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Abstract To identify potential factors influencing age-related cognitive decline and disease, we created MindCrowd. MindCrowd is a cross-sectional web-based assessment of simple visual (sv) reaction time (RT) and paired-associate learning (PAL). svRT and PAL results were combined with 22 survey questions. Analysis of svRT revealed education and stroke as potential modifiers of changes in processing speed and memory from younger to older ages (n total = 75,666, n women = 47,700, n men = 27,966; ages 18–85 years old, mean (M)Age = 46.54, standard deviation (SD) Age = 18.40). To complement this work, we evaluated complex visual recognition reaction time (cvrRT) in the UK Biobank (n total = 158,249 n women = 89,333 n men = 68,916; ages 40–70 years old, M Age = 55.81, SDAge = 7.72). Similarities between the UK Biobank and MindCrowd were assessed using a subset of MindCrowd (UKBb MindCrowd) selected to mirror the UK Biobank demographics (n total = 39,795, n women = 29,640, n men = 10,155; ages 40–70 years old, M Age = 56.59, SDAge = 8.16). An identical linear model (LM) was used to assess both cohorts. Analyses revealed similarities between MindCrowd and the UK Biobank across most results. Divergent findings from the UK Biobank included (1) a first-degree family history of Alzheimer’s disease (FHAD) was associated with longer cvrRT. (2) Men with the least education were associated with longer cvrRTs comparable to women across all educational attainment levels. Divergent findings from UKBb MindCrowd included more education being associated with shorter svRTs and a history of smoking with longer svRTs from younger to older ages.

Abstract Vascular contributions to cognitive impairment and dementia (VCID) include structural and functional blood vessel injuries linked to poor neurocognitive outcomes. Smoking might indirectly increase the likelihood of cognitive impairment by exacerbating vascular disease risks. Sex disparities in VCID have been reported, however, few studies have assessed the sex-specific relationships between smoking and memory performance and with contradictory results. We investigated the associations between sex, smoking, and cardiovascular disease with verbal learning and memory function. Using MindCrowd, an observational web-based cohort of ~ 70,000 people aged 18–85, we investigated whether sex modifies the relationship between smoking and cardiovascular disease with verbal memory performance. We found significant interactions in that smoking is associated with verbal learning performance more in women and cardiovascular disease more in men across a wide age range. These results suggest that smoking and cardiovascular disease may impact verbal learning and memory throughout adulthood differently for men and women.

To understand the genetic basis of complex traits, it is important to be able to efficiently phenotype many genetically distinct individuals. In the nematode Caenorhabditis elegans, individuals have been isolated from diverse populations around the globe and whole-genome sequenced. As a result, hundreds of wild strains with known genome sequences can be used for genome-wide association studies (GWAS). However, phenotypic analysis of these strains can be laborious, particularly for quantitative traits requiring multiple measurements per strain. Starvation resistance is likely a fitness-proximal trait for nematodes, and it is related to metabolic disease risk in humans. However, natural variation in C. elegans starvation resistance has not been systematically characterized, and precise measurement of the trait is time-intensive. Here, we developed a population-selection-and-sequencing-based approach to phenotype starvation resistance in a pool of 96 wild strains. We used restriction site-associated DNA sequencing (RAD-seq) to infer the frequency of each strain among survivors in a mixed culture over time during starvation. We used manual starvation survival assays to validate the trait data, confirming that strains that increased in frequency over time are starvation-resistant relative to strains that decreased in frequency. Further, we found that variation in starvation resistance is significantly associated with variation at a region on chromosome III. Using a near-isogenic line (NIL), we showed the importance of this genomic interval for starvation resistance. This study demonstrates the feasibility of using population selection and sequencing in an animal model for phenotypic analysis of quantitative traits, documents natural variation of starvation resistance in C. elegans, and identifies a genomic region that contributes to such variation.

Reduced insulin-like signaling is required for C. elegans response to many environmental stressors, but how distinct outcomes are achieved is unknown. The authors show that the cytosolic sulfotransferase SSU-1 controls neurohormonal signaling via NHR-1 to specify the animals’ osmotic stress response.

Summary: Standard laboratory culture of Caenorhabditis elegans utilizes solid growth media with a bacterial food source. However, this culture method limits control of food availability and worm population density, factors that impact many life-history traits. Here, we describe liquid-culture protocols for precisely modulating bacterial food availability and population density, facilitating reliable production of arrested L1 larvae, dauer larvae, dietarily restricted worms, or well-fed worms. Worms can be grown in small quantities for standard assays or in the millions for other applications.For complete details on the use and execution of these protocols, please refer to Hibshman et al. (2016), Webster et al. (2018), and Jordan et al. (2019).

