Astrocytes close a motor circuit critical period.

Critical periods-brief intervals during which neural circuits can be modified by activity-are necessary for proper neural circuit assembly. Extended critical periods are associated with neurodevelopmental disorders; however, the mechanisms that ensure timely critical period closure remain poorly understood1,2. Here we define a critical period in a developing Drosophila motor circuit and identify astrocytes as essential for proper critical period termination. During the critical period, changes in activity regulate dendrite length, complexity and connectivity of motor neurons. Astrocytes invaded the neuropil just before critical period closure3, and astrocyte ablation prolonged the critical period. Finally, we used a genetic screen to identify astrocyte-motor neuron signalling pathways that close the critical period, including Neuroligin-Neurexin signalling. Reduced signalling destabilized dendritic microtubules, increased dendrite dynamicity and impaired locomotor behaviour, underscoring the importance of critical period closure. Previous work defined astroglia as regulators of plasticity at individual synapses4; we show here that astrocytes also regulate motor circuit critical period closure to ensure proper locomotor behaviour.

Anti-inflammatory effect of Trichospira verticillata via suppression of the NLRP3 inflammasome in neutrophilic asthma.

Trichospira verticillata is an annual herb that belongs to the family Asteraceae. Trichospira verticillata extract (TVE) elicits anti-plasmodial activity; however, there has been no detailed report about its anti-inflammatory effects and molecular mechanisms. In addition, herbal plants exhibit anti-inflammatory effects by suppressing the NLRP3 inflammasome. Therefore, the primary goal of this study was to examine the effects of TVE on NLRP3 inflammasome activation by measuring interleukin-1ß (IL-1ß) secretion. We treated lipopolysaccharides (LPS)-primed J774A.1 and THP-1 cells with TVE, which attenuated NLRP3 inflammasome activation. Notably, TVE did not affect nuclear factor-kappa B (NF-κB) signalling or intracellular reactive oxygen species (ROS) production and potassium efflux, suggesting that it inactivates the NLRP3 inflammasome via other mechanisms. Moreover, TVE suppressed the formation of apoptosis-associated speck-like protein (ASC) speck and oligomerization. Immunoprecipitation data revealed that TVE reduced the binding of NLRP3 to NIMA-related kinase 7 (NEK7), resulting in reduced ASC oligomerization and speck formation. Moreover, TVE alleviated neutrophilic asthma (NA) symptoms in mice. This study demonstrates that TVE modulates the binding of NLPR3 to NEK7, thereby reporting novel insights into the mechanism by which TVE inhibits NLRP3 inflammasome. These findings suggest TVE as a potential therapeutic of NLRP3 inflammasome-mediated diseases, particularly NA.

Hysteresis in phase volumes, compositions and interfacial roughness in model OPV-small-molecule/polymer thin-films.

Domain morphology and composition, and the structure of interfaces between domains are key factors in the performance and stability of organic photovoltaics (OPVs) fabricated from polymer/small-molecule blends. In this study, we investigate the evolution of composition, phase-volume and interfacial roughness in model polymer/small-molecule bilayers, in response to thermal annealing. Polystyrene/fullerene mixing is studied as a function of annealing temperature, using in situ neutron reflectivity, in thin-film bilayer samples comprising pure component or mixed layers. Remarkably, we discover that thermal annealing at temperatures around or above the reported glass transition temperatures, Tg, of the components can result in extensive mass-transfer between layers, that has the superficial appearance of equilibration, but leaves the layer compositions, thicknesses, and/or the interfacial composition profile in a non-equilibrium state. This is not merely a case of slow kinetics near Tg, as subsequent heating to higher temperatures, followed by cooling, reveals pronounced hysteresis in these systems. This has important implications for the measurement of equilibrium compositions in polymer/small-molecule mixtures for OPV applications, and for device stability during operation.

A global map of travel time to cities to assess inequalities in accessibility in 2015.

