bluuebunny/crossref_metadata_2025 huggingface dataset:
Revascularization strategies in patients with multivessel coronary artery disease: a Bayesian network meta-analysis
Authors: Van den Eynde Jef , Bomhals Katrien , Noé Dries , Jacquemyn Xander , McCutcheon Keir , Bennett Johan , Puskas John D , Oosterlinck Wouter
Published: December 2021

Treatment modalities for multivessel disease have rapidly evolved, yet the preferred strategy remains controversial. This meta-analysis compared outcomes after on-pump (ONCAB), off-pump coronary artery bypass grafting (OPCAB), percutaneous coronary intervention (PCI) or hybrid coronary revascularization. A comprehensive search for observational studies and randomized controlled trials published by August 2020 was performed. A Bayesian network meta-analysis was conducted for early (<30 days) and late (>12 months) outcomes. A total of 119 studies were included (n = 700 458 patients). The main analysis was confined to 31 randomized controlled trials (n = 24 932 patients). PCI was associated with lower early mortality [odds ratio (OR) 0.50, 95% confidence interval (CI) 0.31–0.79] and stroke (OR 0.22, 95% CI 0.06–0.60) rates compared with ONCAB, whereas a reduced risk of early myocardial infarction was observed with OPCAB compared with ONCAB (OR 0.53, 95% CI 0.32–0.83). Late target vessel revascularization and major adverse cardiac and cerebrovascular events were both increased with PCI compared with ONCAB, OPCAB and hybrid coronary revascularization (by 127–203% and 59–64%, respectively), and late major adverse cardiac events were increased in PCI compared with ONCAB and OPCAB (by 64% and 59%). However, PCI was associated with a significantly lower risk of late stroke compared with ONCAB (OR 0.70, 95% CI 0.52–0.89). Sensitivity analyses (i) including observational studies and (ii) limiting to studies with recent cohorts confirmed the findings of the main analysis. Surgical approaches for revascularization remain superior to PCI in patients with multivessel disease. Hybrid coronary revascularization might be viable for some patients, although more evidence from randomized controlled trials is warranted.
Endovascular treatment of traumatic aortic rupture using iliac extension stent-grafts in patients with small aortic diameters
Authors: Schibilsky David , Kondov Stoyan , Gottardi Roman , Kreibich Maximilian , Lehane Cornelius , Berger Tim , Beyersdorf Friedhelm , Siepe Matthias , Czerny Martin , Rylski Bartosz
Published: December 2021

OBJECTIVES

To evaluate outcomes after thoracic endovascular aortic repair in young patients sustaining traumatic blunt aortic injury (BAI) using iliac extension stent-grafts because of small aortic diameters measuring <24 mm.

METHODS

Retrospective analysis regarding clinical presentation, trauma management, endovascular techniques and outcome of patients with a small descending aorta involving an iliac extension stent-graft to treat traumatic BAI.

RESULTS

Among 48 patients who suffered a BAI and underwent thoracic endovascular aortic repair, 7 received iliac extension stent-grafts. They were 27.4/[standard deviation (SD): −13.1] years old and 6 out of 7 were male. The iliac extension stent-graft was used as distal stent-graft, and a thoracic stent-graft was used in most patients as proximal extension. We achieved overall technical success in all patients during a procedure lasting 92.6 (SD: 54.9) min. One patient died 2 days after the endovascular procedure of hypoxic brain injury, and another died after 17 days of liver failure. That patient had also suffered a spinal cord injury following the procedure, as the stent-graft had been deployed in Ishimaru Zone 2, and the carotid to subclavian bypass had to be omitted because of his critical condition. Control computed tomographic angiographs was available in 6 patients after 7.7 (SD: 5.1) days and showed no endoleak. The surviving patients were discharged after 18.4 (SD: 13.4) days.

CONCLUSIONS

Treating traumatic BAI using iliac extension stent-grafts in young patients with small aortic diameters is feasible. We observed no mortality caused by the BAI or related to endovascular therapy within this small patient cohort.
Performance output tracking for a one-dimensional unstable heat equation with input delay
Authors: Wang Li , Feng Hongyinping
Published: December 2021

In this paper, we investigate the performance output tracking for a one-dimensional unstable heat equation with input delay and disturbance. Both the performance output and the disturbance are non-collocated to the controller. By writing the time delay as a transport equation, the control plant becomes a cascade system in which the transport equation can be regarded as the actuator dynamics of the unstable heat equation. As a result, the method of actuator dynamics compensation can be used. The difficulties caused by the non-collocated configuration are figured out in the method of trajectory planning. The full state feedback is presented to realize the output tracking, and an error based observer is constructed successfully. The exponential stability of the closed-loop system and the well-posedness of the observer are proved.
Cost-Effective Use of the Protein S Algorithm in Thrombophilia Testing
Authors: Rollins-Raval Marian A , Mitsios John V , Marlar Richard A
Published: December 2021

Background

One of the most complex risk factors for the laboratory assessment of thrombophilia is Protein S (PS). The testing algorithm for PS employs the plasma-based assays of free PS antigen, total PS antigen, and PS activity creating a complex diagnostic scheme that can lead to misdiagnosis if incorrectly used, and a potential waste of resources and money.