Abstract Background Developmental physiology is very sensitive to nutrient availability. For instance, in the nematode Caenorhabditis elegans, newly hatched L1-stage larvae require food to initiate postembryonic development. In addition, larvae arrested in the dauer diapause, a non-feeding state of developmental arrest that occurs during the L3 stage, initiate recovery when exposed to food. Despite the essential role of food in C. elegans development, the contribution of food perception versus ingestion on physiology has not been delineated. Results We used a pharmacological approach to uncouple the effects of food (bacteria) perception and ingestion in C. elegans. Perception was not sufficient to promote postembryonic development in L1-stage larvae. However, L1 larvae exposed to food without ingestion failed to develop upon return to normal culture conditions, instead displaying an irreversible arrest phenotype. Inhibition of gene expression during perception rescued subsequent development, demonstrating that the response to perception without feeding is deleterious. Perception altered DAF-16/FOXO subcellular localization, reflecting activation of insulin/IGF signaling (IIS). The insulin-like peptide daf-28 was specifically required, suggesting perception in chemosensory neurons, where it is expressed, regulates peptide synthesis and possibly secretion. However, genetic manipulation of IIS did not modify the irreversible arrest phenotype caused by food perception, revealing that wild-type function of the IIS pathway is not required to produce this phenotype and that other pathways affected by perception of food in the absence of its ingestion are likely to be involved. Gene expression and Nile red staining showed that food perception could alter lipid metabolism and storage. We found that starved larvae sense environmental polypeptides, with similar molecular and developmental effects as perception of bacteria. Environmental polypeptides also promoted recovery from dauer diapause, suggesting that perception of polypeptides plays an important role in the life history of free-living nematodes. Conclusions We conclude that actual ingestion of food is required to initiate postembryonic development in C. elegans. We also conclude that polypeptides are perceived as a food-associated cue in this and likely other animals, initiating a signaling and gene regulatory cascade that alters metabolism in anticipation of feeding and development, but that this response is detrimental if feeding does not occur.

Fluctuations in nutrient availability profoundly impact gene expression. Previous work revealed postrecruitment regulation of RNA polymerase II (Pol II) during starvation and recovery in Caenorhabditis elegans, suggesting that promoter-proximal pausing promotes rapid response to feeding. To test this hypothesis, we measured Pol II elongation genome wide by two complementary approaches and analyzed elongation in conjunction with Pol II binding and expression. We confirmed bona fide pausing during starvation and also discovered Pol II docking. Pausing occurs at active stress-response genes that become downregulated in response to feeding. In contrast, “docked” Pol II accumulates without initiating upstream of inactive growth genes that become rapidly upregulated upon feeding. Beyond differences in function and expression, these two sets of genes have different core promoter motifs, suggesting alternative transcriptional machinery. Our work suggests that growth and stress genes are both regulated postrecruitment during starvation but at initiation and elongation, respectively, coordinating gene expression with nutrient availability.

Increasingly, evidence suggests a role for polyphenols in blood glucose control. The objective of this systematic review was to evaluate the effect of polyphenol-rich sources in combination with carbohydrate sources on resulting postprandial glycaemic and insulin responses. A literature search was conducted using Medline, CINHAL and Web of Science databases. Selected studies included randomised controlled trials in which the association of polyphenol-containing food or beverage consumption with a carbohydrate source and effect on acute postprandial glycaemia and/or insulin was reported. A total of thirteen full articles were included in the review. Polyphenol sources included coffee, black tea, fruit juice, plant extracts, berries and different rye breads, and carbohydrate sources included bread, pancakes and simple sugars such as sucrose, glucose and fructose. Although glycaemic and insulin responses differed depending on the polyphenol–carbohydrate combination, overall, polyphenol sources were shown to reduce the peak and early-phase glycaemic response and maintain the glycaemic response in the later stages of digestion. To a lesser extent, polyphenol sources were also shown to reduce peak insulin response and sustain the insulin response, especially when consumed with bread. This review supports epidemiological data suggesting that polyphenols in foods and beverages may have a beneficial effect on reducing the risk of type 2 diabetes. However, the extent of this effect is variable depending on the polyphenol and carbohydrate source.