The economic and man-made resources that sustain human wellbeing are not distributed evenly across the world, but are instead heavily concentrated in cities. Poor access to opportunities and services offered by urban centres (a function of distance, transport infrastructure, and the spatial distribution of cities) is a major barrier to improved livelihoods and overall development. Advancing accessibility worldwide underpins the equity agenda of 'leaving no one behind' established by the Sustainable Development Goals of the United Nations. This has renewed international efforts to accurately measure accessibility and generate a metric that can inform the design and implementation of development policies. The only previous attempt to reliably map accessibility worldwide, which was published nearly a decade ago, predated the baseline for the Sustainable Development Goals and excluded the recent expansion in infrastructure networks, particularly in lower-resource settings. In parallel, new data sources provided by Open Street Map and Google now capture transportation networks with unprecedented detail and precision. Here we develop and validate a map that quantifies travel time to cities for 2015 at a spatial resolution of approximately one by one kilometre by integrating ten global-scale surfaces that characterize factors affecting human movement rates and 13,840 high-density urban centres within an established geospatial-modelling framework. Our results highlight disparities in accessibility relative to wealth as 50.9% of individuals living in low-income settings (concentrated in sub-Saharan Africa) reside within an hour of a city compared to 90.7% of individuals in high-income settings. By further triangulating this map against socioeconomic datasets, we demonstrate how access to urban centres stratifies the economic, educational, and health status of humanity.

Complete tumor necrosis after neoadjuvant chemotherapy defines good responders in patients with Ewing sarcoma.

BACKGROUND: Survival in patients who have Ewing sarcoma is correlated with postchemotherapy response (tumor necrosis). This treatment response has been categorized as the response rate, similar to what has been used in osteosarcoma. There is controversy regarding whether this is appropriate or whether it should be a dichotomy of complete versus incomplete response, given how important a complete response is for in overall survival of patients with Ewing sarcoma. The purpose of this study was to evaluate the impact that the amount of chemotherapy-induced necrosis has on (1) overall survival, (2) local recurrence-free survival, (3) metastasis-free survival, and (4) event-free survival in patients with Ewing sarcoma. METHODS: In total, 427 patients who had Ewing sarcoma or tumors in the Ewing sarcoma family and received treatment with preoperative chemotherapy and surgery at 10 international institutions were included. Multivariate Cox proportional-hazards analyses were used to assess the associations between tumor necrosis and all four outcomes while controlling for clinical factors identified in bivariate analysis, including age, tumor volume, location, surgical margins, metastatic disease at presentation, and preoperative radiotherapy. RESULTS: Patients who had a complete (100%) tumor response to chemotherapy had increased overall survival (hazard ratio [HR], 0.26; 95% CI, 0.14-0.48; p < .01), recurrence-free survival (HR, 0.40; 95% CI, 0.20-0.82; p = .01), metastasis-free survival (HR, 0.27; 95% CI, 0.15-0.46; p ≤ .01), and event-free survival (HR, 0.26; 95% CI, 0.16-0.41; p ≤ .01) compared with patients who had a partial (0%-99%) response. CONCLUSIONS: Complete tumor necrosis should be the index parameter to grade response to treatment as satisfactory in patients with Ewing sarcoma. Any viable tumor in these patients after neoadjuvant treatment should be of oncologic concern. These findings can affect the design of new clinical trials and the risk-stratified application of conventional or novel treatments.

The effects of losartan or angiotensin II receptor antagonists on cartilage: a systematic review.

OBJECTIVE: The aim of this study is to analyze the latest evidence on the effects of losartan or Ang II receptor antagonists on cartilage repair, with a focus on their clinical relevance. DESIGN: The PubMed, Embase, and Cochrane Library databases were searched up to November 12th 2021 to evaluate the effects of losartan or Ang II receptor antagonists on cartilage repair in in vitro studies and in vivo animal studies. Study design, sample characteristics, treatment type, duration, and outcomes were analyzed. The risk of bias and the quality of the eligible studies were assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk of bias assessment tool and Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES). RESULTS: A total of 12 studies were included in this systematic review. Of the 12 eligible studies, two studies were in vitro human studies, three studies were in vitro animal studies, one study was an in vitro human and animal study, and six studies were in vivo animal studies. The risk bias and quality assessments were predominantly classified as moderate. Since meta-analysis was difficult due to differences in treatment type, dosage, route of administration, and method of outcome assessment among the eligible studies, qualitative evaluation was conducted for each study. CONCLUSIONS: Both in vitro and in vivo studies provide evidence to demonstrate beneficial effects of Ang II receptor antagonists on osteoarthritis and cartilage defect models across animal species.

Robust Avoidance of Edge-Localized Modes alongside Gradient Formation in the Negative Triangularity Tokamak Edge.

