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Summary: Background: The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We aimed to estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers. Methods: Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated. Findings: 1298 infections were detected among 9560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95% CI 0.9 to 23.8) overall; 24.0% (95% CI 8.5 to 36.8) in the first 2 months post-vaccination, reducing to 10.3% (95% CI −11.4 to 27.8) and 1.7% (95% CI −17.0 to 17.4) at 2–4 and 4–6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95% CI 46.9 to 75.0) and 29.1% (95% CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0–6, and 6–12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection. Interpretation: Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern. Funding: UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, Bristol, and others.

Background Microarray patches (MAPs) deliver vaccines to the epidermis and the upper dermis, where abundant immune cells reside. There are several potential benefits to using MAPs, including reduced sharps risk, thermostability, no need for reconstitution, tolerability and self-administration. We aimed to explore and evaluate the immunogenicity, safety, usability and acceptability of MAPs for vaccination.Methods We searched CINAHL, Cochrane Library, Ovid Embase, Ovid MEDLINE and Web of Science from inception to January 2023. Eligibility criteria included all research studies in any language, which examined microarrays or microneedles intended or used for vaccination and explored immunogenicity, safety, usability or acceptability in their findings. Two reviewers conducted title and abstract screening, full-text reviewing and data extraction.Results Twenty-two studies were included (quantitative=15, qualitative=2 and mixed methods=5). The risk of bias was mostly low, with two studies at high risk of bias. Four clinical trials were included, three using influenza antigens and one with Japanese encephalitis delivered by MAP. A meta-analysis indicated similar or higher immunogenicity in influenza MAPs compared with needle and syringe (N&S) (standardised mean difference=10.80, 95% CI: 3.51 to 18.08, p

Purpose: The purpose of this study was to evaluate the effect of pre-exercise alkalosis, induced via ingestion of sodium bicarbonate, on changes to lactate/pH regulatory proteins and mitochondrial function induced by a sprint-interval exercise session in humans.Methods: On two occasions separated by 1 week, eight active men performed a 3 × 30-s all-out cycling test, interspersed with 20 min of recovery, following either placebo (PLA) or sodium bicarbonate (BIC) ingestion.Results: Blood bicarbonate and pH were elevated at all time points after ingestion in BIC vs PLA (p < 0.05). The protein content of monocarboxylate transporter 1 (MCT1) and basigin (CD147), at 6 h and 24 h post-exercise, and sodium/hydrogen exchanger 1 (NHE1) 24 h post-exercise, were significantly greater in BIC compared to PLA (p < 0.05), whereas monocarboxylate transporter 4 (MCT4), sodium/bicarbonate cotransporter (NBC), and carbonic anhydrase isoform II (CAII) content was unchanged. These increases in protein content in BIC vs. PLA after acute sprint-interval exercise may be associated with altered physiological responses to exercise, such as the higher blood pH and bicarbonate concentration values, and lower exercise-induced oxidative stress observed during recovery (p < 0.05). Additionally, mitochondrial respiration decreased after 24 h of recovery in the BIC condition only, with no changes in oxidative protein content in either condition.Conclusion: These data demonstrate that metabolic alkalosis induces post-exercise increases in several lactate/pH regulatory proteins, and reveal an unexpected role for acidosis in mitigating the loss of mitochondrial respiration caused by exercise in the short term.

Photosynthetically active radiation (PAR) is the 400–700 nm portion of the solar radiation spectrum that photoautotrophic organisms including plants, algae, and cyanobacteria use for photosynthesis. PAR is a key variable in global ecosystem and Earth system modeling, playing a prominent role in carbon and water cycling. Alongside air temperature, water availability, and atmospheric CO2 concentration, PAR controls photosynthesis and consequently biomass productivity in general. The management of agricultural and horticultural crops, forests, grasslands, and even grasses at sports venues is a non-exhaustive list of applications for which an accurate knowledge of the PAR resource is desirable. Modern agrivoltaic systems also require a good knowledge of PAR in conjunction with the variables needed to monitor the co-located photovoltaic system. In situ quality-controlled PAR sensors provide high-quality information for specific locations. However, due to associated installation and maintenance costs, such high-quality data are relatively scarce and generally extend over a restricted and sometimes non-continuous period. Numerous studies have already demonstrated the potential offered by surface radiation estimates based on satellite information as reliable alternatives to in situ measurements. The accuracy of these estimations is site-dependent and is related, for example, to the local climate, landscape, and viewing angle of the satellite. To assess the accuracy of PAR satellite models, we inter-compared 11 methods for estimating 30 min surface PAR based on satellite-derived estimations at 33 ground-based station locations over several climate regions in Europe, Africa, and South America. Averaged across stations, the results showed average relative biases (relative to the measurement mean) across methods of 1 to 20%, an average relative standard deviation of 25 to 30%, an average relative root mean square error of 25% to 35% and a correlation coefficient always above 0.95 for all methods. Improved performance was seen for all methods at relatively cloud-free sites, and quality degraded towards the edge of the Meteosat Second Generation viewing area. A good compromise between computational time, memory allocation, and performance was achieved for most locations using the Jacovides coefficient applied to the global horizontal irradiance from HelioClim-3 or the CAMS Radiation Service. In conclusion, satellite estimations can provide a reliable alternative estimation of ground-based PAR for most applications.