The Deltatrac™ II Metabolic Monitor (Datex-Ohmeda Inc.) is considered the standard reference machine in indirect calorimetry; however, it is no longer commercially available thus there is a need for new machines. The gas exchange measurement (GEM; GEM Nutrition Ltd) and the ECAL (Health Professional Solutions) are alternative measuring systems. The aim of this study was to compare the ECAL and GEM with Deltatrac for measures of RMR and the GEM to the Deltatrac for measures of diet-induced thermogenesis (DIT). Twenty healthy participants were tested on test day 1 (T1) and test day 2 (T2). RMR was measured in a randomised order for 30 min on the Deltatrac, the GEM and the ECAL. Following this, a 1553 kJ meal was consumed and DIT was measured on the Deltatrac and the GEM in alternating 15 min intervals for 4 h. The GEM reported consistently higher values than the Deltatrac for VO2, VCO2, RMR and fat oxidation (P

Containment conditions after certain postulated severe accident scenarios in nuclear power plants might result in the accumulation of hydrogen in the vessel dome. Inspired by these accident scenarios an experiment for the OECD/NEA benchmark exercise (2014) was carried out in the large scale PANDA facility at the Paul Scherrer Institut in Switzerland. The benchmark experiment was conducted at room temperature and under conditions characterized by an initially positively buoyant jet which becomes negatively buoyant while interacting with a helium layer. The experiment addresses (i) the initial conditions especially at the tube exit and (ii) the details of the entrainment of the helium stratification into the jet and the transport of the mixture towards the lower parts of the vessel. For the tube exit velocity mean and fluctuating quantities we find a reasonable agreement with pipe flow data, but a lack of agreement between past tube exit measurements and our results. It is shown that the axial velocity of the jet experiences a strong deceleration in the vicinity of the helium-rich layer and is finally stopped. Fluid accumulates in this zone and part of this fluid is flowing back in a narrow annular region around the upward flowing jet. Consequently, part of the annular flow is reentrained into the rising jet. During the layer erosion, the flow structure changes from a more downwards oriented annular type to a more horizontally oriented mushroom type of flow. It is found that locations for which we record considerable turbulent kinetic energy k extends above the region where the velocity magnitude v has decayed to almost zero, indicating that the jet deceleration and redirection introduces considerable turbulence in the helium stratification.

A pictorial field guide to the 30 species of sandfly most commonly encountered in Pará State is presented, based on the easily recognised external characters of the length of the 5th palpal segment, thoracic infuscation, abdominal colour and head and body size. In most cases this allows identification to the species. In others, especially with females, it gives an indication of the species, which may then be confirmed with data from more detailed taxanomix studies. This type of field guide helps in teaching, rapid sorting of flies prior to dissection and in acquainting visitors with the variety of species present in a given area.A rapid technique for the taxonomic sorting of unmounted, freshly killed female sandflies is required, prior to the dissection of large numbers of a particular species. Such a method is useful in areas where numerous species occur in studies on natural flagellate infections, age determination and for ecological studies. With the above points in mind a pictorial field guide has been designed that enables the identification of unmounted, unmacerated specimens of the 30 more commonly encountered species of phleboto-mine sandflies (***) in Pará State, North Brazil. It is based on the easily recognised external characters of the length of the 5th palpal segment, thoracic infuscation, ad-dominal colour and proboscis and body size.Taxonomy of male phlebotomine sandflies is based on the structure of the genitalia and, as most of this is external, a wholly external character key is readily made. Female taxonomy, however, is based on the internal character of the cibarium, pharynx and sperma thecae. In order to produce an external character key we therefore return to an unso phisticated "phlebotometry" (see Martins et al., 1978 p. 3 for review), using relative lengths of the proboscis, palpal segments and body, along with the degree of infuscation. Ihis idea is not new; indeed many sandfly specialists presently use external characters to separate certain species (H. Fraiha, R. P. Lane, P. D. Ready, D. G. Young and R. D. Ward personal communications 1983 & 1984).A key used to separate five anthropophillic sandflies by Biagi (1966), in Mexico, was based mainly on palpal segment length and infuscation. Floch and Abonnenc (1952) stressed the use of relative lengths of palpal segments in their keys to the sandflies of French Guiana, and four members of the shannoni group have been similarly separated according to the degree of infuscation by Morales et al. (1982). The use of thoracic infuscation as a reliable character seems to be gaining favour, having been used by young & Fairchild (1974) and Ready & Fraiha (1981). Indeed Chariotis 1974) showed the usefulness of thoracic infuscation to sepenate 7 anthropophillic species, during studies onvesicular stomatitis in Panama. Identification using external characters is essential for work on viral isolations from sandflies, where bulk samples of whole sandflies are used.Perhaps the major advantage of a simple visual guide is for teaching purposes. Technical staff in this lnstitute are able to identify most of the species they encounter without having to use the standard, more unwieldly (and in many cases unavailable) internal character keys, and the guides presented below have allowed rapid species sorting prior to the dissection of sandflies in our leismaniasis study areas (Ryan et at. ,1985).