Content

This paper compares the recently published evidence-based algorithm from the International Society for Hemostasis and Thrombosis (ISTH) with several commonly performed nonevidence-based testing schemes, to demonstrate the efficiency of the evidence-based algorithm for diagnostic efficiency with improved patient care and increased cost savings for the laboratory.

Significant savings (31%–60%) can be realized when the evidence-based algorithm is used in place of other testing modalities of initial PS activity testing (31%) or testing with all 3 assays simultaneously (60%). This study utilizing the PS testing evidence-based algorithm as part of a thrombophilia evaluation demonstrates that the appropriate testing methods can be used to limit wasteful practices while achieving the maximum level of information in this time of limited resources and need for increase monetary savings.
Urinary Pharmacokinetics of Immediate and Controlled Release Oxycodone and its Phase I and II Metabolites Using LC–MS-MS
Authors: Truver Michael T , Jakobsson Gerd , Chermà Maria D , Swortwood Madeleine J , Gréen Henrik , Kronstrand Robert
Published: December 2021

Oxycodone (OC) is a schedule II semisynthetic opioid in the USA that is prescribed for its analgesic effects and has a high potential for abuse. Prescriptions for OC vary based on the dosage and formulation, immediate release (IR) and controlled release (CR). Monitoring OC metabolites is beneficial for forensic casework. The limited studies that involve pharmacokinetics of the urinary excretion of OC metabolites leave a knowledge gap regarding the excretion of conjugated and minor metabolites, pharmacokinetic differences by formulation, and the impact of CYP2D6 activity on the metabolism and excretion of OC. The objectives of this study were to compare urinary excretion of phase I and II metabolites by formulation and investigate if ratio changes over time could be used to predict the time of intake. Subjects (n = 7) received a single 10 mg IR tablet of Oxycodone Actavis. A few weeks later the same subjects received a single 10 mg CR tablet of Oxycodone Actavis. During each setting, urine was collected at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 9, 10, 12, 14, 24, 48 and 72 h. Urine samples (100 µL) were diluted with 900 µL internal standard mixture and analyzed on an Acquity UPLC® I-class coupled to a Waters Xevo TQD using a previously validated method. The CYP2D6 phenotypes were categorized as poor metabolizers (PM), intermediate metabolizers (IM), extensive metabolizers (EM) and ultrarapid metabolizers (UM). Comparisons between IR and CR were performed using two-tailed paired t-test at a significance level of P = 0.05. The metabolite ratios showed a general increase over time. Four metabolite to parent ratios were used to predict the time of intake showing that predictions were best at the early time points.
Physical, Psychological, and Social Outcomes in Pediatric Burn Survivors Ages 5 to 18 Years: A Systematic Review
Authors: Patel Khushbu F , Rodríguez-Mercedes Silvanys L , Grant Gabrielle G , Rencken Camerin A , Kinney Erin M , Austen Amelia , Hou Carina , Brady Keri J S , Schneider Jeffrey C , Kazis Lewis E , Ryan Colleen M
Published: December 2021

Acute pediatric burn injuries often result in chronic sequelae that affect physical, psychological, and social outcomes. To date, no review has comprehensively reported on the impact of burn injuries across all three domains in school-aged children. The aim of this systematic review was to identify published literature that focuses on the impact of burn injuries on physical, psychological, or social functioning, and report upon the nature of study characteristics and their outcomes. We included literature published after 1980, focusing on burn outcomes in children aged 5 to 18 years. Each eligible study was systematically reviewed and primary outcomes were classified into outcome domains based on existing frameworks. Fifty-eight studies met inclusion criteria, and reported on physical (n = 24), psychological (n = 47), and social (n = 29) domains. The majority of the studies had sample sizes of <100 participants, burn size of <40%, and findings reported by parents and/or burn survivors. Only eight of 107 different measures were used in three or more studies. Parents and burn survivors generally reported better physical and social outcomes and worse psychological functioning compared to non-burn populations. Physical disabilities were associated with psychological and social functioning in several studies. Follow-up data reported improvements across domains. This review demonstrates the importance of physical, psychological, and social status as long-term outcomes in burn survivors. Mixed findings across three outcome domains warrant long-term research. Findings of this review will guide the foundation of comprehensive burn and age-specific instruments to assess burn recovery.
Validation and effects of drying and prey hair on fecal hormone concentrations in spotted hyenas
Authors: Greenberg Julia R , Montgomery Tracy M , Holekamp Kay E , Beehner Jacinta C
Published: December 2021