In a series of high performance diverted discharges on DIII-D, we demonstrate that strong negative triangularity (NT) shaping robustly suppresses all edge-localized mode (ELM) activity over a wide range of plasma conditions: ⟨n⟩=0.1-1.5×10^{20} m^{-3}, P_{aux}=0-15 MW, and |B_{t}|=1-2.2 T, corresponding to P_{loss}/P_{LH08}∼8. The full dataset is consistent with the theoretical prediction that magnetic shear in the NT edge inhibits access to ELMing H-mode regimes; all experimental pressure profiles are found to be at or below the infinite-n ballooning stability limit. Our present dataset also features edge pressure gradients in strong NT that are closer to an H-mode than a typical L-mode plasma, supporting the consideration of NT for reactor design.

Dissolution Potential of Elemental Mercury in the Presence of Bisulfide and Implications for Mobilization.

Liquid elemental mercury (Hg0L) pollution can remain in soils for decades and, over time, will undergo corrosion, a process in which the droplet surface oxidizes soil constituents to form more reactive phases, such as mercury oxide (HgO). While these reactive coatings may enhance Hg migration in the subsurface, little is known about the transformation potential of corroded Hg0L in the presence of reduced inorganic sulfur species to form sparingly soluble HgS particles, a process that enables the long-term sequestration of mercury in soils and generally reduces its mobility and bioavailability. In this study, we investigated the dissolution of corroded Hg0L in the presence of sulfide by quantifying rates of aqueous Hg release from corroded Hg0L droplets under different sulfide concentrations (expressed as the S:Hg molar ratio). For droplets corroded in ambient air, no differences in soluble Hg release were observed among all sulfide exposure levels (S:Hg mole ratios ranging from 10-4 to 10). However, for droplets oxidized in the presence of a more reactive oxidant (hydrogen peroxide, H2O2), we observed a 10- to 25-fold increase in dissolved Hg when the oxidized droplets were exposed to low sulfide concentrations (S:Hg ratios from 10-4 to 10-1) relative to droplets exposed to high sulfide concentrations. These results suggest two critical factors that dictate the release of soluble Hg from Hg0L in the presence of sulfide: the extent of surface corrosion of the Hg0L droplet and sufficient sulfide concentration for the formation of HgS solids. The mobilization of Hg0L in porous media, therefore, largely depends on aging conditions in the subsurface and chemical reactivity at the Hg0L droplet interface.

Novel Foscan®-derived ring-fused chlorins for photodynamic therapy of cancer.

Photodynamic therapy (PDT) is an established anticancer treatment that combines the use of a photosensitiser (PS) and a light source of a specific wavelength for the generation of reactive oxygen species (ROS) that are toxic to the tumour cells. Foscan® (mTHPC) is a clinically-approved chlorin used for the PDT treatment of advanced head and neck, prostate and pancreatic cancers but is characterized by being photochemically unstable and associated with prolonged skin photosensitivity. Herein, we report the synthesis of new 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins, having the meso-tetra(3-hydroxyphenyl)macrocycle core of mTHPC, by exploring the [8π + 2π] cycloaddition of a meso-tetra(3-hydroxyphenyl)porphyrin derivative with diazafulvenium methides. These chlorins have photochemical properties similar to Foscan® but are much more photostable. Among the novel compounds, two chlorins with a hydroxymethyl group and its azide derivative present in the 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused system, are promising photodynamic agents with activity in the 100 nM range against triple-negative breast cancer cells and, in the case of azidomethyl chlorin, a safer phototherapeutic index compared to Foscan®.

To BYOD or not: Are device latencies important for bring-your-own-device (BYOD) smartphone cognitive testing?

Studies using remote cognitive testing must make a critical decision: whether to allow participants to use their own devices or to provide participants with a study-specific device. Bring-your-own-device (BYOD) studies have several advantages including increased accessibility, potential for larger sample sizes, and reduced participant burden. However, BYOD studies offer little control over device performance characteristics that could potentially influence results. In particular, response times measured by each device not only include the participant's true response time, but also latencies of the device itself. The present study investigated two prominent sources of device latencies that pose significant risks to data quality: device display output latency and touchscreen input latency. We comprehensively tested 26 popular smartphones ranging in price from < $100 to $1000+ running either Android or iOS to determine if hardware and operating system differences led to appreciable device latency variability. To accomplish this, a custom-built device called the Latency and Timing Assessment Robot (LaTARbot) measured device display output and capacitive touchscreen input latencies. We found considerable variability across smartphones in display and touch latencies which, if unaccounted for, could be misattributed as individual or group differences in response times. Specifically, total device (sum of display and touch) latencies ranged from 35 to 140 ms. We offer recommendations to researchers to increase the precision of data collection and analysis in the context of remote BYOD studies.

