduce organ injury or encourage repair, yet data is lacking on the effects of brain injury on future grafts and which pathways to target. In fact, the consensus view has been that brain death exposes organs to a progressively pro-inflammatory environment, suggesting organ procurement must occur within a limited time window. Here, we developed a novel method of studying time-course changes in serum proteins in a DBD cohort from a UK biobank. Individual donor trajectories were combined to determine the time course of pro-inflammatory (Tumour Necrosis Factor alpha, Interleukin 6, Complement) mediators and markers of central nervous injury (Neuron Specific Enolase, Glial Fibrillary Acidic Protein) after confirmation of brain death. We found no evidence of a rise of TNF-alpha, NSE, IL-6 or C5a with prolonged duration of brain death, questioning the consensus view of progressively pro-inflammatory environment. We also identified complement as a potential target for therapeutic intervention to improve organ quality.
Interactive network-based clustering and investigation of multimorbidity association matrices with associationSubgraphs
Authors: Strayer Nick , Zhang Siwei , Yao Lydia , Vessels Tess , Bejan Cosmin A , Hsi Ryan S , Shirey-Rice Jana K , Balko Justin M , Johnson Douglas B , Philips Elizabeth J , Bick Alex , Edwards Todd L , Velez Edwards Digna R , Pulley Jill M , Wells Quinn S , Savona Michael R , Cox Nancy J , Roden Dan M , Ruderfer Douglas M , Xu Yaomin
Published: February 2022

Making sense of association networks is vitally important to many areas of high-dimensional analysis. Unfortunately, as the data-space dimensions grow, the number of association pairs increases in O(n2); this means traditional visualizations such as heatmaps quickly become too complicated to parse effectively. Here we present associationSubgraphs: a new interactive visualization method to quickly and intuitively explore high-dimensional association datasets using network science-derived statistics and visualization. As a use case example, we apply associationSubgraphs to a phenome-wide multimorbidity association matrix generated from an electronic health record (EHR) and provided an online, interactive demonstration for exploring multimorbidity subgraphs.

Availability

An R package implementing both algorithm and visualization components of associationSubgraphs is available at https://github.com/tbilab/associationsubgraphs. Online documentation is available at https://prod.tbilab.org/associationsubgraphs_info/. A demo using a multimorbidity association matrix is available at https://prod.tbilab.org/associationsubgraphs-example/.
Active perceptual learning involves motor exploration and adaptation of predictive sensory integration
Authors: Hirano Masato , Furuya Shinichi
Published: February 2022

We perceive the external world through both externally generated and self-generated sensory stimuli (i.e., passive and active perception). While the performance in passive perception is improved by training or repetition through the functional and structural reorganization of the central nervous system (i.e., perceptual learning), the mechanisms by which perceptual learning occurs in active perception remain unclear. Here, we sought to explore the mechanisms underlying the improvement of active somatosensory perception and sensorimotor skills through active perceptual learning. Because we previously found that active perceptual learning depends on the expertise of the motor task to be performed, this study focused primarily on trained individuals. To this end, active haptic training (AHT) that targets the active somatosensory perception during the piano keystroke was used as a means of inducing active perceptual learning. We found four main results. First, participants actively modulated the muscle coordination patterns to optimize the movements required by the task through AHT without any explicit instruction on it by the experimenter, suggesting the involvement of active exploration in active perceptual learning. Second, AHT increased the relative reliance on afferent sensory information relative to the predicted one during the piano keystroke. Third, perceptual sensitivity of externally generated keystroke motions remained unchanged through AHT. Finally, AHT improved feedback control of repetitive keystroke movements in expert pianists. These results suggest that active perceptual learning involves changes in both the predictive integration process and active exploration and that the improved feedback control of fine movements benefits from the improvement in active perception.