As fecal steroid methods increasingly are used by researchers to monitor the physiology of captive and wild populations, we need to expand our validation protocols to test the effects of procedural variation and to identify contamination by exogenous sources of steroid hormones. Mammalian carnivore feces often contain large amounts of hair from the prey they consume, which itself may contain high concentrations of hormones. In this study, we report first a validation of two steroid hormone antibodies, corticosterone and progesterone, to determine fecal concentrations of these hormones in wild spotted hyenas (Crocuta crocuta). Next, we expand on these standard validation protocols to test two additional metrics: (i) whether hair from consumed prey or (ii) the specific drying method (oven incubation vs. lyophilization) affect steroid hormone concentrations in feces. In the first biological validation for the progesterone antibody in this species, progesterone concentrations met our expectations: (i) concentrations of plasma and fecal progesterone were lowest in immature females, higher in lactating females, and highest in pregnant females; (ii) across pregnant females, fecal progesterone concentrations were highest during late pregnancy; and (iii) among lactating females, fecal progesterone concentrations were highest after parturition. Our additional validation experiments indicated that contamination with prey hair and drying method are hormone-specific. Although prey hair did not release hormones into samples during storage or extraction for either hormone, its presence appeared to “dilute” progesterone (but not corticosterone) measures indirectly by increasing the dry weight of samples. In addition, fecal progesterone, but not corticosterone, values were lower for lyophilized than for incubated samples. Therefore, in addition to the standard analytical and biological validation steps, additional methodological variables need to be tested whenever we measure fecal hormone concentrations, particularly from predatory mammals.
Papillary thyroid carcinoma from a thyroglossal cyst: case series
Authors: Gómez-Álvarez Luis Rodrigo , Treviño-Lozano Marco Antonio , de la O-Escamilla Manuel Enrique , Vergara-Miranda Héctor , Anda Lilia Andrea Mata-De , Falcón Luis Ángel Ceceñas , Tafoya Ary Rochio
Published: December 2021

Papillary carcinoma originating from a thyroglossal cyst represents an infrequent finding, which occurs in ~1% of cases of thyroglossal cyst and its presentation is usually the same as that of a benign cyst, which represents the most frequent benign congenital lesion of the neck. The diagnosis is usually presented as a finding on the histopathological examination. Two cases of a thyroglossal cyst with later development of malignancy are presented. The first, a 30-year-old female, and the second, a 32-year-old male. Both began their condition after presenting an increase in volume in the neck, the female presented a right sub-mental triangle of 1 year of evolution, and the male on the anterior side of the neck. In both cases, the diagnosis of thyroglossal cyst was made by the physical examination and findings of cervical ultrasound and computed axial tomography. Surgical management consisted of the Sistrunk procedure with a definitive histopathological result for papillary thyroid carcinoma originating from thyroglossal cyst. In the case of the male patient, the Sistrunk procedure was performed along a total thyroidectomy, although in the female patient, a total thyroidectomy was performed in a second stage. Patients were then discharged and referred to the endocrinology service for further medical treatment. The management of these cases continues to be controversial due to the limited number of reported cases, so the multidisciplinary management and individualization of each case plays a fundamental role in the management of this rare condition.
Ribosomal leaky scanning through a translated uORF requires eIF4G2
Authors: Smirnova Victoria V , Shestakova Ekaterina D , Nogina Daria S , Mishchenko Polina A , Prikazchikova Tatiana A , Zatsepin Timofei S , Kulakovskiy Ivan V , Shatsky Ivan N , Terenin Ilya M
Published: December 2021

eIF4G2 (DAP5 or Nat1) is a homologue of the canonical translation initiation factor eIF4G1 in higher eukaryotes but its function remains poorly understood. Unlike eIF4G1, eIF4G2 does not interact with the cap-binding protein eIF4E and is believed to drive translation under stress when eIF4E activity is impaired. Here, we show that eIF4G2 operates under normal conditions as well and promotes scanning downstream of the eIF4G1-mediated 40S recruitment and cap-proximal scanning. Specifically, eIF4G2 facilitates leaky scanning for a subset of mRNAs. Apparently, eIF4G2 replaces eIF4G1 during scanning of 5′ UTR and the necessity for eIF4G2 only arises when eIF4G1 dissociates from the scanning complex. In particular, this event can occur when the leaky scanning complexes interfere with initiating or elongating 80S ribosomes within a translated uORF. This mechanism is therefore crucial for higher eukaryotes which are known to have long 5′ UTRs with highly frequent uORFs. We suggest that uORFs are not the only obstacle on the way of scanning complexes towards the main start codon, because certain eIF4G2 mRNA targets lack uORF(s). Thus, higher eukaryotes possess two distinct scanning complexes: the principal one that binds mRNA and initiates scanning, and the accessory one that rescues scanning when the former fails.
Hepatitis C Virus Is Associated With Increased Mortality Among Incarcerated Hospitalized Persons in Massachusetts
Authors: Wurcel Alysse G , Guardado Rubeen , Beckwith Curt G
Published: December 2021

Hepatitis C virus (HCV) is curable, but incarcerated populations face barriers to treatment. In a cohort of incarcerated hospitalized patients in Boston, Massachusetts, HCV infection was associated with increased mortality. Access to HCV treatment in carceral settings is crucial to avoid unnecessary death and to support HCV elimination efforts.
Effectiveness of Dalbavancin Compared With Standard of Care for the Treatment of Osteomyelitis: A Real-world Analysis
Authors: Cain Alexander R , Bremmer Derek N , Carr Dustin R , Buchanan Carley , Jacobs Max , Walsh Thomas L , Moffa Matthew A , Shively Nathan R , Trienski Tamara L
Published: December 2021

Background

Preliminary data suggest that the effectiveness of dalbavancin may be similar to current standard-of-care (SoC) treatment options for osteomyelitis with an advantageous dosing schedule.

Methods

This was a retrospective, observational cohort study of adult patients diagnosed with osteomyelitis. Patients were matched 1:2 to dalbavancin (administered as 2 doses separated by 1 week) or SoC treatment for osteomyelitis according to the Charlson Comorbidity Index, site of infection, and causative pathogen. The primary objective was to determine the incidence of treatment failure after a 1-year follow-up period. Secondary objectives included hospital length of stay (LOS), infection-related 1-year readmission rates, and treatment-related adverse events.