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10-8. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.

Litter Commensal Bacteria Can Limit the Horizontal Gene Transfer of Antimicrobial Resistance to Salmonella in Chickens.

Fostering a "balanced" gut microbiome through the administration of beneficial microbes that can competitively exclude pathogens has gained a lot of attention and use in human and animal medicine. However, little is known about how microbes affect the horizontal gene transfer of antimicrobial resistance (AMR). To shed more light on this question, we challenged neonatal broiler chicks raised on reused broiler chicken litter-a complex environment made up of decomposing pine shavings, feces, uric acid, feathers, and feed-with Salmonella enterica serovar Heidelberg (S. Heidelberg), a model pathogen. Neonatal chicks challenged with S. Heidelberg and raised on reused litter were more resistant to S. Heidelberg cecal colonization than chicks grown on fresh litter. Furthermore, chicks grown on reused litter were at a lower risk of colonization with S. Heidelberg strains that encoded AMR on IncI1 plasmids. We used 16S rRNA gene sequencing and shotgun metagenomics to show that the major difference between chicks grown on fresh litter and those grown on reused litter was the microbiome harbored in the litter and ceca. The microbiome of reused litter samples was more uniform and enriched in functional pathways related to the biosynthesis of organic and antimicrobial molecules than that in fresh litter samples. We found that Escherichia coli was the main reservoir of plasmids encoding AMR and that the IncI1 plasmid was maintained at a significantly lower copy per cell in reused litter compared to fresh litter. These findings support the notion that commensal bacteria play an integral role in the horizontal transfer of plasmids encoding AMR to pathogens like Salmonella. IMPORTANCE Antimicrobial resistance spread is a worldwide health challenge, stemming in large part from the ability of microorganisms to share their genetic material through horizontal gene transfer. To address this issue, many countries and international organizations have adopted a One Health approach to curtail the proliferation of antimicrobial-resistant bacteria. This includes the removal and reduction of antibiotics used in food animal production and the development of alternatives to antibiotics. However, there is still a significant knowledge gap in our understanding of how resistance spreads in the absence of antibiotic selection and the role commensal bacteria play in reducing antibiotic resistance transfer. In this study, we show that commensal bacteria play a key role in reducing the horizontal gene transfer of antibiotic resistance to Salmonella, provide the identity of the bacterial species that potentially perform this function in broiler chickens, and also postulate the mechanism involved.

Fecal metabolomics reveals products of dysregulated proteolysis and altered microbial metabolism in obesity-related osteoarthritis.

OBJECTIVE: The objective of this exploratory study was to determine if perturbations in gut microbial composition and the gut metabolome could be linked to individuals with obesity and osteoarthritis (OA). METHODS: Fecal samples were collected from obese individuals diagnosed with radiographic hand plus knee OA (n = 59), defined as involvement of at least 3 joints across both hands, and a Kellgren-Lawrence (KL) grade 2-4 (or total knee replacement) in at least one knee. Controls (n = 33) were without hand OA and with KL grade 0-1 knees. Fecal metabolomes were analyzed by a UHPLC/Q Exactive HFx mass spectrometer. Microbiome composition was determined in fecal samples by 16 S ribosomal RNA amplicon sequencing (rRNA-seq). Stepwise logistic regression models were built to determine microbiome and/or metabolic characteristics of OA. RESULTS: Untargeted metabolomics analysis indicated that OA cases had significantly higher levels of di- and tripeptides and significant perturbations in microbial metabolites including propionic acid, indoles, and other tryptophan metabolites. Pathway analysis revealed several significantly perturbed pathways associated with OA including leukotriene metabolism, amino acid metabolism and fatty acid utilization. Logistic regression models selected metabolites associated with the gut microbiota and leaky gut syndrome as significant predictors of OA status, particularly when combined with the rRNA-seq data. CONCLUSIONS: Adults with obesity and knee plus hand OA have distinct fecal metabolomes characterized by increased products of proteolysis, perturbations in leukotriene metabolism, and changes in microbial metabolites compared with controls. These metabolic perturbations indicate a possible role of dysregulated proteolysis in OA.

