bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial and Glycocalyx Biomarkers in Children With Sepsis After One Bolus of Unbalanced or Balanced Crystalloids*
Authors: Fernández-Sarmiento Jaime , Salazar-Peláez Lina María , Acevedo Lorena , Niño-Serna Laura Fernanda , Flórez Steffanie , Alarcón-Forero Laura , Mulett Hernando , Gómez Laura , Villar Juan Carlos
Published: January 2023

OBJECTIVES:

To assess the disruption of endothelial glycocalyx integrity in children with sepsis receiving fluid resuscitation with either balanced or unbalanced crystalloids. The primary outcome was endothelial glycocalyx disruption (using perfused boundary region >2 µm on sublingual video microscopy and syndecan-1 greater than 80 mg/dL) according to the type of crystalloid. The secondary outcomes were increased vascular permeability (using angiopoietin-2 level), apoptosis (using annexin A5 level), and associated clinical changes.

DESIGN:

A single-center prospective cohort study from January to December 2021.

SETTING:

Twelve medical-surgical PICU beds at a university hospital.

PATIENTS:

Children with sepsis/septic shock before and after receiving fluid resuscitation with crystalloids for hemodynamic instability.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

We included 106 patients (3.9 yr [interquartile range, 0.60–13.10 yr]); 58 of 106 (55%) received boluses of unbalanced crystalloid. This group had greater odds of endothelial glycocalyx degradation (84.5% vs 60.4%; adjusted odds ratio, 3.78; 95% CI, 1.49–9.58; p < 0.01) 6 hours after fluid administration, which correlated with increased angiopoietin-2 (rho = 0.4; p < 0.05) and elevated annexin A5 (p = 0.04). This group also had greater odds of metabolic acidosis associated with elevated syndecan-1 (odds ratio [OR], 4.88; 95% CI, 1.23–28.08) and acute kidney injury (OR, 1.7; 95% CI, 1.12–3.18) associated with endothelial glycocalyx damage. The perfused boundary region returned to baseline 24 hours after receiving the crystalloid boluses.

CONCLUSIONS:

Children with sepsis, particularly those who receive unbalanced crystalloid solutions during resuscitation, show loss and worsening of endothelial glycocalyx. The abnormality peaks at around 6 hours after fluid administration and is associated with greater odds of metabolic acidosis and acute kidney injury.
Residual limb support devices on wheelchairs for people with transtibial amputations: A scoping review and survey of rehabilitation professionals in Nova Scotia
Authors: Parker Kim , MacDonald Siobhan , Henley Shalyn , Rutledge Kallen , McLean Katie , Taylor Kristy , Lee Kirby Ronald
Published: January 2023

Purpose:

To determine what research evidence exists for the use of residual limb supports (RLSs) for people with transtibial amputations and to describe clinicians' use of such supports in Nova Scotia.

Methods:

Scoping review of published and gray literature using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews as a guide and an anonymous online and paper-based clinician survey.

Results:

We identified 22 publications meeting criteria for review. Seventeen (77%) of the publications were practice guidelines or systematic reviews about care of people with lower-limb amputations, 4 (18%) involved research about the design of stump supports, and 1 (5%) researched the use of supports. Generally, the use of RLSs was recommended (e.g., to prevent contractures, control edema, and to provide comfort), but many authors acknowledged that the evidence was weak, and additional evidence in support of these treatment goals could not be found. We received 44 survey responses from health care professionals involved with the care of people with transtibial amputations in Nova Scotia. Of the 43 health care professionals who responded to the question “…what percent of patients/clients with transtibial amputations do you estimate receive stump supports…,” the mean (standard deviation) was 86.1% (21.1). The most common reasons for recommending a stump support were to prevent knee contracture (38 [86.4%]), and to prevent swelling (13 [29.5%]).

Conclusions:

Most clinicians who provide services to people with amputations in Nova Scotia believe that RLSs have benefits such as the prevention of contractures, the reduction of edema, and improved patient comfort. However, there is little high-quality research evidence to support their use. There is a need to perform the necessary research or to modify practice guidelines.
OBESE MICE WITH PNEUMONIA HAVE HYPERLEPTINEMIA AND INCREASED PULMONARY SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 ACTIVATION
Authors: Bodilly Lauren , Williamson Lauren , Howell Kendra , Alder Matthew N. , Kaplan Jennifer M.
Published: January 2023

Obesity is an ongoing epidemic that influences pathobiology in numerous disease states. Obesity is associated with increased plasma leptin levels, a hormone that activates the signal transducer and activator of transcription 3 (STAT3) pathway. Pneumonia is a significant cause of morbidity and mortality. During pneumonia, inflammatory pathways including STAT3 are activated. Outcomes in obese patients with pneumonia are mixed, with some studies showing obesity increases harm and others showing benefit. It is unclear whether obesity alters STAT3 activation during bacterial pneumonia and how this might impact outcomes from pneumonia. We used a murine model of obesity and pneumonia challenge with Pseudomonas aeruginosa in obese and nonobese mice to investigate the effect of obesity on STAT3 activation. We found obese mice with bacterial pneumonia had increased mortality compared with nonobese mice. Inflammatory markers, IL-6 and TNF-α, and lung neutrophil infiltration were elevated at 6 h after pneumonia in both nonobese and obese mice. Obese mice had greater lung injury compared with nonobese mice at 6 h after pneumonia. Leptin and insulin levels were higher in obese mice compared with nonobese mice, and obese mice with pneumonia had higher pulmonary STAT3 activation compared with nonobese mice.
ROLE OF PEPTIDYLARGININE DEIMINASE AND NEUTROPHIL EXTRACELLULAR TRAPS IN INJURIES: FUTURE NOVEL DIAGNOSTICS AND THERAPEUTIC TARGETS
Authors: Ho Jessie W. , Quan Chao , Gauger Megan A. , Alam Hasan B. , Li Yongqing
Published: January 2023