Results

A total of 132 patients received dalbavancin (n = 42) or SoC (n = 90). Baseline characteristics, including rates of surgical intervention, were similar between the 2 treatment groups. Treatment failure was similar between those who received dalbavancin and SoC (21.4% vs 23.3%; P = .81). Patients who received dalbavancin had a shorter hospital LOS (5.2 days vs 7.2 days; P = .01). There was no difference in the rates of infection-related readmission between the dalbavancin and the SoC group (31% vs 31.1%; P = .99). There were numerically fewer adverse events in the dalbavancin group compared with the SoC group (21.4% vs 36.7%; P = .08). Peripherally inserted central catheter line–related complications were reported in 17.8% of patients in the SoC group.

Conclusions

Dalbavancin administered as a 2-dose regimen is a safe and effective option for the treatment of osteomyelitis.
Immunogenicity, Safety, and Tolerability of V114, a 15-Valent Pneumococcal Conjugate Vaccine, in Immunocompetent Adults Aged 18–49 Years With or Without Risk Factors for Pneumococcal Disease: A Randomized Phase 3 Trial (PNEU-DAY)
Authors: Hammitt Laura L , Quinn Dean , Janczewska Ewa , Pasquel Francisco J , Tytus Richard , Rajender Reddy K , Abarca Katia , Khaertynova Ilsiyar M , Dagan Ron , McCauley Jennifer , Cheon Kyeongmi , Pedley Alison , Sterling Tina , Tamms Gretchen , Musey Luwy , Buchwald Ulrike K
Published: December 2021

Background

Adults with certain medical and behavioral factors are at increased risk for pneumococcal disease (PD). Sequential vaccination with 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for at-risk adults in some countries.

Methods

This phase 3 trial evaluated the safety, tolerability, and immunogenicity of sequential administration of either V114 (a 15-valent PCV containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 22F, 23F, and 33F) or PCV13, followed 6 months later by PPSV23, in immunocompetent adults aged 18–49 years with or without predefined risk factors for PD (NCT03547167). Overall, 1515 participants were randomized 3:1 to receive either V114 or PCV13, followed by PPSV23.

Results

Most common solicited adverse events (AEs) following administration of V114 or PCV13 as well as PPSV23 were injection-site pain and fatigue. The proportion of participants with AEs was comparable in both groups. V114 and PCV13 were immunogenic based on opsonophagocytic activity (OPA) geometric mean titers (GMTs) 30 days postvaccination for all serotypes contained in each respective vaccine. OPA GMTs to the 2 unique serotypes in V114 were robust in the V114 group. PPSV23 was immunogenic for all 15 serotypes contained in V114 in both vaccination groups, including 22F and 33F.

Conclusions

V114 administered alone or sequentially with PPSV23 is well tolerated and immunogenic for all 15 serotypes, including those not contained in PCV13, in immunocompetent adults aged 18–49 years with or without certain medical or behavioral risk factors for PD.

Clinical Trials Registration

NCT03547167 and EudraCT 2017-004915-38.
Clinical Significance of Staphylococcus aureus in a Single Positive Blood Culture Bottle
Authors: Go John Raymond , Challener Douglas , Corsini Campioli Cristina , Sohail M Rizwan , Palraj Raj , Baddour Larry M , Abu Saleh Omar
Published: December 2021

Clinical significance of a single positive blood culture bottle (SPBCB) with Staphylococcus aureus is unclear. We aimed to assess the significance of an SPBCB by looking at the associated outcomes. We performed a retrospective, multicenter study of patients with an SPBCB with S aureus using data collected from both electronic health records and the clinical microbiology laboratory. Overall, 534 patients with S aureus bacteremia were identified and 118 (22.1%) had an SPBCB. Among cases with an SPBCB, 106 (89.8%) were classified as clinically significant whereas 12 (10.2%) were considered contaminated or of unclear significance. A majority (92.4%) of patients received antibiotic therapy, but patients with clinically significant bacteremia were treated with longer courses (25.9 vs 5.7 days, P < .001). Significant differences in both frequency of echocardiography (65.1% vs 84.6%, P < .001) and infective endocarditis diagnosis (3.8% vs 14.2%, P = .002) were seen in those with an SPBCB compared to those with multiple positive bottles. A longer hospital length of stay and higher 90-day, 6-month, and 1-year mortality rates were seen in patients with multiple positive blood culture bottles. An SPBCB with S aureus was common among our patients. While this syndrome has a more favorable prognosis as compared to those with multiple positive blood cultures, clinicians should remain concerned as it portends a risk of infective endocarditis and mortality.
Coercive Law
Authors: Adams Thomas
Published: December 2021

In this review article I consider Kenneth Einar Himma’s argument that law is necessarily coercive. While casting doubt on Himma’s framing of the issues as well as on his specific claims in support of that conclusion, I suggest some alternate avenues for arguing that law is a coercive institution.
Competitive exposure and existential recognition: Visibility and legitimacy on academic social networking sites
Authors: Francke Helena , Hammarfelt Björn
Published: December 2021