Lutzomyia furcata transmitted Leishmania chagasi to a hamster 10 days after being experimentally fed on an infected spleen. An individual female Psychodopygus carrerai carrerai that had fed on a hamster lesion caused by Leishmania mexicana amazonensis transmitted this parasite 6 days later to another hamster. Transmission electron microscopy of this fly's head revealed a small number of degenerate promastigotes in the foregut, but only a few were attached.O protozoário Leishmania (L.) chagasi foi transmitido experimentalmente a um hamster pela picada do flebotomíneo Lutzomyia furcata. Os insetos foram infectados através de uma membrana (pele de pinto), utilizando-se formas amastigotas provenientes do baço de um hamster infectado. O baço foi triturado em sangue de coelho. A L. (L.) amazonensis foi transmitida a um hamster pela picada do flebotomíneo Psychodopygus c. carrerai, previamente alimentado em lesão de pele de um outro hamster infectado com o parasita. O exame desse flebotomíneo, através de microscópio eletrônico, revelou um número pequeno de flagelados degenerados, livres no lumen do intestino anterior.

The males of the sandfly Lutzomyia longipalpis occur in two forms, one which bears a single pair of pale spots on tergite 4 and another in which an additional pair of spots characterizes tergite 3. Almost complete reproductive isolation between sumpatric populations of the two forms and between allopatric populations of the one-spot form has been reported (Ward et al., 1983). Micromorphological differences in cuticular structures on the spots have also been observed and may be sites of pheromone release (Lane & Ward, 1984). Detais of the known distribution of the two are based on the examination of new specimens captured in Brazil during 1982, as well as museum collections and specimens from other laboratories. Males with a single pair of pale spots have been found from Mexico to southern Brazil, whilst the two-spot form is found only from the state of Maranhão in North Brazil to Minas Gerais and the border with Paraguay. In the eastern area of Brazil the two forms occur sympatrically in some locations and separately in others.Os machos do flebótomo Lutzomyia longipalpis apresentam-se sob duas formas, uma que possui um par de manchas claras apenas no tergito 4, enquanto a outra distingue-se por possuir um par adicional de manchas claras no tergito 3. Isolamento reprodutivo foi observado entre populações simpátricas com as duas formas e também entre populações alopátricas da forma com um só par de manchas (Ward et al., 1983). Foram também constatadas diferenças micromorfológicas em estruturas vuticulares nas manchas, que talvez sejam locias de liberação de ferormônios (Lane & Ward, 1984). Machos com um único par de manchas claras são encontrados desde o México até o sul do Brasil, enquanto a forma com duas manchas é achada somente no Maranhão, no norte do Brasil, até Minas Gerais e a fronteira do Brasil com o Paraguai, ao sul. No leste do Brasil as duas formas são simpátricas em algumas localidades e alopátricas em outras. São apresentados detalhes da distribuição conhecida das duas formas baseados na observação de espécimens capturados no Brasil em 1982, ou vistos em coleções de museus ou recebidos de outros laboratórios.

L'auteur met en évidence des différences dans le taux de cicatrisation et le taux d'usure des ailes qui sont confirmées par la corrélation avec l'âge ovarien utilisé comme échelle de temps. Ces variations concernent Glossina morsitans submorsitans, G. medicorum, G. fusca fusca, G. palpalis gambiensis, G. longipalpis et G. tachinoides en Côte-d'Ivoire; G. morsitans morsitans et G. pallidipes au Zimbabwe; G. morsitans morsitans au Malawi; G. morsitans centralis en Zambie; G. longipennis et G. pallidipes en Somalie. Cette communication est la première concernant le taux de cicatrisation. Celui-ci indique, de même que l'usure des ailes, l'activité de la tsé-tsé mais peut aussi refléter la pression des prédateurs. Les lésions cuticulaires offrent une échelle grossière pour la diagnose de l'âge similaire à celle de l'usure des ailes. Les cicatrices dues à l'accouplement et celles dues à des blessures diffèrent en fonction des espèces et de leur habitat