Significant statement

Our ability to perceive both externally generated and self-generated sensory stimuli can be enhanced through training, known as passive and active perceptual learning. Here, we sought to explore the mechanisms underlying active perceptual learning by using active haptic training (AHT), which has been demonstrated to enhance the somatosensory perception of a finger in a trained motor skill. First, AHT reorganized the muscular coordination during the piano keystroke. Second, AHT increased the relative reliance on afferent sensory information relative to predicted one, in contrast to no increment of overall perceptual sensitivity. Finally, AHT improved feedback movement control of keystrokes. These results suggest that active perceptual learning involves active exploration and adaptation of predictive sensory integration, which underlies the co-enhancement of active perception and feedback control of movements.
Placebo response in chronic peripheral neuropathic pain trials: systematic review and meta-analysis
Authors: Duarte Gonçalo S , Mainoli Beatrice , Rodrigues Filipe B , Rato Fábio , Machado Tiago , Ferreira Joaquim J , Costa João
Published: February 2022

Objective

To estimate the magnitude of the placebo and nocebo responses in chronic peripheral neuropathic pain (CNP) and explore possible associations with trial characteristics.

Methods

We searched CENTRAL, MEDLINE, and Embase for randomized controlled trials (RCTs) from inception to May 2020. We included placebo-controlled RCTs of ≥8 weeks investigating first-line pharmacological interventions for CNP. Primary endpoints were the placebo response, the proportion of patients receiving placebo with pain intensity reduction (PIR) ≥30% from baseline, and the nocebo response, the proportion of patients receiving placebo experiencing adverse events (AEs). Screening, data extraction, and bias assessment (with the Cochrane risk of bias tool) were conducted by independent reviewers. We pooled data using a random-effects model.

Results

We included 50 trials, with a combined 5,693 participants allocated to placebo, conducted between 1998 and 2020. Overall, 38% of patients receiving placebo reported PIR≥30% (95% CI 34 to 42, I2=86%); 23% reported PIR≥50% (95% CI 20 to 26; I2=81%). 50% of patients receiving placebo reported AEs (95% CI 0.43 to 0.58; I2=97%); 2% reported serious AEs (95% CI 2 to 3; I2=58%). In patients receiving active interventions, the placebo response accounts for 75% of the treatment effect on PIR≥30%, and the nocebo response accounts for 75% of the AEs. Interpreted inversely, only 25% of responses and 25% of adverse events can be attributed to the intervention. Publication year positively correlated with PIR≥30% and negatively correlated with AEs. Female sex negatively correlated with AEs.

Conclusions

The placebo and nocebo responses in parallel-designed RCTs in CNP are substantial and should be considered in trial interpretation and in the design of future trials.
Integration of proteomics and metabolomics – insights into inflammation, metabolic dysregulation, and vascular aspects in AD
Authors: Borkowski Kamil , Seyfried Nicholas T. , Arnold Matthias , Lah James J. , Levey Allan I. , Hales Chadwick M. , Dammer Eric B. , Blach Colette , Louie Gregory , Kaddurah-Daouk Rima , Newman John W. ,   Alzheimer’s Disease Metabolomics Consortium
Published: February 2022

Integration of the omics data, including metabolomics and proteomics, provides a unique opportunity to search for new associations in the context of metabolic disorders, including Alzheimer’ s disease. Using targeted metabolomics, we have previously profiled lipid mediators, including oxylipins, endocannabinoids, bile acids and steroids in 293 CSF and 202 matched plasma samples from AD cases and healthy controls, and identified both central and peripheral metabolites of the inflammation-regulating cytochrome p450/soluble epoxide hydrolase pathway as strong predictors for the AD pathology. Additionally, using proteomics, we have identified five cerebrospinal fluid protein panels, involved in regulation of energy metabolism, vasculature, myelin/oligodendrocyte, glia/inflammation, and synapses/neurons affected in AD, and reflective of AD-related changes in brain. In the current manuscript, using metabolomics-proteomics data integration, we describe new associations between peripheral and central lipid mediators, with the above-described cerebrospinal fluid protein panels. Particularly strong associations were observed between cytochrome p450/soluble epoxide hydrolase metabolites, bile acids and CSF proteins involved in glycolysis, blood coagulation and vascular inflammation and the regulators of extracellular matrix. Those metabolic associations were not observed at the gene-coexpression level in the central nervous system, showing the importance of pathway interaction investigation on the level of the terminal part of the biochemical “ omic” cascade. In summary, this manuscript provides new information regarding the Alzheimer’ s disease, linking both central and peripheral inflammatory cascade of cytochrome p450/soluble epoxide hydrolase and bile acids metabolism with AD-affected processes and illustrates the necessity for the “ omics” data integration to uncover associations beyond gene co-expression.
Acute and chronic toxicity of imidacloprid in the pollinator fly, Eristalis tenax
Authors: Nagloo Nicolas , Rigosi Elisa , O'Carroll David Charles
Published: February 2022