Over the past decade, academic social networking sites, such as ResearchGate and Academia.edu, have become a common tool in academia for accessing publications and displaying metrics for research evaluation and self-monitoring. In this conceptual article, we discuss how these academic social networking sites, as devices of evaluation that build on both traditional values, objects, and metrics in academic publishing and on social media logics and algorithmic metrics, come to fulfil a need in the current academic (publishing) ecosystem. We approach this issue by identifying key affordances that arise in the interaction between platform and user. We then position these affordances in relation to potential needs of academics in today’s publishing landscape by drawing on Hafermalz’s metaphor of the ‘fear of exile’, which provides an alternative way of understanding the importance of visibility in the networked world, as a combination of competitive exposure and existential recognition. We end by considering the grounds on which the platforms may be attributed some level of legitimacy. This is done in order to understand the inherent contradiction between the broad use of the platforms and the fact that their integrity has been questioned repeatedly. We seek an answer to a legitimacy for the platforms in the fact that a pragmatic, mutual benefit exists between them and the research community; a benefit that is enhanced by the audit society influencing current academia.
Between-person and within-person associations of sleep and working-memory in the everyday lives of old and very old adults: initial level, learning, and variability
Authors: Lücke Anna J , Wrzus Cornelia , Gerstorf Denis , Kunzmann Ute , Katzorreck Martin , Schmiedek Florian , Hoppmann Christiane , Schilling Oliver K
Published: December 2021

Study Objectives

Sleep duration affects various aspects of cognitive performance, such as working-memory and learning, among children and adults. However, it remains open, whether similar or even stronger associations exist in old and very old age when changes in sleep and cognitive decrements are common.

Methods

Using repeated daily-life assessments from a sample of 121 young-old (66–69 years old) and 39 old-old adults (84–90 years old), we assessed links between sleep duration and different aspects of working-memory (initial level, practice-related learning, and residualized variability) between and within persons. Participants reported their sleep durations every morning and performed a numerical working-memory updating task six times a day for seven consecutive days.

Results

Both people who slept longer and those who slept shorter than the sample average showed lower initial performance levels, but a stronger increase of WM over time (i.e. larger learning effects), relative to people with average sleep. Sleep duration did not predict performance variability. Within-person associations were found for people sleeping relatively little on average: For them, working-memory performance was lower on days with shorter than average sleep, yet higher on days with longer than average sleep. Except for lower initial levels of working-memory in old-old adults, no differences between young-old and old-old adults were observed.

Conclusion

We conclude that sufficient sleep remains important for working-memory performance in older adults and that it is relevant to include different aspects of working-memory performance, because effects differed for initial performance and learning.
Clozapine Induces an Acute Proinflammatory Response That Is Attenuated by Inhibition of Inflammasome Signaling: Implications for Idiosyncratic Drug-Induced Agranulocytosis
Authors: Sernoskie Samantha Christine , Lobach Alexandra R , Kato Ryuji , Jee Alison , Weston Joseph Kyle , Uetrecht Jack
Published: December 2021

Although clozapine is a highly efficacious schizophrenia treatment, it is under-prescribed due to the risk of idiosyncratic drug-induced agranulocytosis (IDIAG). Clinical data indicate that most patients starting clozapine experience a transient immune response early in treatment and a similar response has been observed in clozapine-treated rats, but the mechanism by which clozapine triggers this transient inflammation remains unclear. Therefore, the aim of this study was to characterize the role of inflammasome activation during the early immune response to clozapine using in vitro and in vivo models. In both differentiated and nondifferentiated human monocytic THP-1 cells, clozapine, but not its structural analogues fluperlapine and olanzapine, caused inflammasome-dependent caspase-1 activation and IL-1β release that was inhibited using the caspase-1 inhibitor yVAD-cmk. In Sprague Dawley rats, a single dose of clozapine caused an increase in circulating neutrophils and a decrease in lymphocytes within hours of drug administration along with transient spikes in the proinflammatory mediators IL-1β, CXCL1, and TNF-α in the blood, spleen, and bone marrow. Blockade of inflammasome signaling using the caspase-1 inhibitor VX-765 or the IL-1 receptor antagonist anakinra attenuated this inflammatory response. These data indicate that caspase-1-dependent IL-1β production is fundamental for the induction of the early immune response to clozapine and, furthermore, support the general hypothesis that inflammasome activation is a common mechanism by which drugs associated with the risk of idiosyncratic reactions trigger early immune system activation. Ultimately, inhibition of inflammasome signaling may reduce the risk of IDIAG, enabling safer, more frequent use of clozapine in patients.
Age-related epithelial defects limit thymic function and regeneration
Authors: Kousa Anastasia I. , Jahn Lorenz , Zhao Kelin , Flores Angel E. , Granadier David , Cooper Kirsten , Sheridan Julie M. , Lemarquis Andri , Sikkema Lisa , Argyropoulos Kimon V. , Tsai Jennifer , Lazrak Amina , Nichols Katherine , Lee Nichole , Ghale Romina , Malard Florent , Andrlova Hana , Gomes Antonio L.C. , Velardi Enrico , Youssef Salma , da Silva Marina B. , Docampo Melissa , Sharma Roshan , Mazutis Linas , Wimmer Verena C. , Rogers Kelly L. , DeWolf Susan , Gipson Brianna , Setty Manu , Pe’er Dana , Manley Nancy R. , Gray Daniel H.D. , Dudakov Jarrod A. , van den Brink Marcel R.M.
Published: December 2021

