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Purpose: The aim of this study is to establish which specific cognitive abilities are phenotypically related to reading skill in adolescence and determine whether this phenotypic correlation is explained by polygenetic overlap. Method: In an Australian population sample of twins and non-twin siblings of European ancestry (734 [less than or equal to] N [less than or equal to] 1542 [50.7% < F < 66%], mean age = 16.7, range = 11-28 years) from the Brisbane Adolescent Twin Study, mixed-effects models were used to test the association between a dyslexia polygenic score (based on genome-wide association results from a study of 51,800 dyslexics versus >1 million controls) and quantitative cognitive measures. The variance in the cognitive measure explained by the polygenic score was compared to that explained by a reading difficulties phenotype (scores that were lower than 1.5 SD below the mean reading skill) to derive the proportion of the association due to genetic influences. Results: The strongest phenotypic correlations were between poor reading and verbal tests R[superscript 2] up to 6.2%); visuo-spatial working memory was the only measure that did not show association with poor reading. Dyslexia polygenic scores could completely explain the phenotypic covariance between poor reading and most working memory tasks and were most predictive of performance on a test of arithmetic (R[superscript 2] = 2.9%). Conclusion: Shared genetic pathways are thus highlighted for the commonly found association between reading and mathematics abilities, and for the verbal short-term/working memory deficits often observed in dyslexia.

Abstract Polarized exocytosis induced by local Cdc42 GTPase activity results in membrane flows that deplete low-mobility membrane-associated proteins. A reaction-diffusion particle model comprising Cdc42 positive feedback activation, hydrolysis by GTPase-activating proteins (GAPs), and flow-induced displacement by exo/endocytosis shows that flow-induced depletion of low mobility GAPs promotes polarization. We modified Cdc42 mobility in Schizosaccharomyces pombe by replacing its prenylation site with 1, 2 or 3 repeats of the Rit C-terminal membrane-binding domain (ritC), yielding alleles with progressively lower mobility and increased flow-coupling. While Cdc42-1ritC cells are viable and polarized, Cdc42-2ritC polarize poorly and Cdc42-3ritC are inviable, in agreement with model’s predictions. Deletion of Cdc42 GAPs restores viability to Cdc42-3ritC cells, verifying the model’s prediction that GAP deletion increases Cdc42 activity at the expense of polarization. Our work demonstrates how membrane flows are an integral part of Cdc42-driven pattern formation and require Cdc42-GTP to turn over faster than the surface on which it forms.

Abstract Background A range of strategies are available that can improve the outcomes of older persons particularly in relation to basic activities of daily living during and after an acute care (AC) episode. This paper outlines the original development of outcome-oriented quality indicators (QIs) in relation to common geriatric syndromes and function for the care of the frail aged hospitalized in acute general medical wards. Methods Design QIs were developed using evidence from literature, expert opinion, field study data and a formal voting process. A systematic literature review of literature identified existing QIs (there were no outcome QIs) and evidence of interventions that improve older persons’ outcomes in AC. Preliminary indicators were developed by two expert panels following consideration of the evidence. After analysis of the data from field testing (indicator prevalence, variability across sites), panel meetings refined the QIs prior to a formal voting process. Setting Data was collected in nine Australian general medical wards. Participants Patients aged 70 years and over, consented within 24 h of admission to the AC ward. Measurements The interRAI Acute Care – Comprehensive Geriatric Assessment (interRAI AC-CGA) was administered at admission and discharge; a daily risk assessment in hospital; 28-day phone follow-up and chart audit. Results Ten outcome QIs were established which focused on common geriatric syndromes and function for the care of the frail aged hospitalized in acute general medical wards. Conclusion Ten outcome QIs were developed. These QIs can be used to identify areas where specific action will lead to improvements in the quality of care delivered to older persons in hospital.

Confinement facilities are high-risk settings for the spread of infectious disease, necessitating timely surveillance to inform public health action. To identify jail-associated COVID-19 cases from electronic laboratory reports maintained in the Minnesota Electronic Disease Surveillance System (MEDSS), Minnesota, USA, the Minnesota Department of Health developed a surveillance system that used keyword and address matching (KAM). The KAM system used a SAS program (SAS Institute Inc., https://www.sas.com) and an automated program within MEDSS to identify confinement keywords and addresses. To evaluate KAM, we matched jail booking data from the Minnesota Statewide Supervision System by full name and birthdate to the MEDSS records of adults with COVID-19 for 2022. The KAM system identified 2,212 cases in persons detained in jail; sensitivity was 92.40% and specificity was 99.95%. The success of KAM demonstrates its potential to be applied to other diseases and congregate-living settings for real-time surveillance without added reporting burden.

Abstract DNA methylation is an ideal trait to study the extent of the shared genetic control across ancestries, effectively providing hundreds of thousands of model molecular traits with large QTL effect sizes. We investigate cis DNAm QTLs in three European (n = 3701) and two East Asian (n = 2099) cohorts to quantify the similarities and differences in the genetic architecture across populations. We observe 80,394 associated mQTLs (62.2% of DNAm probes with significant mQTL) to be significant in both ancestries, while 28,925 mQTLs (22.4%) are identified in only a single ancestry. mQTL effect sizes are highly conserved across populations, with differences in mQTL discovery likely due to differences in allele frequency of associated variants and differing linkage disequilibrium between causal variants and assayed SNPs. This study highlights the overall similarity of genetic control across ancestries and the value of ancestral diversity in increasing the power to detect associations and enhancing fine mapping resolution.