Imidacloprid is a neonicotinoid neurotoxin that remains the most used insecticide worldwide. It persists in the environment long after the initial application resulting in chronic exposure to non-target insects. To accurately map the dose-dependent effects of these exposures across taxa, toxicological assays need to assess various modes of exposure across relevant indicator species. However, due to the difficulty of these experiments, contact bioassays are frequently used to quantify dose, and dipterans remain underrepresented. Here, we developed a novel naturalistic feeding bioassay to precisely measure imidacloprid ingestion and its toxicity for acute and chronic exposures in a dipteran pollinator, Eristalis tenax. Flies which ingested imidacloprid dosages lower than 12.1 ng/mg all showed consistent intake volumes and learned improved feeding efficiency over successive feeding sessions. In contrast, at doses of 12.1 ng/mg and higher flies had a rapid onset of severe locomotive impairment which prevented them from completing the feeding task. Neither probability of survival nor severe locomotive impairment were significantly higher than the control group until doses of 1.43 ng/mg or higher were reached. We were unable to measure a median lethal dose for acute exposure (72 hours) due to flies possessing a relatively high tolerance for imidacloprid. However, with chronic exposure (18 days), mortality went up and an LD50 of 0.41 ng/mg was estimated. Severe locomotive impairment tended to occur earlier and at lower dosages than lethality, with ED50s of 0.17 ng/mg and 7.82 ng/mg for acute and chronic exposure, respectively. Although the adult Eristalis is a honeybee mimic, it possesses a much higher tolerance to this toxin than its model. The similarity in the LD50 to other dipterans such as the fruitfly and the housefly suggests that there may be a phylogenetic component to pesticide tolerance that needs to be further investigated. The absence of obvious adverse effects at sublethal dosages also underscores a need to develop better tools for quantifying animal behaviour to evaluate the impact of insecticides on foraging efficiency in economically important species.
Single-cell immune profiling reveals novel thymus-seeding populations, T cell commitment, and multi-lineage development in the human thymus
Authors: Cordes Martijn , Canté-Barrett Kirsten , van den Akker Erik B. , Moretti Federico A. , Kiełbasa Szymon M. , Vloemans Sandra , Garcia-Perez Laura , Teodosio Cristina , van Dongen Jacques J.M. , Pike-Overzet Karin , Reinders Marcel J.T. , Staal Frank J.T.
Published: February 2022

T cell development in the mouse thymus has been studied rather extensively; in contrast, strikingly little is known regarding T cell development in the human thymus. To close this knowledge gap, we used a combination of single-cell techniques and functional assays to perform deep immune profiling of human T cell development, focusing on the initial stages of pre-lineage commitment. We identified three thymus-seeding progenitor populations that also have counterparts in the bone marrow. In addition, we found that the human thymus physiologically supports the development of monocytes, dendritic cells, and NK cells, as well as limited development of B cells. These results are an important step towards monitoring and guiding regenerative therapies in patients following hematopoietic stem cell transplantation.
Porphyrin overdrive rewires pan-cancer cell metabolism
Authors: Adapa Swamy R. , Hunter Gregory A. , Amin Narmin E. , Marinescu Christopher , Borsky Andrew , Sagatys Elizabeth M. , Sebti Said M. , Reuther Gary W. , Ferreira Gloria C. , Jiang Rays H.Y.
Published: February 2022