Diabetes complications can be related to the long duration of the disease or chronic hyperglycemia. The follow-up of diabetic patients is based on the control of chronic hyperglycemia, although this correction, if obtained rapidly in people living with severe chronic hyperglycemia, can paradoxically interfere with the disease or even induce complications. We reviewed the literature describing the impact of the rapid and intense treatment of hyperglycemia on diabetic complications. The literature review showed that worsening complications occurred significantly in diabetic microangiopathy with the onset of specific neuropathy induced by the correction of diabetes. The results for macroangiopathy were somewhat mixed with the intensive and rapid correction of chronic hyperglycemia having a neutral impact on stroke and myocardial infarction but a significant increase in cardiovascular mortality. The management of diabetes has now entered a new era with new therapeutic molecules, such as gliflozin for patients living with type 2 diabetes, or hybrid insulin delivery systems for patients with insulin-treated diabetes. Our manuscript provides evidence in support of these personalized and progressive algorithms for the control of chronic hyperglycemia.

Introduction: Genes encoding catechol-O-methyl-transferase (COMT) and adenosine A2A receptor (ADORA2A) have been shown to influence cognitive performances and responses to caffeine intake during prolonged wakefulness. The rs4680 single-nucleotide polymorphism (SNP) of COMT differentiates on memory score and circulating levels of the neurotrophic factor IGF-1. This study aimed to determine the kinetics of IGF-1, testosterone, and cortisol concentrations during prolonged wakefulness under caffeine or placebo intake in 37 healthy participants, and to analyze whether the responses are dependent on COMT rs4680 or ADORA2A rs5751876 SNPs. Methods: In caffeine (2.5 mg/kg, twice over 24 h) or placebo-controlled condition, blood sampling was performed at 1 h (08:00, baseline), 11 h, 13 h, 25 h (08:00 next day), 35 h, and 37 h of prolonged wakefulness, and at 08:00 after one night of recovery sleep, to assess hormonal concentrations. Genotyping was performed on blood cells. Results: Results indicated a significant increase in IGF-1 levels after 25, 35, and 37 h of prolonged wakefulness in the placebo condition, in subjects carrying the homozygous COMT A/A genotype only (expressed in absolute values [±SEM]: 118 ± 8, 121 ± 10, and 121 ± 10 vs. 105 ± 7 ng/mL for A/A, 127 ± 11, 128 ± 12, and 129 ± 13 vs. 120 ± 11 ng/mL for G/G, and 106 ± 9, 110 ± 10, and 106 ± 10 vs. 101 ± 8 ng/mL for G/A, after 25, 35, and 37 h of wakefulness versus 1 h; p < 0.05, condition X time X SNP). Acute caffeine intake exerted a COMT genotype-dependent reducing effect on IGF-1 kinetic response (104 ± 26, 107 ± 27, and 106 ± 26 vs. 100 ± 25 ng/mL for A/A genotype, at 25, 35, and 37 h of wakefulness vs. 1 h; p < 0.05 condition X time X SNP), plus on resting levels after overnight recovery (102 ± 5 vs. 113 ± 6 ng/mL) (p < 0.05, condition X SNP). Testosterone and cortisol concentrations decreased during wakefulness, and caffeine alleviated the testosterone reduction, unrelated to the COMT polymorphism. No significant main effect of the ADORA2A SNP was shown regardless of hormonal responses. Conclusion: Our results indicated that the COMT polymorphism interaction is important in determining the IGF-1 neurotrophic response to sleep deprivation with caffeine intake (NCT03859882).

Summary: We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.

The RANKL-GLYC study aims to explore the impact of the rapid correction of chronic hyperglycemia on the receptor activator of nuclear factor-kappa B ligand (RANKL) and its antagonist osteoprotegerin (OPG). RANKL and OPG are considered the main factors in the pathophysiology of Charcot neuroarthropathy, a devastating complication of the joints that remains poorly understood. The study began recruiting patients in September 2021 and ends in June 2022; the final study results are scheduled for January 2023.

