-
Clinical Infectious Diseases : An... Apr 2024The rVSVΔG-ZEBOV-GP vaccine (ERVEBO®) is a single-dose, live-attenuated, recombinant vesicular stomatitis virus vaccine indicated for the prevention of Ebola virus... (Randomized Controlled Trial)
Randomized Controlled Trial
Immunogenicity and Vaccine Shedding After 1 or 2 Doses of rVSVΔG-ZEBOV-GP Ebola Vaccine (ERVEBO®): Results From a Phase 2, Randomized, Placebo-controlled Trial in Children and Adults.
BACKGROUND
The rVSVΔG-ZEBOV-GP vaccine (ERVEBO®) is a single-dose, live-attenuated, recombinant vesicular stomatitis virus vaccine indicated for the prevention of Ebola virus disease (EVD) caused by Zaire ebolavirus in individuals 12 months of age and older.
METHODS
The Partnership for Research on Ebola VACcination (PREVAC) is a multicenter, phase 2, randomized, double-blind, placebo-controlled trial of 3 vaccine strategies in healthy children (ages 1-17) and adults, with projected 5 years of follow-up (NCT02876328). Using validated assays (GP-ELISA and PRNT), we measured antibody responses after 1-dose rVSVΔG-ZEBOV-GP, 2-dose rVSVΔG-ZEBOV-GP (given on Day 0 and Day 56), or placebo. Furthermore, we quantified vaccine virus shedding in a subset of children's saliva using RT-PCR.
RESULTS
In total, 819 children and 783 adults were randomized to receive rVSVΔG-ZEBOV-GP (1 or 2 doses) or placebo. A single dose of rVSVΔG-ZEBOV-GP increased antibody responses by Day 28 that were sustained through Month 12. A second dose of rVSVΔG-ZEBOV-GP given on Day 56 transiently boosted antibody concentrations. In vaccinated children, GP-ELISA titers were superior to placebo and non-inferior to vaccinated adults. Vaccine virus shedding was observed in 31.7% of children, peaking by Day 7, with no shedding observed after Day 28 post-dose 1 or any time post-dose 2.
CONCLUSIONS
A single dose of rVSVΔG-ZEBOV-GP induced robust antibody responses in children that was non-inferior to the responses induced in vaccinated adults. Vaccine virus shedding in children was time-limited and only observed after the first dose. Overall, these data support the use of rVSVΔG-ZEBOV-GP for the prevention of EVD in at-risk children. Clinical Trials Registration. The study is registered at ClinicalTrials.gov (NCT02876328), the Pan African Clinical Trials Registry (PACTR201712002760250), and the European Clinical Trials Register (EudraCT number: 2017-001798-18).
Topics: Adult; Child; Humans; Hemorrhagic Fever, Ebola; Ebola Vaccines; Antibodies, Viral; Viral Envelope Proteins; Ebolavirus; Vaccines, Synthetic; Vaccination; Vaccines, Attenuated; Immunogenicity, Vaccine
PubMed: 37967326
DOI: 10.1093/cid/ciad693 -
Cureus Nov 2023Introduction Earlier research has shown an association between pain intensity and everyday activities in adults. However, it is vital to examine the relationship within...
Introduction Earlier research has shown an association between pain intensity and everyday activities in adults. However, it is vital to examine the relationship within the context of Saudi people who have knee osteoarthritis. Therefore, this study aimed to explore the connection between pain intensity and daily activities involving the lower and upper limbs among patients with knee osteoarthritis in Saudi Arabia. Methods This study enrolled 209 individuals aged 55 years and above who were diagnosed with radiographic knee osteoarthritis by physicians from five hospitals in Riyadh, Saudi Arabia, between March 2016 and March 2017. Participants were divided into two groups based on their pain intensity, measured using the visual analog scale. The first group included 141 individuals with mild or moderate pain, while the second group comprised 68 individuals with severe pain. The study assessed the physical functioning of these individuals by evaluating their ability to perform daily activities involving the lower and upper limbs, using the Physical Functioning Subscale of the 36-item Short Form Health Survey, which includes 10 items. Results Adjusted logistic regression analysis revealed that individuals experiencing severe pain related to knee osteoarthritis were more likely to encounter difficulties in climbing several flights of stairs (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.09-1.29), and one flight of stairs (OR = 1.19, 95% CI = 1.06-1.34), with challenges in bending, kneeling, or stooping (OR = 1.14, 95% CI = 1.05-1.23), walking more than one mile (OR = 1.15, 95% CI = 1.06-1.25), walking several blocks (OR = 1.17, 95% CI = 1.08-1.27), and walking one block (OR = 1.19, 95% CI = 1.06-1.34) than those with mild or moderate pain. Conclusion Our study results highlight the significant impact of severe pain on activities like climbing stairs, bending, kneeling, stooping, and walking longer distances among people with knee osteoarthritis in Saudi Arabia.