Porphyrin overdrive rewires pan-cancer cell metabolism

All cancer cells reprogram metabolism to support aberrant growth. Here, we report that cancer cells employ and depend on imbalanced and dynamic heme metabolic pathways for their oncogenic growth. We coined this essential metabolic rewiring ‘porphyrin overdrive’ and determined that it is cancer-universal, cancer-essential, and cancer-specific. While porphyrin overdrive is absent in differentiated cells or somatic stem cells, it is present in patient-derived tumor progenitor cells, demonstrated by single cell RNAseq, and in early embryogenesis. Among the major drivers are proteins involved in biosynthesis of heme intermediates and heme trafficking. CRISPR/Cas9 editing to engineer leukemia cells with impaired heme biosynthetic steps confirmed our whole genomic data analyses that porphyrin overdrive is linked to oncogenic states and cellular differentiation. In conclusion, we identified a dependence of cancer cells on non-homeostatic heme metabolism, and we targeted this cancer metabolic vulnerability with a novel “bait-and-kill” strategy to eradicate malignant cells.

One-Sentence Summary

Porphyrin overdrive reprograms cancer cellular metabolism.
Comparing the value of mono- versus coculture for high-throughput compound screening in hematological malignancies
Authors: Herbst Sophie A. , Kim Vladislav , Roider Tobias , Schitter Eva C. , Bruch Peter-Martin , Liebers Nora , Kolb Carolin , Knoll Mareike , Lu Junyan , Dreger Peter , Müller-Tidow Carsten , Zenz Thorsten , Huber Wolfgang , Dietrich Sascha
Published: February 2022

Large-scale compound screens are a powerful model system for understanding variability of treatment response and for discovering druggable tumor vulnerabilities of hematological malignancies. However, as mostly performed in a monoculture of tumor cells, these assays disregard modulatory effects of thein vivomicroenvironment. It is an open question whether and to what extent coculture with bone marrow stromal cells could improve the biological relevance of drug testing assays over monoculture. Here, we measured ex vivo sensitivity of 108 primary blood cancer samples to 50 drugs in monoculture and in coculture with bone marrow stromal cells. Stromal coculture conferred resistance to 52 % of compounds in chronic lymphocytic leukemia (CLL) and to 36% of compounds in acute myeloid leukemia (AML), including chemotherapeutics, BCR inhibitors, proteasome inhibitors and BET inhibitors. While most of the remaining drugs were similarly effective in mono- and coculture, only the JAK inhibitors ruxolitinib and tofacitinib exhibited increased efficacy in AML and CLL stromal coculture. We further confirmed the importance of JAK-STAT signaling for stroma-mediated resistance by showing that stromal cells induce phosphorylation of STAT3 in CLL cells. We genetically characterized the 108 cancer samples and found that drug-gene associations agreed well between mono- and coculture. Overall, effect sizes were lower in coculture, thus more drug-gene associations were detected in monoculture than in coculture. Our results suggest a two-step strategy for drug perturbation testing, with large-scale screening performed in monoculture, followed by focused evaluation of potential stroma-mediated resistances in coculture.
Single cell analysis of gene expression in the substantia nigra pars compacta of a pesticide-induced mouse model of Parkinson’s disease
Authors: Khan Arshad H. , Lee Lydia K. , Smith Desmond J.
Published: February 2022