Sumas Lake (Xhotsa), located in the Fraser Valley, British Columbia, Canada, was the heart of Semá:th Nation Territory and the epicenter of a complex Indigenous food system. For the Semá:th people, the lake represented life and livelihood. In 1924, the lake was stolen and drained in an instance of land theft that occurred during a nationwide campaign of land dispossession and genocide, decimating an ecology that supported a rich and diverse Indigenous food system and replacing it with a settler food system. A century later, in November 2021 climate change induced flooding caused the lake to return, resulting in the evacuation of thousands of people and causing millions in damages to homes and infrastructure. Since the flood, the response has been a continuation of the status quo to protect settler agricultural lands via increased investment in hard structures that control the flow of water based on assumptions of the predictability of future flow conditions. We offer a missing narrative by bringing together an analysis of Indigenous laws and oral tradition with an assessment of the economic costs of “managed retreat”, defined as the purposeful relocation of people and infrastructure out of harm’s way. We find that the cost of buying out properties in the lakebed and allowing the lake to return is close to half the cost ($1 billion) of maintaining the status quo ($2.4 billion), while facilitating climate adaptation, and restoration of a floodplain ecosystem that supported thriving populations of people, salmon, sturgeon, ducks, and food and medicinal plants– including many species which are now endangered. Returning Sumas Lake by centering ‘Water Back’ as a climate resiliency solution, enacts both food systems and ecological reconciliation, addressing the harms caused by the loss of the lake to the Semá:th People that is still felt to this day. In a time when climate change induced flooding is predicted to increase, this study demonstrates how the inclusion of Indigenous laws and knowledges are critical to the development of solutions toward a more sustainable and just future.

The purpose of this document is to provide an identification guide for Cannabis sativa to be used by growers and land managers by showing key factors to distinguish it from similar-looking plants. The general public and aspiring botanists may also use this document to see how a plant is defined botanically and how those characteristics can distinguish a plant of interest from other look-alike plants. Written by Cliff G. Martin and Zachary T. Brym, and published by the UF/IFAS Agronomy Department, March 2024.

Abstract Background Mucus plugs have been described in the airways of asthmatic subjects, particularly those with associated with type 2 inflammation and sputum eosinophilia. In the current study we addressed the question of whether smoking, neutrophilic inflammation and airway dimensions affected the prevalence of mucus plugs. Methods In a cohort of moderate to severe asthmatics (n = 50), including a group of ex-smokers and current smokers, the prevalence of mucus plugs was quantified using a semi-quantitative score based on thoracic computerized tomography. The relationships between mucus score, sputum inflammatory profile and airway architecture were tested according to patient’s smoking status. Results Among the asthmatics (37% former or active smokers), 74% had at least one mucus plug. The median score was 3 and was unrelated to smoking status. A significant but weak correlation was found between mucus score, FEV1 and FEV1/FVC. Mucus score was significantly correlated with sputum eosinophils. Among former and active smokers, mucus score was correlated with sputum neutrophils. Mucus score was positively associated with FeNO in non-smoking subjects. The lumen dimensions of the main and lobar bronchi were significantly inversely correlated with mucus score. Conclusion Airway mucus plugs could define an asthma phenotype with altered airway architecture and can occur in asthmatic subjects with either neutrophilic or eosinophilic sputum according to their smoking status.

Abstract To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Abstract X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

Advances in high-throughput technologies have enhanced our ability to describe microbial communities as they relate to human health and disease. Alongside the growth in sequencing data has come an influx of resources that synthesize knowledge surrounding microbial traits, functions, and metabolic potential with knowledge of how they may impact host pathways to influence disease phenotypes. These knowledge bases can enable the development of mechanistic explanations that may underlie correlations detected between microbial communities and disease. In this review, we survey existing resources and methodologies for the computational integration of broad classes of microbial and host knowledge. We evaluate these knowledge bases in their access methods, content, and source characteristics. We discuss challenges of the creation and utilization of knowledge bases including inconsistency of nomenclature assignment of taxa and metabolites across sources, whether the biological entities represented are rooted in ontologies or taxonomies, and how the structure and accessibility limit the diversity of applications and user types. We make this information available in a code and data repository at: https://github.com/lozuponelab/knowledge-source-mappings. Addressing these challenges will allow for the development of more effective tools for drawing from abundant knowledge to find new insights into microbial mechanisms in disease by fostering a systematic and unbiased exploration of existing information.

PurposeTo investigate heat stress mitigation strategies on productivity and thermoregulatory responses during simulated occupational work in the heat.MethodsThirteen physically active men (age, 25 ± 4 years; body mass,77.8 ± 14.7 kg; VO2peak, 44.5 ± 9.2 ml·kg−1·min−1) completed five randomized-controlled trials in a hot environment (40°C, 40% relative humidity). Each trial was 4.5 h in duration to simulate an outdoor occupational shift. Thermoregulatory responses (heart rate, HR; rectal temperature, Trec; mean skin temperature, Tsk), perceptual responses (rating of perceived exertion, RPE; thermal sensation; thermal comfort; fatigue) and productivity outcomes (box lifting repetitions, time to exhaustion) were examined in the following heat mitigation strategy interventions: (1) simulated solar radiation with limited fluid intake [SUN]; (2) simulated solar radiation with no fluid restrictions [SUN + H2O]; (3) shade (no simulated solar radiation during trial) with no fluid restrictions [SHADE + H2O]; (4) shade and cooling towels during rest breaks with no fluid restrictions [COOL + H2O]; and (5) shade with cooling towels, cooling vest during activity with no fluid restrictions [COOL + VEST + H2O].Results[COOL + VEST + H2O] had lower Trec compared to [SUN] [p = 0.004, effect size(ES) = 1.48], [SUN + H2O] (p 0.05).ConclusionOur results suggest that during a simulated occupational shift in a laboratory setting, additional heat mitigation strategies ([COOL + VEST + H2O] and [COOL + H2O]) reduced physiological strain and improved box lifting performance to a greater degree than [SUN]. These differences may have been attributed to a larger core to skin temperature gradient or reduction in fatigue, thermal sensation, and RPE during [COOL + H2O] and [COOL + VEST + H2O]. These data suggest that body cooling, hydration, and “shade” (removal of simulated radiant heat) as heat stress mitigation strategies should be considered as it reduces physiological strain while producing no additional harm.