PubMed: 37954623
DOI: 10.7759/cureus.48381 -
JMIR Cardio Oct 2023Overcrowding of hospitals and emergency departments (EDs) is a growing problem. However, not all ED consultations are necessary. For example, 80% of patients in the ED...
BACKGROUND
Overcrowding of hospitals and emergency departments (EDs) is a growing problem. However, not all ED consultations are necessary. For example, 80% of patients in the ED with chest pain do not have an acute coronary syndrome (ACS). Artificial intelligence (AI) is useful in analyzing (medical) data, and might aid health care workers in prehospital clinical decision-making before patients are presented to the hospital.
OBJECTIVE
The aim of this study was to develop an AI model which would be able to predict ACS before patients visit the ED. The model retrospectively analyzed prehospital data acquired by emergency medical services' nurse paramedics.
METHODS
Patients presenting to the emergency medical services with symptoms suggestive of ACS between September 2018 and September 2020 were included. An AI model using a supervised text classification algorithm was developed to analyze data. Data were analyzed for all 7458 patients (mean 68, SD 15 years, 54% men). Specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for control and intervention groups. At first, a machine learning (ML) algorithm (or model) was chosen; afterward, the features needed were selected and then the model was tested and improved using iterative evaluation and in a further step through hyperparameter tuning. Finally, a method was selected to explain the final AI model.
RESULTS
The AI model had a specificity of 11% and a sensitivity of 99.5% whereas usual care had a specificity of 1% and a sensitivity of 99.5%. The PPV of the AI model was 15% and the NPV was 99%. The PPV of usual care was 13% and the NPV was 94%.
CONCLUSIONS
The AI model was able to predict ACS based on retrospective data from the prehospital setting. It led to an increase in specificity (from 1% to 11%) and NPV (from 94% to 99%) when compared to usual care, with a similar sensitivity. Due to the retrospective nature of this study and the singular focus on ACS it should be seen as a proof-of-concept. Other (possibly life-threatening) diagnoses were not analyzed. Future prospective validation is necessary before implementation.
PubMed: 37906226
DOI: 10.2196/51375 -
Human Reproduction (Oxford, England) Jan 2024Does the diagnosis of mosaicism affect ploidy rates across different providers offering preimplantation genetic testing for aneuploidies (PGT-A)?
STUDY QUESTION
Does the diagnosis of mosaicism affect ploidy rates across different providers offering preimplantation genetic testing for aneuploidies (PGT-A)?
SUMMARY ANSWER
Our analysis of 36 395 blastocyst biopsies across eight genetic testing laboratories revealed that euploidy rates were significantly higher in providers reporting low rates of mosaicism.
WHAT IS KNOWN ALREADY
Diagnoses consistent with chromosomal mosaicism have emerged as a third category of possible embryo ploidy outcomes following PGT-A. However, in the era of mosaicism, embryo selection has become increasingly complex. Biological, technical, analytical, and clinical complexities in interpreting such results have led to substantial variability in mosaicism rates across PGT-A providers and clinics. Critically, it remains unknown whether these differences impact the number of euploid embryos available for transfer. Ultimately, this may significantly affect clinical outcomes, with important implications for PGT-A patients.
STUDY DESIGN, SIZE, DURATION
In this international, multicenter cohort study, we reviewed 36 395 consecutive PGT-A results, obtained from 10 035 patients across 11 867 treatment cycles, conducted between October 2015 and October 2021. A total of 17 IVF centers, across eight PGT-A providers, five countries and three continents participated in the study. All blastocysts were tested using trophectoderm biopsy and next-generation sequencing. Both autologous and donation cycles were assessed. Cycles using preimplantation genetic testing for structural rearrangements were excluded from the analysis.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The PGT-A providers were randomly categorized (A to H). Providers B, C, D, E, F, G, and H all reported mosaicism, whereas Provider A reported embryos as either euploid or aneuploid. Ploidy rates were analyzed using multilevel mixed linear regression. Analyses were adjusted for maternal age, paternal age, oocyte source, number of embryos biopsied, day of biopsy, and PGT-A provider, as appropriate. We compared associations between genetic testing providers and PGT-A outcomes, including the number of chromosomally normal (euploid) embryos determined to be suitable for transfer.