Exposure to pesticides in humans increases the risk of Parkinson’s disease (PD), but the mechanisms remain poorly understood. To elucidate these pathways, we dosed C57BL/6J mice with a combination of the pesticides maneb and paraquat (MNPQ). Behavioral analysis revealed motor deficits consistent with PD. Single cell RNA sequencing of substantia nigra pars compacta revealed both cell-type specific genes and genes expressed differentially between pesticide and control, including Fam241b, Emx2os, Bivm, Gm1439, Prdm15 and Rai2. Neurons had the largest number of significant differentially expressed genes, but comparable numbers were found in astrocytes and less so in oligodendrocytes. In addition, network analysis revealed enrichment in functions related to the extracellular matrix. These findings emphasize the importance of support cells in pesticide-induced PD and refocus our attention away from neurons as the sole agent of this disorder.
Effective infection with dengue virus in experimental neonate and adult mice through intranasal route
Authors: Qiu Minyue , Zhao Lixin , Zhang Junjie , Wang Yalan , Liu Minchi , Hua Dong , Ding Xiaoyan , Zhou Xiaoyang , Zeng Jie , Yan Huacheng , Li Jintao
Published: February 2022

As a member of the family Flaviviridae, the dengue virus is transmitted to humans through mosquito vectors. The virus causes dengue fever with flu-like symptoms, life-threatening dengue hemorrhagic fever, and dengue shock syndrome that affects four billion people in 128 countries. It can also be transmitted through atypical routes, such as needle stick injury, vertical transmission, and the receipt of contaminated blood or organs. Although sporadic cases cannot be classified as atypical transmission routes and raise respiratory exposure concerns, the risks remain unclear. Here, we analyzed the respiratory infectivity of the dengue virus in BALB/c suckling and A6 adult mice using the dengue virus serotype 2 and intranasal inoculation. The results showed that the clinical symptoms of intranasally infected mice included excitement, emaciation, malaise, and death, and histopathological changes and viremia dynamics were observed in multiple tissues, including the brain, liver, and spleen. Notably, the DENV serotype 2 showed clear brain tropism after intranasal infection, and viral loads peaked at seven days post-inoculation. Furthermore, the virus was isolated from mouse brains, and the sequence homology between the viral stock and dengue virus isolates was 99.99%. Similar results were observed in adult IFN-α/β receptor-deficient mice. Taken together, our results suggest that the DENV serotype 2 can infect suckling mice and adult immune-deficient mice via the nasal route. The results of our study broaden our perception of atypical dengue transmission routes and may help explain dengue virus infections that occur without the presence of mosquito vectors.

Importance

Dengue is transmitted mainly via mosquito vectors. Flu-like dengue fever or life-threatening severe dengue threatens four billion people in 128 countries. Non-vector dengue cases have occurred occasionally since 1990. These cases cannot be classified as atypical transmission routes and are suspected to have arisen via sexual or respiratory transmission. Recently, the sexual transmission of dengue has been confirmed in humans. The respiratory infectivity of other members of the Flaviviridae family, such as Zika and Japanese encephalitis viruses, has been determined under experimental conditions. The potential for respiratory infection with the dengue virus has not yet been confirmed. In this study, we analyzed the respiratory infectivity of the dengue virus in suckling mice and adult immunodeficient mice via intranasal inoculation, thereby exploring the potential for respiratory transmission in cases with non-vector dengue infection, especially for patients who were exposed to dengue virus contaminants.
Loss of β-ketoacyl acyl carrier protein synthase III activity restores multidrug-resistantEscherichia colisensitivity to previously ineffective antibiotics
Authors: Hong Yaoqin , Qin Jilong , Verderosa Anthony D. , Hawas Sophia , Zhang Bing , Blaskovich Mark A. T. , Cronan John E. , Totsika Makrina
Published: February 2022