Injuries lead to an early systemic inflammatory state with innate immune system activation. Neutrophil extracellular traps (NETs) are a complex of chromatin and proteins released from the activated neutrophils. Although initially described as a response to bacterial infections, NETs have also been identified in the sterile postinjury inflammatory state. Peptidylarginine deiminases (PADs) are a group of isoenzymes that catalyze the conversion of arginine to citrulline, termed citrullination or deimination. PAD2 and PAD4 have been demonstrated to play a role in NET formation through citrullinated histone 3. PAD2 and PAD4 have a variety of substrates with variable organ distribution. Preclinical and clinical studies have evaluated the role of PADs and NETs in major trauma, hemorrhage, burns, and traumatic brain injury. Neutrophil extracellular trap formation and PAD activation have been shown to contribute to the postinjury inflammatory state leading to a detrimental effect on organ systems. This review describes our current understanding of the role of PAD and NET formation following injury and burn. This is a new field of study, and the emerging data appear promising for the future development of targeted biomarkers and therapies in trauma.
ACETAMINOPHEN ATTENUATES PULMONARY VASCULAR RESISTANCE AND PULMONARY ARTERIAL PRESSURE AND INHIBITS CARDIOVASCULAR COLLAPSE IN A PORCINE MODEL OF ENDOTOXEMIA
Authors: Bergström Anna , Lipcsey Miklós , Larsson Anders , Yang Bei , Engblom David , Chew Michelle S. , Elander Louise
Published: January 2023

Acetaminophen (paracetamol) is often used in critically ill patients with fever and pain; however, little is known about the effects of acetaminophen on cardiovascular function during systemic inflammation. Here, we investigated the effect of acetaminophen on changes in the systemic and pulmonary circulation induced by endotoxin (0.5 μg/kg per hour) in anesthetized pigs. Endotoxin infusion led to a rapid increase in pulmonary artery pressure and pulmonary vascular resistance index. Acetaminophen delayed and attenuated this increase. Furthermore, acetaminophen reduced tachycardia and decreased stroke volume, accompanied by systemic inflammation, without affecting inflammatory parameters such as white blood cell count and TNF-α in blood. As a proof of concept, we injected a high dose of endotoxin (100 μg), which induced rapid cardiovascular collapse in pigs. Pigs treated with acetaminophen survived with no obvious hemodynamic instability during the 50-min observation period. In conclusion, acetaminophen attenuates the effects of endotoxin on pulmonary circulation in anesthetized pigs. This may play a role in severe systemic inflammation.
A PREVENTIVE TOOL FOR PREDICTING BLOODSTREAM INFECTIONS IN CHILDREN WITH BURNS
Authors: Tsurumi Amy , Flaherty Patrick J. , Que Yok-Ai , Ryan Colleen M. , Banerjee Ankita , Chakraborty Arijit , Almpani Marianna , Shankar Malavika , Goverman Jeremy , Schulz John T. , Sheridan Robert L. , Friedstat Jonathan , Hickey Sean A. , Tompkins Ronald G. , Rahme Laurence G.
Published: January 2023

Introduction: Despite significant advances in pediatric burn care, bloodstream infections (BSIs) remain a compelling challenge during recovery. A personalized medicine approach for accurate prediction of BSIs before they occur would contribute to prevention efforts and improve patient outcomes. Methods: We analyzed the blood transcriptome of severely burned (total burn surface area [TBSA] ≥20%) patients in the multicenter Inflammation and Host Response to Injury (“Glue Grant”) cohort. Our study included 82 pediatric (aged <16 years) patients, with blood samples at least 3 days before the observed BSI episode. We applied the least absolute shrinkage and selection operator (LASSO) machine-learning algorithm to select a panel of biomarkers predictive of BSI outcome. Results: We developed a panel of 10 probe sets corresponding to six annotated genes (ARG2 [arginase 2], CPT1A [carnitine palmitoyltransferase 1A], FYB [FYN binding protein], ITCH [itchy E3 ubiquitin protein ligase], MACF1 [microtubule actin crosslinking factor 1], and SSH2 [slingshot protein phosphatase 2]), two uncharacterized (LOC101928635, LOC101929599), and two unannotated regions. Our multibiomarker panel model yielded highly accurate prediction (area under the receiver operating characteristic curve, 0.938; 95% confidence interval [CI], 0.881–0.981) compared with models with TBSA (0.708; 95% CI, 0.588–0.824) or TBSA and inhalation injury status (0.792; 95% CI, 0.676–0.892). A model combining the multibiomarker panel with TBSA and inhalation injury status further improved prediction (0.978; 95% CI, 0.941–1.000). Conclusions: The multibiomarker panel model yielded a highly accurate prediction of BSIs before their onset. Knowing patients' risk profile early will guide clinicians to take rapid preventive measures for limiting infections, promote antibiotic stewardship that may aid in alleviating the current antibiotic resistance crisis, shorten hospital length of stay and burden on health care resources, reduce health care costs, and significantly improve patients' outcomes. In addition, the biomarkers' identity and molecular functions may contribute to developing novel preventive interventions.
CIRC_0114428 INFLUENCES THE PROGRESSION OF SEPTIC ACUTE KIDNEY INJURY VIA REGULATING MIR-370-3P/TIMP2 AXIS
Authors: Zhang Bihong , You Ting , Liu Yu , Li Pei
Published: January 2023