The dominant mechanism for generating free-floating planets has so far remained elusive. One suggested mechanism is that planets are ejected from planetary systems due to planet–planet interactions. Instability around a single star requires a very compactly spaced planetary system. We find that around binary star systems instability can occur even with widely separated planets that are on tilted orbits relative to the binary orbit due to combined effects of planet–binary and planet–planet interactions, especially if the binary is on an eccentric orbit. We investigate the orbital stability of planetary systems with various planet masses and architectures. We find that the stability of the system depends upon the mass of the highest-mass planet. The order of the planets in the system does not significantly affect stability, but, generally, the most massive planet remains stable and the lower-mass planets are ejected. The minimum planet mass required to trigger the instability is about that of Neptune for a circular orbit binary and a super-Earth of about 10 Earth masses for highly eccentric binaries. Hence, we suggest that planet formation around inclined binaries can be an efficient formation mechanism for free-floating planets. While most observed free-floating planets are giant planets, we predict that there should be more low-mass free-floating planets that are as of yet unobserved than higher-mass planets.

We investigate the nanometrology of sub-nanometre particle sizes in industrially manufactured sodium silicate liquors at high pH using time-resolved fluorescence anisotropy. Rather than the previous approach of using a single dye label, we investigate and quantify the advantages and limitations of multiplexing two fluorescent dye labels. Rotational times of the non-binding rhodamine B and adsorbing rhodamine 6G dyes are used to independently determine the medium microviscosity and the silicate particle radius, respectively. The anisotropy measurements were performed on the range of samples prepared by diluting the stock solution of silicate to concentrations ranging between 0.2 M and 2 M of NaOH and on the stock solution at different temperatures. Additionally, it was shown that the particle size can also be measured using a single excitation wavelength when both dyes are present in the sample. The recovered average particle size has an upper limit of 7.0 ± 1.2 Å. The obtained results were further verified using small-angle X-ray scattering, with the recovered particle size equal to 6.50 ± 0.08 Å. To disclose the impact of the dye label on the measured complex size, we further investigated the adsorption state of rhodamine 6G on silica nanoparticles using molecular dynamics simulations, which showed that the size contribution is strongly impacted by the size of the nanoparticle of interest. In the case of the higher radius of curvature (less curved) of larger particles, the size contribution of the dye label is below 10%, while in the case of smaller and more curved particles, the contribution increases significantly, which also suggests that the particles of interest might not be perfectly spherical.

The monthly magazine of the United Nations Educational, Scientific and Cultural Organization, founded in 1948 as The UNESCO Courier, represents an extraordinary resource for research on global themes in the humanities. We present the Curated Courier 1.0, a package of digital text corpora, text analysis tools, and supplementary material that aims to make the complete archive of this publication from 1948 to 2020 machine-readable, accessible, and reusable for digital text analysis. One corpus compiles the text of all articles, which we carefully reconstructed and linked to a comprehensive curated metadata index while excluding additional text (masthead, photo captions, letters to the editor, and so on). A second corpus brings together the complete text of all issues. This article first presents the value of Courier as a source for digital research in the global humanities. Second, it outlines how we created the curated corpus and discusses some challenges we met. Third, it offers examples of tools researchers might use to explore and utilize the annotated corpus and discusses a few approaches that we have developed and tested.

We examine the dynamics and stability of circumbinary particles orbiting around the Earth–Moon binary system. The moon formed close to the Earth (semimajor axis a _EM ≈ 3 R _⊕ ) and expanded through tides to its current day semimajor axis ( a _EM = 60 R _⊕ ). Circumbinary orbits that are polar or highly inclined to the Earth–Moon orbit are subject to two competing effects: (i) nodal precession about the Earth–Moon eccentricity vector and (ii) Kozai–Lidov oscillations of eccentricity and inclination driven by the Sun. While we find that there are no stable polar orbits around the Earth–Moon orbit with the current day semimajor axis, polar orbits were stable immediately after the formation of the Moon, at the time when there was a lot of debris around the system, up to when the semimajor axis reached about a _EM ≈ 10 R _⊕ . We discuss implications of polar orbits on the evolution of the Earth–Moon system and the possibility of polar orbiting moons around exoplanet–moon binaries.

We study the effects of general relativity (GR) on the evolution and alignment of circumbinary disks around binaries on all scales. We implement relativistic apsidal precession of the binary into the hydrodynamics code phantom . We find that the effects of GR can suppress the stable polar alignment of a circumbinary disk, depending on how the relativistic binary apsidal precession timescale compares to the disk nodal precession timescale. Studies of circumbinary disk evolution typically ignore the effects of GR, which is an appropriate simplification for low-mass or widely separated binary systems. In this case, polar alignment occurs, provided that the disks initial misalignment is sufficiently large. However, systems with a very short relativistic precession timescale cannot polar align and instead move toward coplanar alignment. In the intermediate regime where the timescales are similar, the outcome depends upon the properties of the disk. Polar alignment is more likely in the wavelike disk regime (where the disk viscosity parameter is less than the aspect ratio, α < H / r ), since the disk is in good radial communication. In the viscous disk regime, disk breaking is more likely. Multiple rings can destructively interact with one another, resulting in short disk lifetimes and the disk moving toward coplanar alignment. Around main-sequence star or stellar mass black hole binaries, polar alignment may be suppressed far from the binary, but in general, the inner parts of the disk can align to polar. Polar alignment may be completely suppressed for disks around supermassive black holes for close binary separations.