The thymus is essential for establishing adaptive immunity yet undergoes age-related atrophy leading to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age. Focusing on non-hematopoietic stromal cells, and using single-cell and spatial transcriptomics, lineage-tracing, and advanced imaging, we discovered two atypical thymic epithelial cell (TEC) states that emerged with age. Age-associated (aa)TECs formed atypical high-density epithelial clusters that were devoid of thymocytes, an accretion of non-functional thymic tissue that worsened with age and exhibited features of partial epithelial-to-mesenchymal transition (EMT).In silicointeraction analysis revealed that aaTEC emergence drew tonic signals from other TEC populations at baseline, acting as a sink for TEC growth factors. Following damage, aaTEC expanded substantially, further perturbing trophic pathways, and correlating with defective regeneration of the involuted thymus. These findings define a unique feature of thymic involution linked to immune aging.
Sex-specific Effects of SGLT2 Inhibition in a Kidney with Reduced Nephron Number: Modeling and Analysis
Authors: Layton Anita T.
Published: December 2021

The kidney plays an essential role in regulating the homeostasis of electrolytes, acid-base species, and fluids. Kidney structure and function are significantly affected in diabetes. These pathophysiological changes include glomerular hyperfiltration and tubular hypertrophy, and ultimately leading to diabetic kidney disease. A class of medications that have shown promise in slowing the progression to diabetic kidney disease are the sodium-glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 inhibitors target Na+ and glucose reabsorption along the proximal convoluted tubule, enhance urinary glucose, Na+ and fluid excretion, and lower hyperglycemia in diabetes. We postulate that both diabetes-induced and SGLT2 inhibition-induced changes in kidney may exhibit significant sex differences, because the distribution of renal transporters along the nephron may be markedly different between women and men, as recently shown in rodents. The goals of this study are to (i) analyze how kidney function is altered in male and female patients with diabetes, (ii) assess the renal effects, in women and men, of an anti-hyperglycemic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules, and (iii) study how those renal effects are altered in uninephrectomy. To accomplish these goals, we have developed computational models of kidney function, separate for male and female patients with diabetes and/or uninephredctomy. The simulation results indicate that by inducing osmotic diuresis in the proximal tubules, SGLT2 inhibition reduces paracellular transport, eventually leading to diuresis and natriuresis.
Chronic Seizures Induce Sex-Specific Cognitive Deficits with Loss of Presenilin 2 Function
Authors: Knox Kevin M. , Beckman Megan , Smith Carole L. , Jayadev Suman , Barker-Haliski Melissa
Published: December 2021

Patients with early-onset Alzheimer’s disease (EOAD) are at elevated risk for seizures, including patients with presenilin 2 (PSEN2) variants. Like people with epilepsy, uncontrolled seizures may worsen cognitive function in AD. While the relationship between seizures and amyloid beta accumulation has been more thoroughly investigated, the role of other drivers of seizure susceptibility in EOAD remain relatively understudied. We therefore sought to define the impact of loss of normal PSEN2 function and chronic seizures on cognitive function in the aged brain. Male and female PSEN2 KO and age- and sex-matched wild-type (WT) mice were sham or corneal kindled beginning at 6-months-old. Kindled and sham-kindled mice were then challenged up to 6 weeks later in a battery of cognitive tests: non-habituated open field (OF), T-maze spontaneous alternation (TM), and Barnes maze (BM), followed by immunohistochemistry for markers of neuroinflammation and neuroplasticity. PSEN2 KO mice required significantly more stimulations to kindle (males: p<0.02; females: p<0.02) versus WT. Across a range of behavioral tests, the cognitive performance of kindled female PSEN2 KO mice was most significantly impaired versus age-matched WT females. Male BM performance was generally worsened by seizures (p=0.038), but loss of PSEN2 function did not itself worsen cognitive performance. Conversely, kindled PSEN2 KO females made the most BM errors (p=0.007). Chronic seizures also significantly altered expression of hippocampal neuroinflammation and neuroplasticity markers in a sex-specific manner. Chronic seizures may thus significantly worsen hippocampus-dependent cognitive deficits in aged female, but not male, PSEN2 KO mice. Our work suggests that untreated focal seizures may worsen cognitive burden with loss of normal PSEN2 function in a sex-related manner.
Nanoscale patterning of in vitro neuronal circuits
Authors: Mateus José C. , Weaver Sean , van Swaay Dirk , Renz Aline F. , Hengsteler Julian , Aguiar Paulo , Vörös János
Published: December 2021

Methods for patterning neurons in vitro have gradually improved and are used to investigate questions difficult to address in or ex vivo. Though these techniques guide axons between groups of neurons, multiscale control of neuronal connectivity, from circuits to synapses, is yet to be achieved in vitro. As studying neuronal circuits with synaptic resolution in vivo poses significant challenges, an in vitro alternative could serve as a testbed for in vivo experiments or as a platform for validating biophysical and computational models. In this work we use a combination of electron beam and photolithography to create polydimethylsiloxane (PDMS) structures with features ranging from 150 nanometers to a few millimeters. Leveraging the difference between average axon and dendritic spine diameters, we restrict axon growth while allowing spines to pass through nanochannels to guide synapse formation between small groups of neurons (i.e. nodes). We show this technique can be used to generate large numbers of isolated feed-forward circuits where connections between nodes are restricted to regions connected by nanochannels. Using a genetically encoded calcium indicator in combination with fluorescently tagged post synaptic protein, PSD-95, we demonstrate functional synapses can form in this region. Although more work needs to be done to control connectivity in vitro, we believe this is a significant step in that direction.
Amyloidogenesis of SARS-CoV-2 Spike Protein
Authors: Nyström Sofie , Hammarström Per
Published: December 2021