Microtubules are cytoskeletal polymers whose function depends on their property to switch between states of growth and shrinkage. Growing microtubules are thought to be stabilized by a GTP cap at their ends. The nature of this cap, however, is still poorly understood. End Binding proteins (EBs) recruit a diverse range of regulators of microtubule function to growing microtubule ends. Whether the EB binding region is identical to the GTP cap is unclear. Using mutated human tubulin with blocked GTP hydrolysis, we demonstrate that EBs bind with high affinity to the GTP conformation of microtubules. Slowing-down GTP hydrolysis leads to extended GTP caps. We find that cap length determines microtubule stability and that the microtubule conformation changes gradually in the cap as GTP is hydrolyzed. These results demonstrate the critical importance of the kinetics of GTP hydrolysis for microtubule stability and establish that the GTP cap coincides with the EB-binding region.

The extent to which global legal systems are generated by, derived from, and adhere to European values is so widespread that it has become trite to present such an observation in conclusion to a series of high-quality essays as contained in this Special Issue [...]

Several genetic polymorphisms differentiate between healthy individuals who are more cognitively vulnerable or resistant during total sleep deprivation (TSD). Common metrics of cognitive functioning for classifying vulnerable and resilient individuals include the Psychomotor Vigilance Test (PVT), Go/noGo executive inhibition task, and subjective daytime sleepiness. We evaluated the influence of 14 single-nucleotide polymorphisms (SNPs) on cognitive responses during total sleep deprivation (continuous wakefulness for 38 h) in 47 healthy subjects (age 37.0 ± 1.1 years). SNPs selected after a literature review included SNPs of the adenosine-A2A receptor gene (including the most studied rs5751876), pro-inflammatory cytokines (TNF-α, IL1-β, IL-6), catechol-O-methyl-transferase (COMT), and PER3. Subjects performed a psychomotor vigilance test (PVT) and a Go/noGo-inhibition task, and completed the Karolinska Sleepiness Scale (KSS) every 6 h during TSD. For PVT lapses (reaction time >500 ms), an interaction between SNP and SDT (p < 0.05) was observed for ADORA2A (rs5751862 and rs2236624) and TNF-α (rs1800629). During TSD, carriers of the A allele for ADORA2A (rs5751862) and TNF-α were significantly more impaired for cognitive responses than their respective ancestral G/G genotypes. Carriers of the ancestral G/G genotype of ADORA2A rs5751862 were found to be very similar to the most resilient subjects for PVT lapses and Go/noGo commission errors. Carriers of the ancestral G/G genotype of COMT were close to the most vulnerable subjects. ADORA2A (rs5751862) was significantly associated with COMT (rs4680) (p = 0.001). In conclusion, we show that genetic polymorphisms in ADORA2A (rs5751862), TNF-α (rs1800629), and COMT (rs4680) are involved in creating profiles of high vulnerability or high resilience to sleep deprivation. (NCT03859882).

History of present illness: A 45-year-old male presented to the emergency department with chief complaint of left ear pain with yellow discharge for several days. He had associated decrease in appetite. The patient denied any history of fever, headache, dizziness, hearing loss, or tinnitus. On physical exam, the patient was found to have yellow discharge in the left ear canal with a perforated tympanic membrane. He was also found to have significant tenderness to palpation over the left mastoid bone. Significant findings: The patient underwent computed tomography (CT) of the head which revealed opacification of the left middle ear (red arrow) and mastoid air cells (red circles). Additionally, there was thickening of the soft tissues of the external auditory canal (blue arrowhead), likely reflecting concurrent otitis externa. Based on the imaging, he was admitted for findings consistent with acute otomastoiditis. Discussion: Mastoiditis is an infection of the mastoid air cells of the temporal bone often secondary to undertreated or untreated otitis media. On CT, purulent material and mucosal swelling cause opacification of the air cells, as seen in this patient.1 The inflammation can erode into the mastoid septae causing acute coalescent otomastoiditis. Mastoiditis can invade intracranially leading to sigmoid sinus thrombosis, perisinus empyema, epidural abscess, subdural abscess or meningitis.1 Presentation of mastoiditis includes fever, otalgia and otorrhea. Patients may also have erythema and swelling overlying the mastoid process.2 Most patients presenting with acute mastoiditis will require hospital admission for intravenous (IV) antibiotics. Antibiotics should cover the common causative agents of otitis media including H influenzae, M catarrhalis, S pneumoniae as well as S aureus. Mastoidectomy is reserved for cases where medical management fails.3 In the antibiotic era, the incidence of clinically significant acute mastoiditis has decreased to 1.2-2 per 100,000.2 However, it is important to recognize that acute mastoiditis may present with severe intracranial complications resulting in significant morbidity and mortality.3 Therefore, patients with suspected mastoiditis should receive a thorough physical examand cranial imaging studies to evaluate for bone erosion and other sequelae.4 The patient in this case remained afebrile without leukocytosis throughout hospitalization. A final blood culture yielded gram positive cocci, gram negative cocci, gram positive rods and methicillin resistant staph aureus with Clindamycin susceptibility. The otolaryngologist (ENT) started the patient on IV ceftriaxone and IV clindamycin for 72 hours. He was discharged with ENT follow-up on an oral regimen of clindamycin and cefuroxime for two weeks. He was also administered ofloxacin otic solution throughout his hospitalization and at discharge. Topics: Mastoiditis, otomastoiditis, otitis externa, CT