We develop a new method for spatially mapping a lower limit on the mass fraction of the cold neutral medium by analyzing the amplitude structure of ${\hat{T}}_{b}({k}_{v})$ , the Fourier transform of T _b ( v ), the spectrum of the brightness temperature of the H i 21 cm line emission with respect to the radial velocity v . This advances a broader effort exploiting 21 cm emission line data alone (without absorption line data, τ ) to extract integrated properties of the multiphase structure of the H i gas and to map each phase separately. Using toy models, we illustrate the origin of interference patterns seen in ${\hat{T}}_{b}({k}_{v})$ . Building on this, a lower limit on the cold gas mass fraction is obtained from the amplitude of ${\hat{T}}_{b}$ at high k _v . Tested on a numerical simulation of thermally bi-stable turbulence, the lower limit from this method has a strong linear correlation with the “true” cold gas mass fraction from the simulation for a relatively low cold gas mass fraction. At a higher mass fraction, our lower limit is lower than the “true” value, because of a combination of interference and opacity effects. Comparison with absorption surveys shows a similar behavior, with a departure from linear correlation at N _H I ≳ 3–5 × 10 ^20 cm ^−2 . Application to the DRAO Deep Field from DHIGLS reveals a complex network of cold filaments in the Spider, an important structural property of the thermal condensation of the H i gas. Application to the HI4PI survey in the velocity range −90 < v < 90 km s ^−1 produces a full sky map of a lower limit on the mass fraction of the cold neutral medium at 16.′2 resolution. Our new method has the ability to extract a lower limit on the cold gas mass fraction for massive amounts of emission line data alone with low computing time and memory, pointing the way to new approaches suitable for the new generation of radio interferometers.

Cancer-specific CD8+ cytotoxic T cells play important roles in preventing cancer growth, and IFN-γ, in addition to IL-12 and type I interferon, is critical for activating CD8+ cytotoxic T cells. We recently identified the capability of the amino-terminus region of dense granule protein 6 (GRA6Nt) of Toxoplasma gondii, an intracellular protozoan parasite, to activate IFN-γ production of microglia, a tissue-resident macrophage population. Therefore, in the present study, we examined whether recombinant GRA6Nt protein (rGRA6Nt) functions as an effective adjuvant to potently activate cancer-specific protective immunity using a murine model of MC38 colorectal cancer (CRC). When mice were immunized with non-replicable (either treated with mitomycin C or irradiated by X-ray) MC38 CRC cells in combination with rGRA6Nt adjuvant and received a challenge implantation of replication-capable MC38 tumor cells, those mice markedly inhibited the growth of the implanted tumors in association with a two-fold increase in CD8+ T cell density within the tumors. In addition, CD8+ T cells of the immunized mice secreted significantly increased amounts of granzyme B, a key mediator of the cytotoxic activity of CD8+ T cells, and IFN-γ in response to MC38 CRC cells in vitro when compared to the T cells from unimmunized mice. Notably, the protective effects of the immunization were specific to MC38 CRC cells, as the immunized mice did not exhibit a significantly inhibited growth of EL4 lymphoma tumors. These results indicate that rGRA6Nt is a novel and effective protein adjuvant when used in immunizations with non-replicable cancer cells to potently activate the protective immunity specifically against the cancer cells employed in the immunization.

Second Harmonic Scattering (SHS) is a suitable technique to investigate the orientational correlations between molecules. This article explores the organization of different dye molecules adsorbed within the hydrophobic porosity of a hybrid organic-inorganic nanotube. Experimental polarization resolved SHS measurements highlight different orientational orders ranking from highly ordered and rigid organizations to disordered assemblies. Microscopic models of assemblies inside the pores are presented and discussed in the context of orientational correlation between the dye molecules. This work shows that the degree of order in the nanotube cavity follows the molecule's affinity within the porosity., (© 2024 Author(s). Published under an exclusive license by AIP Publishing.)

Aim: Diverting ileostomy (DS) after restorative proctocolectomy (RPC) can be omitted in selected patients. Its omission could improve functional outcomes and quality of life (QoL), as has been demonstrated in patients after proctectomy. The aim of this study was to report the impact of diverting ileostomy on functional outcomes and QoL after ileal pouch-anal anastomosis (IPAA)., Methods: This was a retrospective study including all patients operated (2015-2020) for RPC with IPAA. Functional outcome was evaluated by validated scores (LARS, Wexner, Öresland, pouch functional score [PFS] and the ileoanal pouch syndrome severity [IPSS] score). Global health-related QoL was evaluated with the SF-36. We also analysed demographic characteristics, morbidity, correlation between functional outcomes and QoL., Results: Among 179 eligible patients, 150 responded (84%): S- (no stoma = 78; 52%) and S+ (had stoma = 72; 48%). Overall morbidity and anastomotic leak rates were 46% and 9.3%, respectively without difference between the groups. Medians for the functional scores were comparable between the S- and S+ group, respectively: 18 [12.5-31] versus 18 [11-31], p = 0.48 for LARS; 9 [7-11] versus 9 [7-12], p = 0.23 for Wexner's score; 6 [3-13] versus 8 [5-11], p = 0.22 for Öresland's score, 6 [3-13] versus 6.8 [4-12], p = 0.174 for PFS score, and 40 [35-45] versus 46 [42-51], p = 0.045 for IPSS score. The SF-36 summary score was comparable between the two groups without any difference in eight specific health dimensions. After propensity score matching, results were still comparable between the two groups for all scores. Linear regression found a significant correlation between all QoL domains and all functional scores (p < 0.001)., Conclusion: DS for IPAA does not alter either functional outcomes or QoL and can be omitted in selected patients., (© 2024 The Author(s). Colorectal Disease published by John Wiley & Sons Ltd on behalf of Association of Coloproctology of Great Britain and Ireland.)