MAIN RESULTS AND THE ROLE OF CHANCE
The mean maternal age (±SD) across all providers was 36.2 (±5.2). Our findings reveal a strong association between PGT-A provider and the diagnosis of euploidy and mosaicism. Amongst the seven providers that reported mosaicism, the rates varied from 3.1% to 25.0%. After adjusting for confounders, we observed a significant difference in the likelihood of diagnosing mosaicism across providers (P < 0.001), ranging from 6.5% (95% CI: 5.2-7.4%) for Provider B to 35.6% (95% CI: 32.6-38.7%) for Provider E. Notably, adjusted euploidy rates were highest for providers that reported the lowest rates of mosaicism (Provider B: euploidy, 55.7% (95% CI: 54.1-57.4%), mosaicism, 6.5% (95% CI: 5.2-7.4%); Provider H: euploidy, 44.5% (95% CI: 43.6-45.4%), mosaicism, 9.9% (95% CI: 9.2-10.6%)); and Provider D: euploidy, 43.8% (95% CI: 39.2-48.4%), mosaicism, 11.0% (95% CI: 7.5-14.5%)). Moreover, the overall chance of having at least one euploid blastocyst available for transfer was significantly higher when mosaicism was not reported, when we compared Provider A to all other providers (OR = 1.30, 95% CI: 1.13-1.50). Differences in diagnosing and interpreting mosaic results across PGT-A laboratories raise further concerns regarding the accuracy and relevance of mosaicism predictions. While we confirmed equivalent clinical outcomes following the transfer of mosaic and euploid blastocysts, we found that a significant proportion of mosaic embryos are not used for IVF treatment.
LIMITATIONS, REASONS FOR CAUTION
Due to the retrospective nature of the study, associations can be ascertained, however, causality cannot be established. Certain parameters such as blastocyst grade were not available in the dataset. Furthermore, certain platform-related and clinic-specific factors may not be readily quantifiable or explicitly captured in our dataset. As such, a full elucidation of all potential confounders accounting for variability may not be possible.
WIDER IMPLICATIONS OF THE FINDINGS
Our findings highlight the strong need for standardization and quality assurance in the industry. The decision not to transfer mosaic embryos may ultimately reduce the chance of success of a PGT-A cycle by limiting the pool of available embryos. Until we can be certain that mosaic diagnoses accurately reflect biological variability, reporting mosaicism warrants utmost caution. A prudent approach is imperative, as it may determine the difference between success or failure for some patients.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by the Torres Quevedo Grant, awarded to M.P. (PTQ2019-010494) by the Spanish State Research Agency, Ministry of Science and Innovation, Spain. M.P., L.B., A.R.L., A.L.R.d.C.L., N.P.P., M.P., D.S., F.A., A.P., B.M., L.D., F.V.M., D.S., M.R., E.P.d.l.B., A.R., and R.V. have no competing interests to declare. B.L., R.M., and J.A.O. are full time employees of IB Biotech, the genetics company of the Instituto Bernabeu group, which performs preimplantation genetic testing. M.G. is a full time employee of Novagen, the genetics company of Cegyr, which performs preimplantation genetic testing.
TRIAL REGISTRATION NUMBER
N/A.
Topics: Female; Humans; Pregnancy; Aneuploidy; Bias, Implicit; Blastocyst; Cohort Studies; Genetic Testing; Mosaicism; Preimplantation Diagnosis; Retrospective Studies; Adult
PubMed: 37873575
DOI: 10.1093/humrep/dead213 -
Frontiers in Computational Neuroscience 2023Patients with Parkinson's disease (PD) exhibit distinct abnormal postures, including neck-down, stooped postures, and Pisa syndrome, collectively termed "abnormal...