Antibiotic resistance is one of the most prominent threats to modern medicine. In the latest World Health Organization list of bacterial pathogens that urgently require new antibiotics, nine out of 12 are Gram-negative, with four being of ‘Critical Priority’. One crucial barrier restricting antibiotic efficacy against Gram-negative bacteria is their unique cell envelope. While fatty acids are a shared constituent of all structural membrane lipids, their biosynthesis pathway in bacteria is distinct from eukaryotes making it an attractive target for new antibiotic development that remains less explored. Here, we interrogated the redundant components of the bacterial Type IIFattyAcidSynthesis (FAS II) pathway, showing that disrupting FAS II homeostasis inEscherichia colithrough deletion of thefabHgene damages the cell envelope of antibiotic susceptible and antibiotic resistant clinical isolates. ThefabHgene encodes the β-ketoacyl acyl carrier protein synthase III (KAS III), which catalyzes the initial condensation reactions during fatty acid biosynthesis. We show thatfabHnull mutation potentiated the killing of multi-drug resistantE. coliby a broad panel of previously ineffective antibiotics, despite the presence of relevant antibiotic resistance determinants, for example, carbapenemasekpc2. Enhanced antibiotic sensitivity was additionally demonstrated in the context of eradicating established biofilms and treating established human cell infectionin vitro. Our findings showcase the potential of FabH as a promising target that could be further explored in the development of therapies that may repurpose currently ineffective antibiotics or rescue failing last-resort antibiotics against Gram-negative pathogens.

IMPORTANCE

Gram-negative pathogens are a major concern for global public health due to increasing rates of antibiotic resistance and the lack of new drugs. A major contributing factor towards antibiotic resistance in Gram-negative bacteria is their formidable outer membrane, which acts as a permeability barrier preventing many biologically active antimicrobials from reaching the intracellular targets and thus limiting their efficacy. Fatty acids are the fundamental building blocks of structural membrane lipids and their synthesis constitutes an attractive antimicrobial target as it follows distinct pathways in prokaryotes and eukaryotes. Herein, we identified a component of fatty acid synthesis, FabH, as a ‘gate-keeper’ of outer membrane barrier function. Without FabH, Gram-negative bacteria become susceptible to otherwise impermeable antibiotics and are re-sensitised to killing by last-resort antibiotics. This study supports FabH as a promising target for inhibition in future antimicrobial therapies.
Identification of a SARS-CoV-2 host metalloproteinase-dependent entry pathway differentially used by SARS-CoV-2 and variants of concern Alpha, Delta, and Omicron
Authors: Benlarbi Mehdi , Laroche Geneviève , Fink Corby , Fu Kathy , Mulloy Rory P. , Phan Alexandra , Ariana Ardeshir , Stewart Corina M. , Prévost Jérémie , Beaudoin-Bussières Guillaume , Daniel Redaet , Bo Yuxia , Yockell-Lelièvre Julien , Stanford William L. , Giguère Patrick M. , Mubareka Samira , Finzi Andrés , Dekaban Gregory A. , Dikeakos Jimmy D. , Côté Marceline
Published: February 2022

To infect cells, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) binds to angiotensin converting enzyme 2 (ACE2) via its spike glycoprotein (S), delivering its genome upon S-mediated membrane fusion. SARS-CoV-2 uses two distinct entry pathways: 1) a surface, serine protease-dependent or 2) an endosomal, cysteine protease-dependent pathway. In investigating serine protease-independent cell-cell fusion, we found that the matrix metalloproteinases (MMPs), MMP2/9, can activate SARS-CoV-2 S fusion activity, but not that of SARS-CoV-1. Importantly, metalloproteinase activation of SARS-CoV-2 S represents a third entry pathway in cells expressing high MMP levels. This route of entry required cleavage at the S1/S2 junction in viral producer cells and differential processing of variants of concern S dictated its usage. In addition, metalloproteinase inhibitors reduced replicative Alpha infection and abrogated syncytia formation. Finally, we found that the Omicron S exhibit reduced metalloproteinase-dependent fusion and viral entry. Taken together, we identified a MMP2/9-dependent mode of activation of SARS-CoV-2 S. As MMP2/9 are released during inflammation and severe COVID-19, they may play important roles in SARS-CoV-2 S-mediated cytopathic effects, tropism, and disease outcome.