Competing Interests: Competing interests: None declared.

Description: In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective., Methods: The U.S. Department of Health and Human Services requested that the National Institutes of Health (NIH) take the lead in expeditiously convening a panel of experts to create "living" guidelines that would be widely accessible and capable of frequent updating as important new information became available., Recommendations: The purpose of this article is to expand on the experiences of the NIH COVID-19 Treatment Guidelines Panel (the Panel) over the past 4 years, summarize the Panel's final recommendations for COVID-19, highlight some challenges and unanswered questions about COVID-19 management, and inform future responses to public health emergencies. The Panel was formed in March 2020, and the first iteration of the guidelines was released in April 2020. Now that the public health emergency has ended, the NIH COVID-19 Treatment Guidelines have sunsetted. This role will now fall to professional societies and organizations, such as the American College of Physicians, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the World Health Organization, all of which have been active in this area., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Altered mitochondrial structure and function are implicated in the functional decline of skeletal muscle. Numerous cytoskeletal proteins are known to affect mitochondrial homeostasis, but this complex network is still being unraveled. Here, we investigated mitochondrial alterations in mice lacking the cytoskeletal adapter protein, XIN (XIN-/-). XIN-/- and wild-type littermate male and female mice were fed a chow or high-fat diet (HFD; 60% kcal fat) for 8 weeks before analyses of their skeletal muscles were conducted. Immuno-electron microscopy (EM) and immunofluorescence staining revealed XIN in the mitochondria and peri-mitochondrial areas, as well as the myoplasm. Intermyofibrillar mitochondria in chow-fed XIN-/- mice were notably different from wild-type (large, and/or swollen in appearance). Succinate dehydrogenase and Cytochrome Oxidase IV staining indicated greater evidence of mitochondrial enzyme activity in XIN-/- mice. No difference in body mass gains or glucose handling was observed between cohorts with HFD. However, EM revealed significantly greater mitochondrial density with evident structural abnormalities (swelling, reduced cristae density) in XIN-/- mice. Absolute Complex I and II-supported respiration was not different between groups, but relative to mitochondrial density, was significantly lower in XIN-/-. These results provide the first evidence for a role of XIN in maintaining mitochondrial morphology and function., Competing Interests: The authors have nothing to disclose.

Powdered samples of three imogolite materials with an inner surface covered with Si-CH 3 groups (hybrid IMO-CH 3 ) were prepared by ambient drying at 323 K, freeze drying, and spray drying. Reliable estimates of the intra-tube ( S A ), inter-tube ( S B ), and inter-bundle ( S C ) specific surface areas of these samples were inferred from a model-guided correlation between the results of measurements by small angle X-ray scattering (SAXS), nitrogen gas adsorption, and immersion calorimetry into water. Since the SAXS studies indicated no significant deformations of IMO-CH 3 g 2 adsorption at 77 K indicated the intra-tube and inter-bundle specific surface areas as being only accessible to this adsorbate. The outer curved surfaces of IMO nanotubes, including the inter-tube surface areas, were evaluated based on the calorimetric measurements of the enthalpy of immersion into water, using the enthalpy of immersion per unit surface area for a modelled curved surface of gibbsite as the conversion factor. Given the uncertainty in the determination of surface areas, the IMO-CH 3 samples were found to possess the limiting values of specific surface areas ranging between 1150 and 1480 m 2 g -1 . In contrast to the two other materials, ambient-dried IMO-CH 3 was characterized by the highest value of S C parameter due to the much smaller bundles formed by the constituent imogolite nanotubes. The accessibility of these surface areas, together with the hydrophobic and hydrophilic surface domains, was demonstrated to depend on the nature of the surrounding medium and the size of the adsorbing species.