Background: Septic acute kidney injury (AKI) is a serious complication of sepsis, which greatly threatened the life safety of critically ill patients. Recently, circular RNA is considered to be implicated in sepsis-induced renal cell damage. However, the role of circ_0114428 in sepsis AKI is still unclear. Methods: LPS was used to establish a sepsis-related AKI cell model. The expression of circ_0114428, microRNA (miR)-370-3p, tissue inhibitor of metalloproteinase-2 (TIMP2), Proliferating cell nuclear antigen, Bax, and Bcl-2 were detected by quantitative real-time polymerase chain reaction and Western blot. Cell counting kit 8 and enzyme-linked immunosorbent assay were used to measure cell proliferation ability and the secretion of inflammatory factors (tumor necrosis factor α, interleukin 1β, and interleukin 6), respectively. Cell cycle and apoptosis rate were analyzed by flow cytometry. Caspase-3 assay kits were used to detect Caspase-3 activity. Interaction between miR-370-3p and circ_0114428 or TIMP2 was analyzed by bioinformatics analysis, a dual-luciferase reporter assay, and RNA immunoprecipitation assay. Results: Circ_0114428 was upregulated in septic AKI serum samples and LPS-induced HK2 cells. The knockdown of circ_0114428 notably promoted cell proliferation and cycle, whereas it restrained cell inflammation and apoptosis in LPS-stimulated HK2 cells. Subsequent mechanism analysis revealed that miR-370-3p was a target of circ_0114428, and miR-370-3p inhibition could rescue the effects of circ_0114428 downregulation on LPS-induced cell injury. Meanwhile, TIMP2 was a target gene of miR-370-3p. miR-370-3p mimic could attenuate LPS-induced cell injury, whereas these impacts were overturned by overexpressed TIMP2. Furthermore, circ_0114428 enhanced TIMP2 protein expression by sponging miR-370-3p. Conclusion: Our data demonstrated that circ_0114428 contributed to septic AKI progression by regulating miR-370-3p–mediated TIMP2 expression, which provided a promising target for septic AKI treatment.
Infiltrating anti-inflammatory monocytes modulate microglial activation through toll-like receptor 4/interferon–dependent pathways following traumatic brain injury
Authors: El Baassiri Mahmoud G. , Chun Young H. , Rahal Simon S. , Fulton William B. , Sodhi Chhinder P. , Hackam David J. , Nasr Isam W.
Published: January 2023

BACKGROUND

Traumatic brain injury (TBI) is the leading cause of morbidity and mortality in the pediatric population. Microglia and infiltrating monocyte-derived macrophages are crucial immune cells that modulate the neuroinflammatory response following TBI. Using C34, a novel pharmacologic toll-like receptor 4 inhibitor, we investigated the intricate interactions between these cells in a murine TBI model.

METHODS

A murine controlled cortical impact model was used, and the results were analyzed on postinjury days 1, 7, 28, and 35. The experimental groups are as follows: (1) sham C57BL/6 wild-type (WT), (2) TBI WT, (3) sham WT + C34, and (4) TBI WT + C34. Quantitative real-time polymerase chain reaction was used to quantify gene expression associated with microglial activation, apoptotic pathways, and type 1 interferon pathway. Flow cytometry was used to isolate microglia and infiltrating monocytes. Brain lesion volumes were assessed using magnetic resonance imaging. Last, neurocognitive outcomes were evaluated using the Morris Water Maze test. Student's t test and one-way analysis of variance were used for statistical analysis with significance achieved when p < 0.05.

RESULTS

Toll-like receptor 4 inhibition leads to improved neurological sequela post-TBI, possibly because of an increase in infiltrating anti-inflammatory monocytes and a decrease in IFN regulatory factor 7 during acute inflammation, followed by a reduction in apoptosis and M2 microglial expression during chronic inflammation.

CONCLUSION

Toll-like receptor 4 inhibition with C34 skews infiltrating monocytes toward an anti-inflammatory phenotype, leading to enhanced neurocognitive outcomes. Moreover, although M2 microglia have been consistently shown as inducers of neuroprotection, our results clearly demonstrate their detrimental role during the chronic phases of healing post-TBI.
Carbonic anhydrases in development: morphological observations and gene expression profiling in sea urchin embryos exposed to acetazolamide
Authors: Zito Francesca , Bonaventura Rosa , Costa Caterina , Russo Roberta
Published: January 2023