Differential Tunneling-Driven and Vibrationally-Induced Reactivity in Isomeric Benzazirines.

Quantum mechanical tunneling of heavy-atoms and vibrational excitation chemistry are unconventional and scarcely explored types of reactivity. Once fully understood, they might bring new avenues to conduct chemical transformations, providing access to a new world of molecules or ways of exquisite reaction control. In this context, we present here the discovery of two isomeric benzazirines exhibiting differential tunneling-driven and vibrationally-induced reactivity, which constitute exceptional results for probing into the nature of these phenomena. The isomeric 6-fluoro- and 2-fluoro-4-hydroxy-2H-benzazirines (3-a and 3'-s) were generated in cryogenic krypton matrices by visible-light irradiation of the corresponding triplet nitrene 3 2-a, which was produced by UV-light irradiation of its azide precursor. The 3'-s was found to be stable under matrix dark conditions, whereas 3-a spontaneously rearranges (τ1/2 ∼64 h at 10 and 20 K) by heavy-atom tunneling to 3 2-a. Near-IR-light irradiation at the first OH stretching overtone frequencies (remote vibrational antenna) of the benzazirines induces the 3'-s ring-expansion reaction to a seven-member cyclic ketenimine, but the 3-a undergoes 2H-azirine ring-opening reaction to triplet nitrene 3 2-a. Computations demonstrate that 3-a and 3'-s have distinct reaction energy profiles, which explain the different experimental results. The spectroscopic direct measurement of the tunneling of 3-a to 3 2-a constitutes a unique example of an observation of a species reacting only by nitrogen tunneling. Moreover, the vibrationally-induced sole activation of the most favorable bond-breaking/bond-forming pathway available for 3-a and 3'-s provides pioneer results regarding the selective nature of such processes.

Phylotranscriptomics of Theaceae: generic-level relationships, reticulation and whole-genome duplication.

BACKGROUND AND AIMS: Theaceae, with three tribes, nine genera and more than 200 species, are of great economic and ecological importance. Recent phylogenetic analyses based on plastomic data resolved the relationships among the three tribes and the intergeneric relationships within two of those tribes. However, generic-level relationships within the largest tribe, Theeae, were not fully resolved. The role of putative whole-genome duplication (WGD) events in the family and possible hybridization events among genera within Theeae also remain to be tested further. METHODS: Transcriptomes or low-depth whole-genome sequencing of 57 species of Theaceae, as well as additional plastome sequence data, were generated. Using a dataset of low-copy nuclear genes, we reconstructed phylogenetic relationships using concatenated, species tree and phylogenetic network approaches. We further conducted molecular dating analyses and inferred possible WGD events by examining the distribution of the number of synonymous substitutions per synonymous site (Ks) for paralogues in each species. For plastid protein-coding sequences , phylogenies were reconstructed for comparison with the results obtained from analysis of the nuclear dataset. RESULTS: Based on the 610 low-copy nuclear genes (858 606 bp in length) investigated, Stewartieae was resolved as sister to the other two tribes. Within Theeae, the Apterosperma-Laplacea clade grouped with Pyrenaria, leaving Camellia and Polyspora as sister. The estimated ages within Theaceae were largely consistent with previous studies based mainly on plastome data. Two reticulation events within Camellia and one between the common ancestor of Gordonia and Schima were found. All members of the tea family shared two WGD events, an older At-γ and a recent Ad-ß; both events were also shared with the outgroups (Diapensiaceae, Pentaphylacaceae, Styracaceae and Symplocaceae). CONCLUSIONS: Our analyses using low-copy nuclear genes improved understanding of phylogenetic relationships at the tribal and generic levels previously proposed based on plastome data, but the phylogenetic position of the Apterosperma-Laplacea clade needs more attention. There is no evidence for extensive intergeneric hybridization within Theeae or for a Theaceae-specific WGD event. Land bridges (e.g. the Bering land bridge) during the Late Oligocene may have permitted the intercontinental plant movements that facilitated the putative ancient introgression between the common ancestor of Gordonia and Schima.

Utility of Diffusive Gradient in Thin-Film Passive Samplers for Predicting Mercury Methylation Potential and Bioaccumulation in Freshwater Wetlands.