Introduction: The use of strategic learning strategies has been positively associated with academic performance in several graduate health profession programs. This finding suggests that it may be an important construct to explore in Doctor of Physical Therapy (DPT) education. The Learning and Study Strategies Inventory (LASSI) summarizes a student's perception and use of 10 learning and study strategies., Review of Literature: Although the LASSI has limited reporting in DPT education, other health care education programs have shown correlation with academic performance. The purpose of this study was to examine DPT students' early perceptions of strategic learning with descriptive summaries of LASSI data and examine correlations between demographic and admissions-related data., Subjects: Matriculated DPT students (n = 294) at a 2-year hybrid program who completed the LASSI at orientation in 2020 and 2021., Methods: This was a descriptive study that retrospectively analyzed LASSI scores in entry-level DPT students. LASSI score differences among demographic groups and Spearman's rho correlations between the LASSI, Graduate Record Examination (GRE) scores, grade point averages, grit, and emotional intelligence (EI) were explored., Results: LASSI score means were in the 50th-75th percentile (moderate category) suggesting a need for further development in strategic learning. Group differences in LASSI scores were noted for gender identity (male higher Anxiety management, P < .001; female higher Attitude, P < .001, Time Management, P = .003, and Use of Academic Resources, P = .003), racial-ethnic minoritized group (higher Self-regulation, P = .013), first-generation college students (higher Attitude, P = .047), physical therapy assistants (higher Information Processing, P = .047), students with a primary language other than English (higher Time Management, P = .046), and older students (higher Anxiety management, P = .026). Weak but significant correlations were identified between LASSI scale and component scores and several admissions variables. Highest correlations were with grit (Will, ρ = 0.319, P < .001; Concentration, ρ = 0.312, P < .001), EI (Will, ρ = 0.328, P < .001; Attitude, ρ = 0.302, P < .001; Self-regulation, ρ = 0.382, P < .001; Use of Academic Resources ρ = 0.331, P < .001), and quantitative GRE scores (Anxiety management, ρ = 0.341, P < .001)., Discussion/conclusion: All LASSI scale scores and components were in the moderate category, potentially indicating a need to coach and develop strategic learning strategies. Group differences in LASSI scores may represent varied student needs. The weak relationship between LASSI scores and admissions variables could suggest that the constructs measured by LASSI are not currently captured through typical DPT admissions practices., Competing Interests: The author declares no conflicts of interest., (Copyright © 2024 Academy of Physical Therapy Education, APTA.)

Calcifying organisms are suffering from negative impacts induced by climate change, such as CO 2 -induced acidification, which may impair external calcified structures. Freshwater mollusks have the potential to suffer more from CO 2 -induced acidification than marine calcifiers due to the lower buffering capacity of many freshwater systems. One of the most important enzymes contributing to the biomineralization reaction is carbonic anhydrase (CA), which catalyzes the reversible conversion of CO 2 to bicarbonate, the major carbon source of the calcareous structure in calcifiers. In this study we characterized two α-CA isoforms (LsCA1 and LsCA4) from the freshwater snail Lymnaea stagnalis using a combination of gene sequencing, gene expression, phylogenetic analysis and biochemical assays. Both CA isoforms demonstrated high expression levels in the mantle tissue, the major site for biomineralization. Furthermore, expression of LsCA4 during development parallels shell formation. The primary protein structure analysis, active site configuration and the catalytic activity of LsCA4 together suggest that the LsCA4 is embedded in the apical and basolateral membranes of mantle cells; while LsCA1 is proposed to be cytosolic and might play an important role in acid-base regulation. These findings of LsCA isoforms form a strong basis for a more detailed physiological understanding of the effects of elevated CO 2 on calcification in freshwater mollusks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Human immune system (HIS) mice generated using human CD34 + hematopoietic stem cells serve as a pivotal model for the in vivo evaluation of immunotherapies for humans. Yet, HIS mice possess certain limitations. Rats, due to their size and comprehensive immune system, hold promise for translational experiments. Here, we describe an efficacious method for long-term immune humanization, through intrahepatic injection of hCD34 + cells in newborn immunodeficient rats expressing human SIRPα. In contrast to HIS mice and similar to humans, HIS rats showed in blood a predominance of T cells, followed by B cells. Immune humanization was also high in central and secondary lymphoid organs. HIS rats treated with the anti-human CD3 antibody were depleted of human T cells, and human cytokines were detected in sera. We describe for the first time a method to efficiently generate HIS rats. HIS rats have the potential to be a useful model for translational immunology., Competing Interests: Declaration of interests F.R.-D., G.M., and K.T. are employees of genOway., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Progressive multifocal leukoencephalopathy (PML) is a severe neurologic disease resulting from JC virus reactivation in immunocompromised patients. Certain multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with PML risk, such as natalizumab and, more rarely, sphingosine-1-phosphate receptor modulators (S1P-RMs). Although natalizumab-associated PML is well documented, information on S1P-RM-associated PML is limited. The aim of this study is to compare clinical presentations and outcomes between the 2 groups., Methods: A retrospective multicenter cohort study included patients with PML from 2009 to 2022 treated with S1P-RMs or natalizumab. Data on clinical and radiologic presentation, outcomes, immune reconstitution inflammatory syndrome (IRIS), survival, disability (using the modified Ranking scale-mRS), and MS relapses post-PML were analyzed., Results: Of 88 patients, 84 were analyzed (20 S1P-RM, 64 natalizumab). S1P-RM-associated PML was diagnosed in older patients (median age 52 vs 44 years, p < 0.001) and after longer treatment duration (median 63.9 vs 40 months, p < 0.001). Similarly, S1P-RM patients were more prone to show symptoms at diagnosis (100 vs 80.6%, p = 0.035), had more disseminated lesions (80% vs 34.9%, p = 0.002), and had higher gadolinium enhancement (65% vs 39.1%, p = 0.042). Natalizumab patients had a higher IRIS development rate (OR: 8.3 [1.92-33.3]). Overall, the outcome (mRS) at 12 months was similar in the 2 groups (OR: 0.81 [0.32-2.0]). Yet, post-treatment MS activity was higher in S1P-RM cases (OR: 5.7 [1.4-22.2])., Discussion: S1P-RM-associated PML shows reduced IRIS risk but higher post-treatment MS activity. Clinicians should tailor post-PML treatment based on pre-PML medication.