Carbonic anhydrases (CANs) are conserved metalloenzymes catalysing the reversible hydration of carbon dioxide into protons and bicarbonate, with important roles in cells physiology. Some CAN-coding genes were found in sea urchin genome, although only one involved in embryonic skeletogenesis was described inParacentrotus lividus. Here, we investigated gene expression patterns ofP. lividusembryos cultured in the presence of acetazolamide (AZ), a CAN inhibitor, to combine morphological defects with their molecular underpinning. CAN inhibition blocked skeletogenesis, affected the spatial/temporal expression of some biomineralization-related genes, inhibited embryos swimming. A comparative analysis on the expression of 127 genes in control and 3 h/24 h AZ-treated embryos, using NanoString technology, showed the differential expression of genes encoding for structural/regulatory proteins, with different embryonic roles: biomineralization, transcriptional regulation, signalling, development and defence response. The study of the differentially expressed genes and the signalling pathways affected, besidesin silicoanalyses and a speculative ‘interactomic model’, leads to predicting the presence of various CAN isoforms, possibly involved in different physiological processes/activities in sea urchin embryo, and their potential target genes/proteins. Our findings provide new valuable molecular data for further studies in several biological fields: developmental biology (biomineralization, axes patterning), cell differentiation (neural development) and drug toxicology (AZ effects on embryos/tissues).
Does tolerance allow bonobos to outperform chimpanzees on a cooperative task? A conceptual replication of Hare
et al
., 2007
Authors: Nolte Suska , Sterck Elisabeth H. M. , van Leeuwen Edwin J. C.
Published: January 2023

Across various taxa, social tolerance is thought to facilitate cooperation, and many species are treated as having species-specific patterns of social tolerance. Yet studies that assess wild and captive bonobos and chimpanzees result in contrasting findings. By replicating a cornerstone experimental study on tolerance and cooperation in bonobos and chimpanzees (Hare
et al
. 2007
Cur. Biol.
17
, 619–623 (
doi:10.1016/j.cub.2007.02.040
)), we aim to further our understanding of current discrepant findings. We tested bonobos and chimpanzees housed at the same facility in a co-feeding and cooperation task. Food was placed on dishes located on both ends or in the middle of a platform. In the co-feeding task, the tray was simply made available to the ape duos, whereas in the cooperation task the apes had to simultaneously pull at both ends of a rope attached to the platform to retrieve the food. By contrast to the published findings, bonobos and chimpanzees co-fed to a similar degree, indicating a similar level of tolerance. However, bonobos cooperated more than chimpanzees when the food was monopolizable, which replicates the original study. Our findings call into question the interpretation that at the species level bonobos cooperate to a higher degree because they are inherently more tolerant.
Changes in the mechanical properties of human mesenchymal stem cells during differentiation
Authors: He Fei , Yang Chendong , Liu Haoye , Wang Jizeng
Published: January 2023

A thorough understanding of the changes in mechanical property behind intracellular biophysical and biochemical processes during differentiation of human mesenchymal stem cells (hMSCs) is helpful to direct and enhance the commitment of cells to a particular lineage. In this study, displacement creep of the mesenchymal cell lineages (osteogenic, chondrogenic and adipogenic hMSCs) were determined by using atomic force microscopy, which was then used to determine their mechanical properties. We found that at any stages of differentiation, the mesenchymal cell lineages are linear viscoelastic materials and well matched with a simple power-law creep compliance. In addition, the viscoelasticity of mesenchymal cell lineages showed different trends during differentiation. The adipogenic hMSCs showed continuous softening at all stages. The osteogenic and chondrogenic hMSCs only continuously soften and become more fluid-like in the early stage of differentiation, and get stiffened and less fluid-like in the later stage. These findings will help more accurately imitate cellular biomechanics in the microenvironment, and provided an important reference in the biophysics biomimetic design of stem cell differentiation.
The role of body shape and mass in skimming on water
Authors: Palmer R. A. , Smith F. T.
Published: January 2023

Over many years, there has been great practical interest in how solid bodies interact with and skim on liquid layers. In the present investigation, the focus is on the important role of body mass and shape in such skimming motions. Considering a thin two-dimensional solid body that impacts obliquely and then rebounds on a shallow inviscid water layer, we develop a mathematical model to predict quantitatively the duration and evolution of the body and fluid motions and indeed the success or failure of the whole skim. In the current setting, the shallow water layer thickness is small relative to the representative body length. The combined roles of increased mass and shape are found to be crucial, governed by a similarity solution. The relationship

C
∼

M

2

/

3

between scaled body curvature and mass is identified and highlighted. In particular, increased convex curvature of the underbody is found to alter the interactive pressure in such a way that it inhibits the occurrence of a super-elastic response in the exit vertical velocity and height of the body, and in effect enables a much heavier body to skim successfully provided the above relationship is maintained.
SINDy for delay-differential equations: application to model bacterial zinc response
Authors: Sandoz Antoine , Ducret Verena , Gottwald Georg A. , Vilmart Gilles , Perron Karl
Published: January 2023

We extend the data-driven method of sparse identification of nonlinear dynamics (SINDy) developed by Brunton
et al.
,
Proc. Natl Acad. Sci. USA
113
(2016) to the case of delay differential equations (DDEs). This is achieved in a bilevel optimization procedure by first applying SINDy for fixed delay and then subsequently optimizing the error of the reconstructed SINDy model over delay times. We test the SINDy-delay method on a noisy short dataset from a toy DDE and show excellent agreement. We then apply the method to experimental data of gene expressions in the bacterium
Pseudomonas aeruginosa
subject to the influence of zinc. The derived SINDy model suggests that the increase in zinc concentration mainly affects the time delay and not the strengths of the interactions between the different agents controlling the zinc export mechanism.
Albatrosses develop attraction to fishing vessels during immaturity but avoid them at old age
Authors: Weimerskirch Henri , Corbeau Alexandre , Pajot Adrien , Patrick Samantha C. , Collet Julien
Published: January 2023