Mercury is a risk in aquatic ecosystems when the metal is converted to methylmercury (MeHg) and subsequently bioaccumulates in aquatic food webs. This risk can be difficult to manage because of the complexity of biogeochemical processes for mercury and the need for accessible techniques to navigate this complexity. Here, we explored the use of diffusive gradient in thin-film (DGT) passive samplers as a tool to simultaneously quantify the methylation potential of inorganic Hg (IHg) and the bioaccumulation potential of MeHg in freshwater wetlands. Outdoor freshwater wetland mesocosms were amended with four isotopically labeled and geochemically relevant IHg forms that represent a range of methylation potentials (202Hg2+, 201Hg-humic acid, 199Hg-sorbed to FeS, and 200HgS nanoparticles). Six weeks after the spikes, we deployed DGT samplers in the mesocosm water and sediments, evaluated DGT-uptake rates of total Hg, MeHg, and IHg (calculated by difference) for the Hg isotope spikes, and examined correlations with total Hg, MeHg, and IHg concentrations in sediment, water, and micro and macrofauna in the ecosystem. In the sediments, we observed greater relative MeHg concentrations from the initially dissolved IHg isotope spikes and lower MeHg levels from the initially particulate IHg spikes. These trends were consistent with uptake flux of IHg into DGTs deployed in surface sediments. Moreover, we observed correlations between total Hg-DGT uptake flux and MeHg levels in periphyton biofilms, submergent plant stems, snails, and mosquitofish in the ecosystem. These correlations were better for DGTs deployed in the water column compared to DGTs in the sediments, suggesting the importance of vertical distribution of bioavailable MeHg in relation to food sources for macrofauna. Overall, these results demonstrate that DGT passive samplers are a relatively simple and efficient tool for predicting IHg methylation and MeHg bioaccumulation potentials without the need to explicitly delineate IHg and MeHg speciation and partitioning in complex ecosystems.

Reinfection by the SARS-CoV-2 Gamma variant in blood donors in Manaus, Brazil.

BACKGROUND: The city of Manaus, north Brazil, was stricken by a second epidemic wave of SARS-CoV-2 despite high seroprevalence estimates, coinciding with the emergence of the Gamma (P.1) variant. Reinfections were postulated as a partial explanation for the second surge. However, accurate calculation of reinfection rates is difficult when stringent criteria as two time-separated RT-PCR tests and/or genome sequencing are required. To estimate the proportion of reinfections caused by Gamma during the second wave in Manaus and the protection conferred by previous infection, we identified anti-SARS-CoV-2 antibody boosting in repeat blood donors as a mean to infer reinfection. METHODS: We tested serial blood samples from unvaccinated repeat blood donors in Manaus for the presence of anti-SARS-CoV-2 IgG antibodies using two assays that display waning in early convalescence, enabling the detection of reinfection-induced boosting. Donors were required to have three or more donations, being at least one during each epidemic wave. We propose a strict serological definition of reinfection (reactivity boosting following waning like a V-shaped curve in both assays or three spaced boostings), probable (two separate boosting events) and possible (reinfection detected by only one assay) reinfections. The serial samples were used to divide donors into six groups defined based on the inferred sequence of infection and reinfection with non-Gamma and Gamma variants. RESULTS: From 3655 repeat blood donors, 238 met all inclusion criteria, and 223 had enough residual sample volume to perform both serological assays. We found 13.6% (95% CI 7.0-24.5%) of all presumed Gamma infections that were observed in 2021 were reinfections. If we also include cases of probable or possible reinfections, these percentages increase respectively to 22.7% (95% CI 14.3-34.2%) and 39.3% (95% CI 29.5-50.0%). Previous infection conferred a protection against reinfection of 85.3% (95% CI 71.3-92.7%), decreasing to respectively 72.5% (95% CI 54.7-83.6%) and 39.5% (95% CI 14.1-57.8%) if probable and possible reinfections are included. CONCLUSIONS: Reinfection by Gamma is common and may play a significant role in epidemics where Gamma is prevalent, highlighting the continued threat variants of concern pose even to settings previously hit by substantial epidemics.

Photochromism of a Spiropyran in Low-Temperature Matrices: Unprecedented Bidirectional Switching between a Merocyanine and an Allene Intermediate.