SARS-CoV-2 infection is associated with a surprising number of morbidities. Uncanny similarities with amyloid-disease associated blood coagulation and fibrinolytic disturbances together with neurologic and cardiac problems led us to investigate the amyloidogenicity of the SARS-CoV-2 Spike protein (S-protein). Amyloid fibril assays of peptide library mixtures and theoretical predictions identified seven amyloidogenic sequences within the S-protein. All seven peptides in isolation formed aggregates during incubation at 37°C. Three 20-amino acid long synthetic Spike peptides (sequence 191-210, 599-618, 1165-1184) fulfilled three amyloid fibril criteria: nucleation dependent polymerization kinetics by ThT, Congo red positivity and ultrastructural fibrillar morphology. Full-length folded S-protein did not form amyloid fibrils, but amyloid-like fibrils with evident branching were formed during 24 hours of S-protein co-incubation with the protease neutrophil elastase (NE) in vitro. NE efficiently cleaved S-protein rendering exposure of amyloidogenic segments and accumulation of the peptide 193-202, part of the most amyloidogenic synthetic Spike peptide. NE is overexpressed at inflamed sites of viral infection and at vaccine injection sites. Our data propose a molecular mechanism for amyloidogenesis of SARS-CoV-2 S-protein in humans facilitated by endoproteolysis. The potential implications of S-protein amyloidogenesis in COVID-19 disease associated pathogenesis and consequences following S-protein based vaccines should be addressed in understanding the disease, long COVID-19, and vaccine side effects.
Assembly of recombinant tau into filaments identical to those of Alzheimer’s disease and chronic traumatic encephalopathy
Authors: Lövestam Sofia , Koh Fujiet Adrian , van Knippenberg Bart , Kotecha Abhay , Murzin Alexey G. , Goedert Michel , Scheres Sjors H.W.
Published: December 2021

Abundant filamentous inclusions of tau are characteristic of more than 20 neurodegenerative diseases that are collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of tau amyloid filaments from human brain revealed that distinct tau folds characterise many different diseases. A lack of laboratory-based model systems to generate these structures has hampered efforts to uncover the molecular mechanisms that underlie tauopathies. Here, we report in vitro assembly conditions with recombinant tau that replicate the structures of filaments from both Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE), as determined by cryo-EM. Our results suggest that post-translational modifications of tau modulate filament assembly, and that previously observed additional densities in AD and CTE filaments may arise from the presence of inorganic salts, like phosphates and sodium chloride. In vitro assembly of tau into disease-relevant filaments will facilitate studies to determine their roles in different diseases, as well as the development of compounds that specifically bind to these structures or prevent their formation.
A high-throughput neutralization assay for yellow fever serodiagnostics
Authors: Rasulova Madina , Vercruysse Thomas , Paulissen Jasmine , Coun Catherina , Suin Vanessa , Heyndrickx Leo , Ma Ji , Geerts Katrien , Timmermans Jolien , Mishra Niraj , Li Li-Hsin , Kum Dieudonné Buh , Coelmont Lotte , Van Gucht Steven , Karimzadeh Hadi , Thorn-Seshold Julia , Rothenfußer Simon , Ariën Kevin K. , Neyts Johan , Dallmeier Kai , Thibaut Hendrik Jan
Published: December 2021

Quick and accurate detection of neutralizing antibodies (nAbs) against yellow fever is essential in serodiagnosis during outbreaks, for surveillance and to evaluate vaccine efficacy in population-wide studies. All this requires serological assays that can process a large number of samples in a highly standardized format. Albeit being laborious, time-consuming and limited in throughput, classical plaque reduction neutralization test (PRNT) is still considered gold standard for the detection and quantification of nAbs due to its sensitivity and specificity. Here we report the development of an alternative fluorescence-based serological assay (SNTFLUO) with an equally high sensitivity and specificity that is fit for high-throughput testing with the potential for automation. Finally, our novel SNTFLUO was cross-validated in several reference laboratories and against international WHO standards showing its potential to be implemented in clinical use. SNTFLUO assays with similar performance are available for the Japanese encephalitis, Zika and dengue viruses amenable for differential diagnostics.