Animals have to develop novel behaviours to adapt to anthropogenic activities or environmental changes. Fishing vessels constitute a recent feature that attracts albatrosses in large numbers. While they provide a valuable food source through offal and bait, they cause mortalities through bycatch, such that selection on vessel attraction will depend on the cost–benefit balance. We examine whether attraction to fishing and other vessels changes through the lifetime of great albatrosses, and show that attraction differed between age classes, sexes and personality. Juveniles encountered fewer vessels than adults, but also showed a lower attraction to vessels when encountered. Attraction rates, especially for fishing vessels, increased through immaturity to peak during adulthood, decreasing with old age. Shy females had lower attraction to vessels and shy males remained at vessels longer, suggesting that bolder individuals may outcompete shyer ones, with positive consequences for mass gain. These results suggest that attraction to vessels is a learned process, leading to an increase with age, and is not the result of preferential attraction to new objects by juveniles. Overall, our findings have important conservation implications as a result of potential strong differential selection on the risk of bycatch for age classes, personality types, populations and species.
Investigating Klebsiella pneumoniae Biofilm Preservation for Scanning Electron Microscopy
Authors: Fleeman Renee M , Mikesh Michelle , Davies Bryan W
Published: January 2023

Klebsiella pneumoniae biofilm formation is associated with chronic and relapsing infections. Scanning electron microscopy (SEM) is a powerful tool for characterizing biofilm structure and studying their formation. Reliable visualization of biofilm structure requires careful sample preservation, otherwise there may be loss of non-covalent interactions that are susceptible to damage during the dehydration and washing preparation steps. However, no standard procedure has been adopted in literature to fix K. pneumoniae biofilm for scanning electron microscopy studies. This lack of standardization makes it challenging to compare results between studies and determine the degree to which native structures have been preserved. To advance this critical area of study, we investigated different scanning electron microscopy fixation methods for K. pneumoniae biofilm preservation. Our study reveals the impact preparation steps can have on retaining in biofilm architecture observed using scanning electron microscopy. Using fixation methods developed through our studies, we show that although species that overproduce capsular extracellular polysaccharides produced more robust biofilms, K. pneumoniae can form a developed biofilm in the absence of capsular polysaccharides.
Attitudes towards booster, testing and isolation, and their impact on COVID-19 response in winter 2022/2023 in France, Belgium, and Italy
Authors: de Meijere Giulia , Valdano Eugenio , Castellano Claudio , Debin Marion , Kengne-Kuetche Charly , Turbelin Clément , Noël Harold , Weitz Joshua , Paolotti Daniela , Hermans Lisa , Hens Niel , Colizza Vittoria
Published: January 2023

European countries are focusing on testing, isolation, and boosting strategies to counter the 2022/2023 winter surge due to Omicron subvariants. However, widespread pandemic fatigue and limited compliance potentially undermine mitigation efforts. To establish a baseline for interventions, we ran a multicountry survey to assess respondents’ willingness to receive booster vaccination and comply with testing and isolation mandates. The vast majority of survey participants (N=4,594) was willing to adhere to testing (>91%) and rapid isolation (>88%) across the three countries. Pronounced differences emerged in the declared senior adherence to booster vaccination (73% in France, 94% in Belgium, 86% in Italy). Next, we inferred the vaccine-induced population immunity profile at the winter start from prior vaccination data, immunity waning, and declared booster uptake. Integrating survey and estimated immunity data in a branching process epidemic spreading model, we evaluated the effectiveness and costs of current protocols in France, Belgium, and Italy to manage the winter wave. Model results estimate that testing and isolation protocols would confer significant benefit in reducing transmission (17-24%) with declared adherence. Achieving a mitigating level similar to the French protocol, the Belgian protocol would require 30% fewer tests and avoid the long isolation periods of the Italian protocol (average of 6 days vs. 11). A cost barrier to test would significantly decrease adherence in France and Belgium, undermining protocols’ effectiveness. Simpler mandates for isolation may increase awareness and actual compliance, reducing testing costs, without compromising mitigation. High booster vaccination uptake remains key for the control of the winter wave.
Methods for a population-based Comprehensive Eye care Workload Assessment (CEWA) Study in Southern India
Authors: Vardhan Ashok , Rajendran Vinoth Kumar , Joseph Sanil , Pooludaiyar Lakshmanan , Datta Dipankar , Fletcher Astrid E , Ravilla Thulasiraj
Published: January 2023

Eye care programs, in developing countries, are often planned using the cataract surgical rate (CSR) targets - retrospectively estimated from Rapid Assessment (RAAB) surveys. A limitation of this approach is that it ignores the annual overall eye care requirements for a given population. Moreover, targets set are arbitrary, often influenced by capacity rather than need. To address this lacunae, we implemented a novel study design to estimate the annual need for comprehensive eye care in a 1.2 million population.

We conducted a population-based longitudinal study in Theni district, Tamil Nadu, India. All permanent residents of all ages were included. We conducted the study in three phases, (i) household-level enumeration and enrolment, (ii) basic eye examination (BEE) at household one-year post-enrolment, and (iii) assessment of eye care utilization and full eye examination (FEE) at central locations. All people aged 40 and above were invited to the FEE. Those aged less than 40 years were invited to the when FEE if indicated.

We conducted three pilot studies to test the study and clinical examination protocols. In the main study we enrolled 24,327 subjects (58% aged below 40 years and 42% aged 40 years and above). Of those less than 40 years, 72% completed the BEE, of whom 20% were referred for FEE and 70% of people aged ≥40 years underwent a comprehensive eye examination at central location.