Patients with Parkinson's disease (PD) exhibit distinct abnormal postures, including neck-down, stooped postures, and Pisa syndrome, collectively termed "abnormal posture" henceforth. In the previous study, when assuming an upright stance, patients with PD exhibit heightened instability in contrast to healthy individuals with disturbance, implying that abnormal postures serve as compensatory mechanisms to mitigate sway during static standing. However, limited studies have explored the relationship between abnormal posture and sway in the context of static standing. Increased muscle tone (i.e., constant muscle activity against the gravity) has been proposed as an underlying reason for abnormal postures. Therefore, this study aimed to investigate the following hypothesis: abnormal posture with increased muscle tone leads to a smaller sway compared with that in other postures, including normal upright standing, under the sway minimization criterion. To investigate the hypothesis, we assessed the sway in multiple postures, which is determined by joint angles, including cases with bended hip joints. Our approach involved conducting forward dynamics simulations using a computational model comprising a musculoskeletal model and a neural controller model. The neural controller model proposed integrates two types of control mechanisms: feedforward control (representing muscle tone as a vector) and feedback control using proprioceptive and vestibular sensory information. An optimization was performed to determine the posture of the musculoskeletal model and the accompanied parameters of the neural controller model for each of the given muscle tone vector to minimize sway. The optimized postures to minimize sway for the optimal muscle tone vector of patients with PD were compared to the actual postures observed in these patients. The results revealed that on average, the joint-angle differences between these postures was <4°, which was less than one-tenth of the typical joint range of motion. These results suggest that patients with PD exhibit less sway in the abnormal posture than in other postures. Thus, adopting an abnormal posture with increased muscle tone can potentially serve as a valid strategy for minimizing sway in patients with PD.
PubMed: 37867918
DOI: 10.3389/fncom.2023.1218707 -
Neuropharmacology Jan 2024Individuals with opioid use disorder (OUD) frequently use other substances, including cocaine. Opioid withdrawal is associated with increased likelihood of cocaine use,...
Individuals with opioid use disorder (OUD) frequently use other substances, including cocaine. Opioid withdrawal is associated with increased likelihood of cocaine use, which may represent an attempt to ameliorate opioid withdrawal effects. Clinically, 30% of co-using individuals take opioids and cocaine exclusively in a sequential manner. Preclinical studies evaluating mechanisms of drug use typically study drugs in isolation. However, polysubstance use is a highly prevalent clinical issue and thus, we established a novel preclinical model of sequential oxycodone and cocaine self-administration (SA) whereby rats acquired oxycodone and cocaine SA in an A-B-A-B design. Somatic signs of withdrawal were evaluated at 0, 22, and 24h following oxycodone SA, with the 24h timepoint representing somatic signs immediately following cocaine SA. Preclinically, aberrant glutamate signaling within the nucleus accumbens core (NAcore) occurs following use of cocaine or opioids, whereby medium spiny neurons (MSNs) rest in a potentiated or depotentiated state, respectively. Further, NAcore glial glutamate transport via GLT-1 is downregulated following SA of either drug alone. However, it is not clear if cocaine can exacerbate opioid-induced changes in glutamate signaling. In this study, NAcore GLT-1 protein and glutamate plasticity were measured (via AMPA/NMDA ratio) following SA. Rats acquired SA of both oxycodone and cocaine regardless of sex, and the acute oxycodone-induced increase in somatic signs at 22h was positively correlated with cocaine consumption during the cocaine testing phase. Cocaine use following oxycodone SA downregulated GLT-1 and reduced AMPA/NMDA ratios compared to cocaine use following food SA. Further, oxycodone SA alone was associated with reduced AMPA/NMDA ratio. Together, behavioral signs of oxycodone withdrawal may drive cocaine use and further dysregulate NAcore glutamate signaling.
Topics: Rats; Animals; Cocaine; Oxycodone; Glutamic Acid; Rats, Sprague-Dawley; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Analgesics, Opioid; N-Methylaspartate; Cocaine-Related Disorders; Nucleus Accumbens; Self Administration
PubMed: 37865136
DOI: 10.1016/j.neuropharm.2023.109773 -
Sensors (Basel, Switzerland) Oct 2023Work-related musculoskeletal disorders (WMSDs) are often caused by repetitive lifting, making them a significant concern in occupational health. Although wearable assist...
Work-related musculoskeletal disorders (WMSDs) are often caused by repetitive lifting, making them a significant concern in occupational health. Although wearable assist devices have become the norm for mitigating the risk of back pain, most spinal assist devices still possess a partially rigid structure that impacts the user's comfort and flexibility. This paper addresses this issue by presenting a smart textile-actuated spine assistance robotic exosuit (SARE), which can conform to the back seamlessly without impeding the user's movement and is incredibly lightweight. To detect strain on the spine and to control the smart textile automatically, a soft knitting sensor that utilizes fluid pressure as a sensing element is used. Based on the soft knitting hydraulic sensor, the robotic exosuit can also feature the ability of monitoring and rectifying human posture. The SARE is validated experimentally with human subjects (N = 4). Through wearing the SARE in stoop lifting, the peak electromyography (EMG) signals of the lumbar erector spinae are reduced by 22.8% ± 12 for lifting 5 kg weights and 27.1% ± 14 in empty-handed conditions. Moreover, the integrated EMG decreased by 34.7% ± 11.8 for lifting 5 kg weights and 36% ± 13.3 in empty-handed conditions. In summary, the artificial muscle wearable device represents an anatomical solution to reduce the risk of muscle strain, metabolic energy cost and back pain associated with repetitive lifting tasks.