The HelioClim-1 database contains daily values of the solar radiation reaching the ground. This GEOSS (Global Earth Observation System of Systems) Data Collection of Open Resources for Everyone (Data-CORE) covers Europe, Africa and the Atlantic Ocean, from 1985 to 2005. It is freely accessible at no cost through the SoDa Service (www.soda-is.com). Several assessments of the HelioClim-1 data against measurements made in meteorological networks reveal that the HelioClim-1 database offers a reliable and accurate knowledge of the solar radiation and its daily, seasonal and annual variations over recent years. The HelioClim-1 data may help in qualifying in situ measurements and may supplement them, thus offering 21 years of accurate daily means of surface solar irradiance. Several published works benefited from openness, availability and accuracy of the HelioClim-1 database in various domains: oceanography, climate, energy production, life cycle analysis, agriculture, forestry, architecture, health and air quality. This demonstration of the benefit of the HelioClim-1 database draws attention to resources open to everyone such as those labeled GEOSS Data-CORE.

Several sectors need global horizontal irradiance (GHI) data for various purposes. However, the availability of a long-term time series of high quality in situ GHI measurements is limited. Therefore, several studies have tried to estimate GHI by re-analysing climate data or satellite images. Validation is essential for the later use of GHI data in the regions with a scarcity of ground-recorded data. This study contributes to previous studies that have been carried out in the past to validate HelioClim-3 version 5 (HC3v5) and the Copernicus Atmosphere Monitoring Service, using radiation service version 3 (CRSv3) data of hourly GHI from satellite-derived datasets (SDD) with nine ground stations in northeast Iraq, which have not been used previously. The validation is carried out with station data at the pixel locations and two other data points in the vicinity of each station, which is something that is rarely seen in the literature. The temporal and spatial trends of the ground data are well captured by the two SDDs. Correlation ranges from 0.94 to 0.97 in all-sky and clear-sky conditions in most cases, while for cloudy-sky conditions, it is between 0.51–0.72 and 0.82–0.89 for the clearness index. The bias is negative for most of the cases, except for three positive cases. It ranges from −7% to 4%, and −8% to 3% for the all-sky and clear-sky conditions, respectively. For cloudy-sky conditions, the bias is positive, and differs from one station to another, from 16% to 85%. The root mean square error (RMSE) ranges between 12–20% and 8–12% for all-sky and clear-sky conditions, respectively. In contrast, the RMSE range is significantly higher in cloudy-sky conditions: above 56%. The bias and RMSE for the clearness index are nearly the same as those for the GHI for all-sky conditions. The spatial variability of hourly GHI SDD differs only by 2%, depending on the station location compared to the data points around each station. The variability of two SDDs is quite similar to the ground data, based on the mean and standard deviation of hourly GHI in a month. Having station data at different timescales and the small number of stations with GHI records in the region are the main limitations of this analysis.

Kidins220/ARMS is a transmembrane protein playing a crucial role in neuronal and cardiovascular development. Kidins220/ARMS is a downstream target of neurotrophin receptors and interacts with several signalling and trafficking factors. Through computational modelling, we found two potential sites for alternative splicing of Kidins220/ARMS. The first is located between exon 24 and exon 29, while the second site replaces exon 32 by a short alternative terminal exon 33. Here we describe the conserved occurrence of several Kidins220/ARMS splice isoforms at RNA and protein levels. Kidins220/ARMS splice isoforms display spatio-temporal regulation during development with distinct patterns in different neuronal populations. Neurotrophin receptor stimulation in cortical and hippocampal neurons and neuroendocrine cells induces specific Kidins220/ARMS splice isoforms and alters the appearance kinetics of the full-length transcript. Remarkably, alternative terminal exon splicing generates Kidins220/ARMS variants with distinct cellular localisation: Kidins220/ARMS containing exon 32 is targeted to the plasma membrane and neurite tips, whereas Kidins220/ARMS without exon 33 mainly clusters the full-length protein in a perinuclear intracellular compartment in PC12 cells and primary neurons, leading to a change in neurotrophin receptor expression. Overall, this study demonstrates the existence of novel Kidins220/ARMS splice isoforms with unique properties, revealing additional complexity in the functional regulation of neurotrophin receptors, and potentially other signalling pathways involved in neuronal and cardiovascular development.