Our study design provides appropriate long-term public health intervention planning, resource allocation, efficient delivery of care, and designing of eye care services for resource-limited settings.
L-shape distribution of the relative substitution rate (c/μ) observed for SARS-COV-2’s genome, inconsistent with the selectionist theory, the neutral theory and the nearly neutral theory but a near-neutral balanced selection theory: implication on “neutralist-selectionist” debate
Authors: Wu Chun , Paradis Nicholas J. , Lakernick Phillip M. , Hryb Mariya
Published: January 2023

The genomic substitution rate (GSR) of SARS-CoV-2 exhibits a molecular clock feature and does not change under fluctuating environmental factors such as the infected human population (100-107), vaccination etc.. The molecular clock feature is believed to be inconsistent with the selectionist theory (ST). The GSR shows lack of dependence on the effective population size, suggesting Ohta’s nearly neutral theory (ONNT) is not applicable to this virus. Big variation of the substitution rate within its genome is also inconsistent with Kimura’s neutral theory (KNT). Thus, all three existing evolution theories fail to explain the evolutionary nature of this virus. In this paper, we proposed a Segment Substitution Rate Model (SSRM) under non-neutral selections and pointed out that a balanced mechanism between negative and positive selection of some segments that could also lead to the molecular clock feature. We named this hybrid mechanism as near-neutral balanced selection theory (NNBST) and examined if it was followed by SARS-CoV-2 using the three independent sets of SARS-CoV-2 genomes selected by the Nextstrain team. Intriguingly, the relative substitution rate of this virus exhibited an L-shaped probability distribution consisting with NNBST rather than Poisson distribution predicted by KNT or an asymmetric distribution predicted by ONNT in which nearly neutral sites are believed to be slightly deleterious only, or the distribution that is lack of nearly neutral sites predicted by ST. The time-dependence of the substitution rates for some segments and their correlation with the vaccination were observed, supporting NNBST. Our relative substitution rate method provides a tool to resolve the long standing “neutralist-selectionist” controversy. Implications of NNBST in resolving Lewontin’s Paradox is also discussed.
Participant Demographics and Testing Trends: A Community Pandemic Response Program
Authors: García Yury E. , Solis Leslie , Daza–Torres Maria L. , Montesinos-López Cricelio , Pollock Brad H. , Nuño Miriam
Published: January 2023

Objective

This study aimed to identify demographic characteristics of test participants and changes in testing participation over time in a community pandemic-response program launched in a college town in California, USA.

Methods

We described overall testing participation, identified demographic characteristics of frequent testers, and evaluated changes in testing participation over four different periods of the COVID-19 pandemic.

Results

A total of 770,165 tests were performed between November 18, 2020, and June 30, 2022, among 89,924 residents of Yolo County (41.1% of population), with significant participation from racially/ethnically diverse participants and across age groups. Most positive cases (49.9%) were captured during Omicron, which also corresponds to the period with the highest daily participation (895 per 100K population). The proportion of participants which we considered “frequent testers” (28.9% vs. 39.7%,p <0.0001) and individuals that tested once (39.5% vs. 47.9%,p <0.0001) increased significantly from Delta to Omicron. Women (58.8%), participants of age 19-34 years (38.8%), and White (53.2%) tested more frequently throughout the program. The proportion of tests conducted among Latinos remained steady around 18% over time, with the exception of the post-Omicron period (13%).

Conclusion

The unique features of a pandemic response program that supported communitywide access to free asymptomatic testing provides a unique opportunity to evaluate adherence to testing recommendations, and testing trends over time. Identification of individual and group-level factors associated with testing behaviors is essential to improve access and protect communities at-large.
The time between vaccination and infection impacts immunity against SARS-CoV-2 variants
Authors: Bates Timothy A. , Leier Hans C. , McBride Savannah K. , Schoen Devin , Lyski Zoe L. , Lee David X. , Messer William B. , Curlin Marcel E. , Tafesse Fikadu G.
Published: January 2023

As the COVID-19 pandemic continues, long-term immunity against SARS-CoV-2 will be globally important. Official weekly cases have not dropped below 2 million since September of 2020, and continued emergence of novel variants have created a moving target for our immune systems and public health alike. The temporal aspects of COVID-19 immunity, particularly from repeated vaccination and infection, are less well understood than short-term vaccine efficacy. In this study, we explore the impact of combined vaccination and infection, also known as hybrid immunity, and the timing thereof on the quality and quantity of antibodies produced by a cohort of 96 health care workers. We find robust neutralizing antibody responses among those with hybrid immunity against all variants, including Omicron BA.2, and we further found significantly improved neutralizing titers with longer vaccine-infection intervals up to 400 days. These results indicate that anti-SARS-CoV-2 antibody responses undergo continual maturation following primary exposure by either vaccination or infection for at least 400 days after last antigen exposure. We show that neutralizing antibody responses improved upon secondary boosting with greater impact seen after extended intervals. Our findings may also extend to booster vaccine doses, a critical consideration in future vaccine campaign strategies.
Genomic characterization and molecular evolution of SARS-CoV-2 in Rio Grande do Sul State, Brazil
Authors: de Menezes Mayer Amanda , Gröhs Ferrareze Patrícia Aline , de Oliveira Luiz Felipe Valter , Gregianini Tatiana Schäffer , Moreira Neves Carla Lucia Andretta , Caldana Gabriel Dickin , Kmetzsch Lívia , Thompson Claudia Elizabeth
Published: January 2023