Objectives: The impact of incident investigations in improving patient safety may be linked to the quality of risk controls recommended in investigation reports. We aimed to identify the range and apparent strength of risk controls generated from investigations into serious incidents, map them against contributory factors identified in investigation reports, and characterize the nature of the risk controls proposed., Methods: We undertook a content analysis of 126 action plans of serious incident investigation reports from a multisite and multispeciality UK hospital over a 3-year period to identify the risk controls proposed. We coded each risk control against the contributory factor it aimed to address. Using a hierarchy of risk controls model, we assessed the strength of proposed risk controls. We used thematic analysis to characterize the nature of proposed risk controls., Results: A substantial proportion (15%) of factors identified in investigation reports as contributing to serious incidents were not addressed by identifiable risk controls. Of the 822 proposed risk controls in action plans, most (74%) were assessed as weak, typically focusing on individualized interventions-even when the problems were organizational or systemic in character. The following 6 broad approaches to risk controls could be identified: improving individual or team performance; defining, standardizing, or reinforcing expected practice; improving the working environment; improving communication; process improvements; and disciplinary actions., Conclusions: The identified shortfalls in the quality of risk controls following serious incident investigations-including a 15% mismatch between contributory factors and aligned risk controls and 74% of proposed risk controls centering on weaker interventions-represent significant gaps in translating incident investigations into meaningful systemic improvements. Advancing the quality of risk controls after serious incident investigations will require involvement of human factors specialists in their design, a theory-of-change approach, evaluation, and curation and sharing of learning, all supported by a common framework., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

The present research aimed to explore whether negative stereotypes and domain identification moderate novice participants' performance on a soccer-dribbling task, using a novel statistical procedure to explore within-subjects moderation effects. Fifty-four women with no soccer experience (Mage = 19.92, SDage = 1.0) were recruited and assigned to a negative stereotype condition or a nullified-stereotype condition and performed a soccer-dribbling task as fast as possible. Using moderation analyses for repeated measures, results showed (i) that inducing a negative stereotype did not moderate participants' performance, and (ii) that domain identification did not moderate participants' performance in a stereotype threat situation. In conclusion, the novice participants performance did not depend on the value of domain identification and the stereotype condition. More research is nonetheless needed to disentangle the question of how and why novice participants can be impacted by a stereotype threat situation., Competing Interests: Declaration of competing interest No conflict of interest will arise from any of the authors involved in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Influenza vaccines are effective in decreasing hospitalizations and mortality related to influenza and its complications. However, the Vaccine Coverage Rate of influenza remains low and multifaceted efforts are required to improve it. The aim of this study was to assess the impact on influenza vaccine perception using a digital tool among outpatients and health care workers (HCWs)., Methods: A study was performed among outpatients and the HCWs of 23 hospital departments from 4 hospitals affiliated to Lyon university Hospitals (France), between October 2022 and February 2023. By scanning QR (Quick Response) codes, displayed on posters for patients, their companions, as well as in the letters sent to HCWs, users accessed anonymously to a web-application (ELEFIGHT®), which provided information on influenza and invited them to initiate a discussion on influenza prevention with their physicians during the consultation. Patients were also invited to complete a questionnaire regarding their perception of influenza vaccination before and after reading the information on ELEFIGHT®. The retention rate (RR = proportion of people who remain on the page for >2 s), the conversion rate (CR = proportion of people who click on the "Call-To-Action" button) and the absolute variation (difference in the perception before/after) and relative variation (absolute change as a percentage of the initial perception) in perception regarding influenza vaccination before and after consulting the application were calculated., Results: 3791 scans were performed by 3298 patients and/or their companions with a RR of 52% and a CR of 55.1% and 253 scans by 221 HCWs with a RR of 71.2% and a CR of 115.3%. Participants spent an average of 47 s on the application. The questionnaire on influenza vaccination perception was completed by 1533 participants (46.5%); 1390 (90.7%) maintained the same position (neutral, favorable or unfavorable) on this vaccination before and after consulting the application. The relative variations in favor of vaccination were + 7.2% (unfavorable then favorable) and + 19.8% (neutral then favorable)., Conclusion: This study suggests that a facilitated direct access to medical information through QR codes disseminated in health settings can help nudge people to foster their awareness of influenza and its prevention. Future deployments in a similar context or to other populations could be envisaged. Other vaccine-preventable and/or chronic diseases could also be the target of similar projects as part of public health programs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nagham Khanafer, Florence Ader, Frédéric Berard, Françoise Bouhour, Roland Chapurlat, Sybil Charriere, Cyrille Confavreux, Gilles Devouassoux, Emmanuel Disse, Jean-Pierre Fauvel, Denis Fouque, Herve Ghesquieres, Sophie Hyvert, Anne Jolivot, Gilles Leboucher, Catherine Lombard, Géraldine Martin-Gaujard, Jean-Francois Mornex, Marc Nicolino, Nathalie Obadia, Gérald Raverot, Philippe Reix, Alain Ruffion, Pascal Seve, Eric Truy, Fabien Zoulim and Philippe Vanhems have no conflicts of interest related to this study to declare. Catherine Planckaert, Rym Bouhalila, Camille Mena and Nadège Trehet Mandel have been mandated and paid by the HCL. Sylvain Oudot, Margot Maligeay, Joséphine Clamens and Marie-Pierre Ayala are employed by Sanofi., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Physical activity is recognized as beneficial for older individuals in preventing falls. Achieving high adherence to exercise programs among the elderly poses challenges for administrations and healthcare systems. This study explored the facilitators and barriers perceived by both the participants and nurse trainers involved in an exercise program aimed at preventing falls in primary healthcare., Methods: Sixteen semi-structured interviews with elderly people who had participated in the Otago Exercise Program and a focus group of nurse trainers of this program were conducted between October 2018 and September 2019 in primary health care centers in Lleida, Spain. Interviews were transcribed and analyzed using inductive thematic analysis with Atlas.ti 8 software., Results: Analysis revealed five overarching categories and 17 subcategories. Key facilitators included personal motivation, the perceived benefits of exercise, and the supportive role of nurse trainers. Primary barriers encompassed factors such as the excessive duration of the program, not considering personal preferences for individual or group participation, and differences in physical condition among group participants., Conclusions: To increase participation and adherence to exercise programs, it is necessary to consider the important role of the nursing professionals that recommend program enrolment and the participants' personal motivations. The program with group sessions is a model that is easy to integrate into Primary Healthcare centers, which must always take into account the preferences and physical conditions of the participants., (© 2024 The Author(s). Public Health Nursing published by Wiley Periodicals LLC.)