IMPORTANCE

Fast and accurate detection of neutralizing antibodies (nAbs) against yellow fever virus (YFV) is key in yellow fever serodiagnosis, outbreak surveillance and monitoring of vaccine efficacy. Although classical PRNT still remains gold standard for measuring YFV nAbs, this methodology suffers from inherent limitations such as a low throughput and an overall high labor intensity. We present a novel fluorescence-based serum neutralization test (SNTFLUO) with equally high sensitivity and specificity that is fit for processing large number of samples in a highly standardized manner and has the potential to be implemented in clinical use. In addition, we present SNTFLUO assays with similar performance for Japanese encephalitis, Zika and dengue viruses opening new avenues for differential diagnostics.
Classification and Regression Models for Genomic Selection of Skewed Phenotypes: A Case for Disease Resistance in Winter Wheat (Triticum aestivumL.)
Authors: Merrick Lance F. , Lozada Dennis N. , Chen Xianming , Carter Arron H.
Published: December 2021

Most genomic prediction models are linear regression models that assume continuous and normally distributed phenotypes, but responses to diseases such as stripe rust (caused byPuccinia striiformisf. sp. tritici) are commonly recorded in ordinal scales and percentages. Disease severity (SEV) and infection type (IT) data in germplasm screening nurseries generally do not follow these assumptions. On this regard, researchers may ignore the lack of normality, transform the phenotypes, use generalized linear models, or use supervised learning algorithms and classification models with no restriction on the distribution of response variables, which are less sensitive when modeling ordinal scores. The goal of this research was to compare classification and regression genomic selection models for skewed phenotypes using stripe rust SEV and IT in winter wheat. We extensively compared both regression and classification prediction models using two training populations composed of breeding lines phenotyped in four years (2016-2018, and 2020) and a diversity panel phenotyped in four years (2013-2016). The prediction models used 19,861 genotyping-by-sequencing single-nucleotide polymorphism markers. Overall, square root transformed phenotypes using rrBLUP and support vector machine regression models displayed the highest combination of accuracy and relative efficiency across the regression and classification models. Further, a classification system based on support vector machine and ordinal Bayesian models with a 2-Class scale for SEV reached the highest class accuracy of 0.99. This study showed that breeders can use linear and non-parametric regression models within their own breeding lines over combined years to accurately predict skewed phenotypes.
Concerted modification of nucleotides at functional centers of the ribosome revealed by single-molecule RNA modification profiling
Authors: Bailey Andrew D. , Talkish Jason , Ding Hongxu , Igel Haller , Durán Alejandra , Mantripragada Shreya , Paten Benedict , Ares Manuel
Published: December 2021

Nucleotides in RNA and DNA are chemically modified by numerous enzymes that alter their function. Eukaryotic ribosomal RNA (rRNA) is modified at more than 100 locations, particularly at highly conserved and functionally important nucleotides. During ribosome biogenesis, modifications are added at various stages of assembly. The existence of differently modified classes of ribosomes in normal cells is unknown because no method exists to simultaneously evaluate the modification status at all sites within a single rRNA molecule. Using a combination of yeast genetics and nanopore direct RNA sequencing, we developed a reliable method to track the modification status of single rRNA molecules at 37 sites in 18S rRNA and 73 sites in 25S rRNA. We use our method to characterize patterns of modification heterogeneity and identify concerted modification of nucleotides found near functional centers of the ribosome. Distinct, undermodified subpopulations of rRNAs accumulate upon loss of Dbp3 or Prp43 RNA helicases, suggesting overlapping roles in ribosome biogenesis. Modification profiles are surprisingly resistant to change in response to many genetic and acute environmental conditions that affect translation, ribosome biogenesis, and pre-mRNA splicing. The ability to capture single molecule RNA modification profiles provides new insights into the roles of nucleotide modifications in RNA function.

Highlights

method enabling single-molecule profiling of RNA modifications is developed and reveals heterogeneous classes of modified ribosomes.

rRNA 2’O methylation and pseudouridylation modifications are independent of each other.

in functional centers of the ribosome are modified in a concerted fashion.

of function for RNA helicases Dbp3 and Prp43 produce discrete overlapping subpopulations of incompletely modified ribosomes.

modification profiles are resilient to rapidly changing nutrient conditions and perturbation of translation
Tryptophol acetate and tyrosol acetate, small molecule metabolites identified in a probiotic mixture, inhibit hyperinflammation
Authors: Malka Orit , Malishev Ravit , Bersudsky Marina , Rajendran Manikandan , Krishnamohan Mathumathi , Shaik Jakeer , Chamovitz Daniel A. , Tikhonov Evgeni , Sultan Eliya , Koren Omry , Apte Ron N. , Rosental Benyamin , Voronov Elena , Jelinek Raz
Published: December 2021

Probiotic fermented foods are perceived as contributing to human health, however solid evidence for their presumptive therapeutic systemic benefits is generally lacking. Here we report that tryptophol acetate and tyrosol acetate, small molecule metabolites secreted by the probiotic milk-fermented yeastKluyveromyces marxianusinhibit hyperinflammation (e.g., “cytokine storm”). Comprehensivein vivoandin vitroanalyses, employing LPS-induced hyperinflammation models, reveal dramatic effects of the molecules, added in tandem, on mice morbidity, laboratory parameters, and mortality. Specifically, we observed attenuated levels of the pro-inflammatory cytokines IL-6, IL-1α, IL-1β and TNF-α, and reduced reactive oxygen species. Importantly, tryptophol acetate and tyrosol acetate did not completely suppress pro-inflammatory cytokine generation, rather brought their concentrations back to baseline levels thus maintaining core immune functions, including phagocytosis. The anti-inflammatory effects of tryptophol acetate and tyrosol acetate were mediated through downregulation of TLR4, IL-1R, and TNFR signaling pathways and increased A20 expression, leading to NF-kB inhibition. Overall, this work illuminates phenomenological and molecular details underscoring anti-inflammatory properties of small molecules identified in a probiotic mixture, pointing to potential therapeutic avenues against severe inflammation.