The SARS-CoV-2 is the virus responsible for the COVID-19 pandemic and is plaguing the world since the end of 2019. Different lineages have been discovered ever since and the Gamma lineage, which started the second wave of infections, was first described in Brazil, one of the most affected countries by pandemic. Describing the viral genome and how the virus behaves is essential to contain its propagation and to the development of medications and vaccines. Therefore, this study analyzed SARS-CoV-2 sequenced genomes from Esteio city in Rio Grande do Sul, Southern Brazil. We also comparatively analyzed genomes of the two first years of the pandemic from Rio Grande do Sul state for understanding their genomic and evolutionary patterns. The phylogenomic analysis showed monophyletic groups for Alpha, Gamma, Delta and Omicron, as well as for other circulating lineages in the state. Molecular evolutionary analysis identified several sites under adaptive selection in membrane and nucleocapsid proteins which could be related to a prevalent stabilizing effect on membrane protein structure, as well as majoritarily destabilizing effects on C-terminal nucleocapsid domain.
Mifepristone as a pharmacological intervention for stress-Induced alcohol craving: a translational crossover randomized trial
Authors: Haass-Koffler Carolina L. , Magill Molly , Cannella Nazzareno , Brown Joshua C. , Aoun Elie G. , Cioe Patricia A. , Sinha Rajita , Swift Robert M. , Ciccocioppo Roberto , Leggio Lorenzo
Published: January 2023

Preclinical and clinical work suggests that mifepristone (glucocorticoid receptor antagonist), may be a viable treatment for alcohol use disorder (AUD). The aim of this work was to translate our preclinical mifepristone study using yohimbine (α2 receptor antagonist) stress-induced reinstatement of alcohol-seeking to a clinical setting. This was a Phase 1/2, outpatient, cross-over, randomized, double-blind, placebo-controlled trial with non-treatment-seeking individuals with AUD (N=32). We investigated the safety, alcohol craving and consumption after oral administration of mifepristone (600mg daily for a week) in a human laboratory study comprised of administration of yohimbine in a cue-reactivity procedure and alcohol self-administration. Outcomes were assessed using Generalized Estimating Equations and mediation and moderation analyses assessed mechanisms of action and precision medicine targets. We did not observe serious adverse events related to the study drugs or study procedure and mild to moderate non-serious adverse events were reported by both study conditions. Also, there was no statistically-significant difference between the mifepristone and placebo in the hemodynamic response, alcohol subjective effects and pharmacokinetics parameters. Mifepristone significantly reduced alcohol craving and increased cortisol levels. Mifepristone-induced cortisol increase was not a mediator of alcohol craving. Moderation analysis with family history density of AUD (FHDA) and mifepristone, suggested that reduced craving was present in individuals withlow, but nothighFHDA. Mifepristone, compared to placebo, did not reduce alcohol consumption in the laboratory or in a naturalistic setting. This study successfully translated a preclinical paradigm to a human laboratory study confirming safety, tolerability and efficacy of mifepristone in an alcohol paradigm. Mediation analysis showed that the effect of mifepristone on craving was not related to mifepristone-induced increases in cortisol and moderation of FHDA suggested the importance of evaluating AUD endophenotypes for pharmacotherapies.

Clinical trial registration

Clinicaltrials.gov;NCT02243709

IND/FDA

121984, mifepristone and yohimbine (Holder: Haass-Koffler)
Leveraging global genomic sequencing data to estimate local variant dynamics
Authors: Susswein Zachary , Johnson Kaitlyn E. , Kassa Robel , Parastaran Mina , Peng Vivian , Wolansky Leo , Scarpino Samuel V. , Bento Ana I.
Published: January 2023

Accurate, reliable, and timely estimates of pathogen variant risk are essential for informing public health responses. Unprecedented rates of genomic sequencing have generated new insights into variant dynamics. However, estimating the fitness advantage of a novel variant shortly after emergence, or its dynamics more generally in data-sparse settings, remains difficult. This challenge is exacerbated in countries where surveillance is limited or intermittent. To stabilize inference in these data-sparse settings, we develop a hierarchical modeling approach to estimate variant fitness advantage and prevalence by pooling data across geographic regions. We demonstrate our method by reconstructing SARS-CoV-2 BA.5 variant emergence, and assess performance using retrospective, out-of-sample validation. We show that stable and robust estimates can be obtained even when sequencing data are sparse. Finally, we discuss how this method can inform risk assessment of novel variants and provide situational awareness on circulating variants for a range of pathogens and use-cases.
The Physical Basis of Osmosis
Authors: Manning Gerald S. , Kay Alan R.
Published: January 2023

Osmosis is an important force in all living organisms, yet the molecular basis of osmosis is widely misunderstood as arising from differences in water concentration in solutions of differing osmolarities. In 1923 Debye proposed a physical model for a semipermeable membrane that was hardly noticed at the time and slipped out of view. We show that Debye’s analysis of van’t Hoff’s law for osmotic equilibrium provides a consistent and plausible explanation for osmotic flow. A difference in osmolyte concentrations in solutions separated by a semipermeable membrane generates different pressures at the two water-membrane interfaces. Water is therefore driven through the membrane for exactly the same reason that pure water flows in response to an imposed hydrostatic pressure difference. In this paper we present the Debye model in both equilibrium and flow conditions. We point out its applicability regardless of the nature of the membrane with examples ranging from predominantly convective flow of water through synthetic membranes to purely diffusive flow of independent water molecules through a lipid bilayer and the flow of strongly interacting water molecules in single file across narrow protein channels.
Estimating long-term vaccine effectiveness against SARS-CoV-2 variants: a model-based approach
Authors: Hogan Alexandra B , Doohan Patrick , Wu Sean L , Mesa Daniela Olivera , Toor Jaspreet , Watson Oliver J , Winskill Peter , Charles Giovanni , Barnsley Gregory , Riley Eleanor M , Khoury David S , Ferguson Neil M , Ghani Azra C
Published: January 2023