Photochromism of spiropyrans has attracted much attention due to its potential in many light-controlled system applications. However, several fundamental aspects regarding the structure, energetics, and mechanistic details of the transformations of spiropyrans are still not well understood. Here, we report the study of the photochromism of a 6-hydroxy-spiropyran (HBPS) under conditions of matrix isolation, where monomers of the compound are frozen in a solidified noble gas (krypton, at 15 K). The structure of the matrix-isolated HBPS was first elucidated by infrared (IR) spectroscopy supported by density functional theory computations. Then, the photochromism of HBPS, from the colorless spiropyran to the colored merocyanine, was induced by ultraviolet (UV) irradiation at 310 nm. The analysis of the IR spectrum of the photoproduced species revealed the exclusive formation of the most stable merocyanine MC-TTC stereoisomer. Subsequent visible-light (550 nm) irradiation of MC-TTC generated a new colorless allenic isomeric species ALN, where the UV irradiation (310 nm) of ALN was found to convert this species back to MC-TTC. This constitutes an unprecedented bidirectional transformation between a colored merocyanine and a colorless allene species. The newly observed photoswitching reaction (or photochromism) occurs along an intramolecular hydrogen bond existing in both merocyanine and allenic species, thus suggesting that it might be generally feasible in the chemistry of spiropyrans. On the other hand, the usual assumption that, as a general rule, merocyanines photochemically revert to spiropyrans is not supported in this work.

The COVID-19 pandemic and its consequences for chronic pain: a narrative review.

The COVID-19 pandemic transformed everyday life, but the implications were most impactful for vulnerable populations, including patients with chronic pain. Moreover, persistent pain is increasingly recognised as a key manifestation of long COVID. This narrative review explores the consequences of the COVID-19 pandemic for chronic pain. Publications were identified related to the COVID-19 pandemic influence on the burden of chronic pain, development of new-onset pain because of long COVID with proposed mechanisms and COVID-19 vaccines and pain interventions. Broadly, mechanisms underlying pain due to SARS-CoV-2 infection could be caused by 'systemic inflammatory-immune mechanisms', 'direct neuropathic mechanisms' or 'secondary mechanisms due to the viral infection or treatment'. Existing chronic pain populations were variably impacted and social determinants of health appeared to influence the degree of effect. SARS-CoV-2 infection increased the absolute numbers of patients with pain and headache. In the acute phase, headache as a presenting symptom predicted a milder course. New-onset chronic pain was reportedly common and likely involves multiple mechanisms; however, its prevalence decreases over time and symptoms appear to fluctuate. Patients requiring intensive support were particularly susceptible to long COVID symptoms. Some evidence suggests steroid exposure (often used for pain interventions) may affect vaccine efficacy, but there is no evidence of clinical repercussions to date. Although existing chronic pain management could help with symptomatic relief, there is a need to advance research focusing on mechanism-based treatments within the domain of multidisciplinary care.

Understanding public attitudes to death talk and advance care planning in Northern Ireland using health behaviour change theory: a qualitative study.

OBJECTIVES: Advance care planning is a key preparatory step in ensuring high-quality palliative and end of life care, and should be considered as a process, beginning with community-level conversations among lay persons. There is, however, indication that death talk among community-dwelling adults is not occurring, and there is a dearth of research examining why this is the case. This study aims to provide the first examination of barriers and facilitators to talking about death and dying among the general population in a UK region (Northern Ireland), and to provide a novel application of health behaviour change theory towards developing a theoretical understanding of the sources of this behaviour. METHODS: The study involved qualitative analysis of responses (n = 381 participants) to two open-ended questions within a cross-sectional online survey, with recruitment via social media of adults currently living in Northern Ireland. Reflexive thematic analysis was conducted on open text responses per question, with the barriers and facilitators mapped on to health behaviour change models (the Behaviour Change Wheel COM-B and the Theoretical Domains Framework). RESULTS: The findings evidence a myriad of barriers and facilitators to engaging in death talk, with themes aligning to areas such as lack of acceptance of death in social contexts and fear of upsetting self or others, and a need to improve interpersonal communication skills for facilitating conversations and improve knowledge of the existing services around death and dying. A theoretical understanding of the drivers of death talk is presented with findings mapped across most components of the COM-B Behaviour Change Model and the Theoretical Domains Framework. CONCLUSIONS: This study contributes to a small but emergent research area examining barriers and facilitators to talking about death and dying. Findings from this study can be used to inform new public health programmes towards empowering adults to have these conversations with others in their community towards upstreaming advance care planning.