PCR is tolerant to single nucleotide mismatches. Therefore, genotyping of point mutations by PCR requires special conditions for the amplification of allele-specific PCR fragments. MS-PCR (mutagenically separated PCR) is an improved version of ARMS (amplification refractory mutation system) in which additional nucleotide mismatches near the mutation site are used to separate the wt fragments from the mutant fragments in a single-tube PCR. In the originally described procedure, the resulting fragments are resolved on agarose gels according to differences in size introduced by different lengths of the allele-specific primers. In order to evaluate the PCR fragments by melting curve analysis, we enlarged the difference in the melting temperatures of the fragments of the two alleles by increasing the GC content of the longer allele-specific primer resulting in a higher melting temperature of the corresponding fragment. Using the murine retinal degeneration mutations rd1 and rd8 as an example, we show that such primers result in an easy to handle genotyping procedure: qPCR followed by melting curve analysis. In summary, MS-PCR is a simple and easy-to-use method for detecting single nucleotide variants., (© 2024. The Author(s).)

Current rates of habitat degradation and climate change are causing unprecedented declines in global biodiversity. Studies on vertebrates highlight how conservation genomics can be effective in identifying and managing threatened populations, but it is unclear how vertebrate-derived metrics of genomic erosion translate to invertebrates, with their markedly different population sizes and life histories. The Black-veined White butterfly (Aporia crataegi) was extirpated from Britain in the 1920s. Here, we sequenced historical DNA from 17 specimens collected between 1854 and 1924 to reconstruct demography and compare levels of genomic erosion between extirpated British and extant European mainland populations. We contrast these results using modern samples of the Common Blue butterfly (Polyommatus icarus); a species with relatively stable demographic trends in Great Britain. We provide evidence for bottlenecks in both these species around the period of post-glacial colonization of the British Isles. Our results reveal different demographic histories and N e for both species, consistent with their fates in Britain, likely driven by differences in life history, ecology and genome size. Despite a difference, by an order of magnitude, in historical effective population sizes (N e ), reduction in genome-wide heterozygosity in A. crataegi was comparable to that in P. icarus. Symptomatic of A. crataegi's disappearance were marked increases in runs-of-homozygosity (RoH), potentially indicative of recent inbreeding, and accumulation of putatively mildly and weakly deleterious variants. Our results provide a rare glimpse of genomic erosion in a regionally extinct insect and support the potential use of genomic erosion metrics in identifying invertebrate populations or species in decline., (© 2024 The Author(s). Molecular Ecology published by John Wiley & Sons Ltd.)

Staphylococcus aureus is a leading cause of healthcare-associated infections globally. Vancomycin-resistant S. aureus (VRSA), those with high-level resistance [minimum inhibitory concentration (MIC) of 16-32 µg/mL vancomycin], are uncommon, whereas vancomycin-intermediate S. aureus (VISA; MIC of 4-8 µg/mL), are isolated more frequently and develop during long-term and/or repeated use of the antibiotic. VISA can be difficult to eradicate and infections may persist. Our knowledge of mechanisms that underlie the development of VISA is incomplete. We used a genomics approach to investigate the VISA phenotype in three prominent S. aureus lineages. All VISA clinical isolates tested had increased cell wall thickness compared with vancomycin-susceptible S. aureus strains. Growth rates of clonal complex (CC) 5, CC8, and CC45 clinical isolates were reduced in 2 µg/mL vancomycin compared to media alone. Culture in 2 and 4 µg/mL vancomycin sequentially for two weeks reduced susceptibility to daptomycin, televancin, tigecycline, and vancomycin in a majority of CC5, CC8, and CC45 isolates tested. We identified alleles reported previously to contribute to the VISA phenotype, but unexpectedly, these alleles were unique to each CC. A subtherapeutic concentration of vancomycin elicited changes in the VISA transcriptome-common and unique-among the three CCs tested. Multiple genes, including those encoding a glycerate kinase, an M50 family metallopeptidase, and an uncharacterized membrane protein, were upregulated among all three lineages and not reported previously as associated with VISA. Although there are lineage-specific changes in DNA sequence, our findings suggest changes in the VISA transcriptome constitute a general response to stress that confers reduced susceptibility to multiple antibiotics., Importance: Our understanding of the mechanisms that underlie the development of vancomycin-intermediate Staphylococcus aureus (VISA) is incomplete. To provide a more comprehensive view of this process, we compared genome sequences of clonal complex (CC) 5, CC8, and CC45 VISA clinical isolates and measured changes in the transcriptomes of these isolates during culture with a subtherapeutic concentration of vancomycin. Notably, we identified differentially expressed genes that were lineage-specific or common to the lineages tested, including genes that have not been previously reported to contribute to a VISA phenotype. Changes in gene expression were accompanied by reduced growth rate, increased cell wall thickness, and reduced susceptibility to daptomycin, televancin, tigecycline, and vancomycin. Our results provide support to the idea that changes in gene expression contribute to the development of VISA among three CCs that are a prominent cause of human infections., Competing Interests: The authors declare no conflict of interest.