Cet article présente les travaux que nous avons menés ces dernières années autour de l'analyse d'images Météosat Seconde Génération (MSG). Comparés à la première génération, les données MSG possèdent une résolution spatiale et temporelle plus élevée, autorisant l'accès à un certain nombre d'informations liées aux phénomènes climatiques observés. Cependant, l'étape consistant à remonter à cette information physique à partir des données images s'avère délicate car nous sommes confrontés à des structures soumises à de très fortes déformations, parfois observées en transparence et avec une durée de vie variable. Par conséquent, les outils classiques issus de l'analyse d'images se révèlent souvent limités et il est nécessaire de les adapter à cette spécificité. Nous nous focalisons ici sur trois applications particulières : l'estimation du mouvement, permettant de remonter aux vents atmosphériques, le suivi de masses nuageuses, autorisant par exemple l'analyse de phénomènes convectifs et la détection de fronts, appliquée ici aux brises de mer.

To investigate the effects of fatigue and metabolite accumulation on the postexercicse parasympathetic reactivation, 11 long-sprint runners performed on an outdoor track an exhaustive 400 m long sprint event and a 300 m with the same 400 m pacing strategy. Time constant of heart rate recovery (HRR𝜏), time (RMSSD), and frequency (HF, and LF) varying vagal-related heart rate variability indexes were assessed during the 7 min period immediately following exercise. Biochemical parameters (blood lactate, pH, PO2, PCO2, SaO2, and HCO3−) were measured at 1, 4 and 7 min after exercise. Time to perform 300 m was not significantly different between both running trials. HHR𝜏 measured after the 400 m running exercise was longer compared to 300 m running bouts (183.7±11.6 versus 132.1±9.8 s, 𝑃

We have developed a multivariate and multidisciplinary lab experiment on the synthesis of alginate hydrogel beads of various sizes and dye encapsulation for upper-division undergraduate and graduate students. This experiment introduces students to several common concepts in polymer chemistry, materials science, and drug delivery. The experiment series runs over two 3-h laboratories where students first synthesize alginate beads by dropwise addition of an alginate solution into aqueous CaCl2. The alginate bead size is regulated physically via the dropper opening and chemically via cross-linking ion variation, cross-linking time, and surfactant. During the second lab session, students explore the effects of bead size and solution environment on the gel's loading capacity, encapsulation efficiency, and controlled release using a model dye. Finally, students present their results, methodology, and data analysis to the class. A report and an exam allow the students to demonstrate their knowledge. Students learn critical drug delivery concepts throughout the project, including controlling particle size, loading capacity, and encapsulation efficiency. They also acquire valuable insight into the applications of gel particles and standard techniques used in industrial and academic research. The developed lab experience includes experiments of varying difficulty and can be adapted to first- and second-year undergraduate students by simplifying the suggested laboratory procedures.

Repeating the title and bibliographic info here: I The Freelance Editor's Handbook: A Complete Guide to Making Your Business Thrive i , by Suzy Bills in consultation with Aaron Ostler (U of Calif. Something along the lines of "Freelance Experienced Copy Editor and Proofreader Improving Accuracy and Turnaround Times" (eighty-nine characters) or "Freelance Experienced Copy Editor Focusing on Clarity and Concision" (sixty-six characters). Unlike a certain European book reviewer - whose name and nationality here will go unmentioned - who claimed never to have read a book that he (or she) had been assigned to review on the grounds that doing so might jeopardize his (or her) objectivity, let me immediately place my book reviewing credibility on the line by establishing two relevant points, to wit: I am one of those individuals who must read (and at times reread) every word of any book I review before feeling comfortable about putting my thoughts about it on paper and - I will be frank - I wish that I had had the opportunity to read Suzy Bills's I The Freelance Editor's Handbook: A Complete Guide to Making Your Business Thrive i (or some of its many comprehensive insights) years ago. [Extracted from the article]