With the ongoing evolution of the SARS-CoV-2 virus, variant-adapted vaccines are likely to be required. Given the challenges of conducting clinical trials against a background of widespread infection-induced immunity, updated vaccines are likely to be adopted based on immunogenicity data. We extended a modelling framework linking immunity levels and protection and fitted the model to vaccine effectiveness data from England for three vaccines (Oxford/AstraZeneca AZD1222, Pfizer-BioNTech BNT162b2, Moderna mRNA-1273) and two variants (Delta and Omicron) to predict longer-term effectiveness against mild disease, hospitalisation and death. We use these model fits to predict the effectiveness of the Moderna bivalent vaccine (mRNA1273.214) against the Omicron variant using immunogenicity data. Our results suggest sustained protection against hospitalisation and death from the Omicron variant over the first six months following boosting with the monovalent vaccines but a gradual waning to moderate protection after 1 year (median predicted vaccine effectiveness at 1 year in 65+ age group: AZD1222 38.9%, 95% CrI 31.8%-46.8%; BNT162b2 53.3%, 95% CrI 49.1%-56.9%; mRNA-1273 60.0%, 95% CrI 56.0%-63.6%). Furthermore, we predict almost complete loss of protection against mild disease over this period (mean predicted effectiveness at 1 year 7.8% for AZD1222, 13.2% for BNT162b2 and 16.7% for mRNA-1273). Switching to a second booster with the bivalent mRNA1273.214 vaccine against Omicron BA.1/2 is predicted to prevent nearly twice as many hospitalisations and deaths over a 1-year period compared to administering a second booster with the monovalent mRNA1273 vaccine. Ongoing production and administration of variant-specific vaccines are therefore likely to play an important role in protecting against severe outcomes from the ongoing circulation of SARS-CoV-2.
Diagnostic testing in people with primary ciliary dyskinesia: an international participatory study
Authors: Schreck Leonie D , Pedersen Eva SL , Cizeau Isabelle , Müller Loretta , Kruljac Catherine , Lucas Jane S , Goutaki Myrofora ,   COVID-PCD patient advisory group, Kuehni Claudia E
Published: January 2023

Diagnostic tests are important in primary ciliary dyskinesia (PCD), a rare disease, to confirm the diagnosis and characterize the disease. We compared diagnostic tests for PCD between countries worldwide, assessed whether people with PCD recall their tests, and identified factors associated with the use of tests. We used cross-sectional data from COVID-PCD—an international participatory cohort study collecting information directly from people with PCD. The baseline questionnaire inquired about tests used for PCD diagnosis. Using logistic regression, we investigated factors associated with measurement of nasal nitric oxide (nNO), biopsy for electron or video microscopy, and genetic testing. We included data from 747 participants (60% females) from 49 countries worldwide with median age 27 (interquartile range 12–44). Most (92%) reported diagnostic tests for PCD. Participants reported measurements of nNO (342; 49%), biopsy samples (561; 75%), and genetic tests (435; 58%). The reported use of individual tests, such as genetics, varied between countries from 38% in Switzerland to 68% in North America. Participant recall of test type also differed between countries with lowest recall in Switzerland. One-third (232; 36%) of participants reported all three tests (nNO, biopsy, and genetics). Recently diagnosed people reported more tests [nNO odds ratio (OR) 2.2, 95% Confidence Interval (CI) 1.5–3.2; biopsy OR 3.2, 95%CI 2.1–4.9; genetics OR 4.7, 95%CI 3.2–6.9] and those with situs abnormalities fewer tests (nNO OR 0.5, 95%CI 0.4–0.7; biopsy OR 0.5, 95%CI 0.4–0.8; genetics OR 0.7, 95%CI 0.5–0.94). Our results indicate PCD diagnostic testing differed widely around the world and many patients received incomplete diagnostic work-up based only on clinical features or single tests. People diagnosed long ago and those with situs abnormalities possibly benefit from supplementary testing to refine their diagnosis as a prerequisite for personalized medicine.
A CLOSER LOOK AT INDIRECT CAUSES OF DEATH AFTER HURRICANE MARIA USING A SEMIPARAMETRIC MODEL
Authors: Lugo Oscar , Rivera Roberto
Published: January 2023

The Covid-19 pandemic as well as other recent natural emergencies have put the spotlight on emergency planning. One important aspect is that natural disasters or emergencies often lead to indirect deaths and studying the behavior of indirect deaths during emergencies can guide emergency planning. While many studies have implied a large number of indirect deaths in Puerto Rico due to Hurricane Maria; the specific causes of these deaths have not being carefully studied. In this paper, we use a semiparametric model and mortality data to evaluate cause of death trends. Our model adjusts for cause of death effect potentially varying over time while also inferring on how long excess deaths occurred. From September 2017 to March 2018, after adjusting for intra-annual variability and population displacement, we find evidence of significant excess deaths due to Alzheimer’s/Parkinson, heart disease, sepsis, diabetes, renal failure, and pneumonia & influenza. In contrast, for the same time period we find no evidence of significant excess deaths due to cancer, hypertension, respiratory diseases, cerebrovascular disease, suicide, homicide, falling accidents and traffic accidents.