Topics: Humans; Electromyography; Movement; Posture; Spine; Back Pain; Lifting; Biomechanical Phenomena
PubMed: 37837159
DOI: 10.3390/s23198329 -
Scientific Reports Oct 2023Linguistic experience plays a clear role in accounting for variability in sentence comprehension behavior across individuals and across sentence types. We aimed to...
Linguistic experience plays a clear role in accounting for variability in sentence comprehension behavior across individuals and across sentence types. We aimed to understand how individual differences in reading experience predict reading behavior. Corpus analyses revealed the frequencies with which our experimental items appeared in written and spoken language. We hypothesized that reading experience should affect sentence comprehension most substantially for sentence types that individuals primarily encounter through written language. Readers with more text exposure were faster and more accurate readers overall, but they read sentence types biased to written language particularly faster than did readers with less text exposure. We see clear effects of text exposure on sentence comprehension in ways that allow explicit links between written and spoken corpus statistics and behavior. We discuss theoretical implications of effects of text exposure for experience-based approaches to sentence processing.
Topics: Humans; Comprehension; Individuality; Language; Linguistics; Reading
PubMed: 37798346
DOI: 10.1038/s41598-023-43801-8 -
The Journal of Pediatric Pharmacology... 2023Acute kidney injury (AKI) is a common complication among patients admitted to the neonatal intensive care unit. Nephrotoxic medications (NTMs) are known to increase the...
Acute kidney injury (AKI) is a common complication among patients admitted to the neonatal intensive care unit. Nephrotoxic medications (NTMs) are known to increase the incidence of AKI, but the use of these -medications is often unavoidable. Baby NINJA (Nephrotoxic Injury Negated by Just-in-Time Action) is a -quality improvement (QI) project that may be implemented at individual institutions and aims to systematically identify AKI in neonates and infants receiving NTMs. The purpose of this review is to describe nephrotoxic AKI in the neonatal population, introduce the Baby NINJA QI project and its potential to reduce neonatal AKI, and outline strategies for effective implementation of Baby NINJA.
PubMed: 37795277
DOI: 10.5863/1551-6776-28.4.287 -
Journal of Neurochemistry Nov 2023Tyrosine hydroxylase catalyzes the initial and rate-limiting step in the biosynthesis of the neurotransmitter dopamine. The phosphorylation state of Ser40 and Ser31 is...
Tyrosine hydroxylase catalyzes the initial and rate-limiting step in the biosynthesis of the neurotransmitter dopamine. The phosphorylation state of Ser40 and Ser31 is believed to exert a direct effect on the enzymatic activity of tyrosine hydroxylase. Interestingly, some studies report that Ser31 phosphorylation affects Ser40 phosphorylation, while Ser40 phosphorylation has no effect on Ser31 phosphorylation, a process named hierarchical phosphorylation. Here, we provide a detailed investigation into the signal transduction mechanisms regulating Ser40 and Ser31 phosphorylation in dopaminergic mouse MN9D and Neuro2A cells. We find that cyclic nucleotide signaling drives Ser40 phosphorylation, and that Ser31 phosphorylation is strongly regulated by ERK signaling. Inhibition of ERK1/2 with UO126 or PD98059 reduced Ser31 phosphorylation, but surprisingly had no effect on Ser40 phosphorylation, contradicting a role for Ser31 in the regulation of Ser40. Moreover, to elucidate a possible hierarchical mechanism controlling tyrosine hydroxylase phosphorylation, we introduced tyrosine hydroxylase variants in Neuro2A mouse neuroblastoma cells that mimic either phosphorylated or unphosphorylated serine residues. When we introduced a Ser40Ala tyrosine hydroxylase variant, Ser31 phosphorylation was completely absent. Additionally, neither the tyrosine hydroxylase variant Ser31Asp, nor the variant Ser31Ala had any significant effect on basal Ser40 phosphorylation levels. These results suggest that tyrosine hydroxylase is not controlled by hierarchical phosphorylation in the sense that first Ser31 has to be phosphorylated and subsequently Ser40, but, conversely, that Ser40 phosphorylation is essential for Ser31 phosphorylation. Overall our study suggests that Ser40 is the crucial residue to target so as to modulate tyrosine hydroxylase activity.
PubMed: 37776259
DOI: 10.1111/jnc.15963