Des captures continues de Glossina pallidipes ont été effectuées sur 1,2 ha le long de la rivière Shebeli, en Somalie, au moyen de pièges biconiques. La densité relative (D.R.), représentée par le nombre de mouches capturées par un piège en un jour, a diminué pendant 5 jours, puis s'est brusquement accrue en 24 h pour diminuer à nouveau pendant les 3 jours suivants. En appliquant à ces deux périodes les principes de la soustraction par piégeage, les densités de tsétsé sont respectivement estimées à 967 ± 251 et 953 ± 208 mâles, et à 1 865 ± 186 et 2 483 ± 128 femelles par hectare. Le principal facteur qui a probablement provoqué cette modification de la D.R. est l'apparition de fortes pluies entre les 2 périodes de capture. Ces pluies ont affecté directement la disponibilité des mouches pour les pièges, ou indirecte-ment en modifiant le comportement des phacochères qui, d'après les résultats de 123 analyses de repas de sang, constituent leur hôte préférentiel. On a également établi une relation avec les maximums journaliers de température, mais elle ne suffit pas à expliquer les variations de la D.R.

L'efficacité relative de différents pièges (pièges biconiques, pièges de Manitoba, pièges adhésifs diversement colorés, piège de Catts, piège à eau, pièges de Moloo et de Swynnerton) a été comparée par des méthodes faciles à mettre en ouvre et ayant déjà fait leurs preuves. Les pièges biconiques standards capturent au moins deux fois plus de Glossina palpalis s.l. et de G. morsitans centralis que tous les autres pièges, mais ils ne récoltent que peu de simulies ou de tabanides. Les pièges Manitoba capturent huit fois plus de Tabanus taeniola, T. gratus et T. par que les autres pièges. Les pièges adhésifs, à eau et Malaise récoltent diverses espèces, mais en très faibles quantités. La capture au filet à main sur un homme appât est comparée aux pièges biconiques et à des écrans adhésifs ou électriques portés à dos d'homme pour G. palpalis s.l., à la capture dans un véhicule en mouvement et aux pièges biconiques pour G. morsitans centralis. Des essaims suiveurs de cette dernière espèce ont été observés et capturés. Par contre, G. palpalis s.l. est peu attirée par l'homme. Le ton de la teinture bleue du matériel utilisé pour les pièges biconiques influe de façon décisive sur la capture de G. tachinoides, mais pas sur celle de G. palpalis s.l. La collecte de G. morsitans centralis à l'aide d'appareils mobiles fournit un grand nombre de mâles âgés et quelques jeunes femelles, alors qu'avec G. palpalis s.l. on n'obtient que de très faibles quantités de chacune de ces catégories. Par contre les pièges biconiques capturent, pour ces deux epèces, de grandes quantités de chaque sexe, avec une bonne représentation de tous les âges. L'inverse est vrai pour les femelles de Simulium damnosum s.l. qui approchent volontiers l'homme mais sont très peu attirées par les pièges biconiques. De petits nombres de conopides Stylogaster leonum, de G. pallicera et de G. fusca ont également été capturés par les pièges biconiques.

A closed Lutzomyia longipalpis colony, from Ceará has been used to transmit Leishmania chagasi isolated from a fox in Pará state. The last time this colony was successfully used in similar transmission experiments was eight years (64 generations) ago indicating that this colony of Lu. longipalpis has fully maintained its vectorial capacity in spite of such a long period of maintainance in the laboratory.Lutzomyia longipalpis foi alimentado através de membrana com uma suspensão de macerado de fígado e baço em sangue desfibrinado de coelho. Este material foi originário de um hamster infectado com Leishmania chagasi, realimentado em hamsters limpos, transmitindo os parasitos em duas ocasiões. Esta mesma colônia de Lu. longipalpis, do Ceará, foi usada para a primeira transmissão há oito anos e 64 gerações atrás e não teve a capacidade vetorial diminuída.

Dissection of Lutzomyia longipalpis, captured in the São Luis focus of visceral Leishmaniasis revealed a 1.8% promastigote infection rate.Foram dissecados Lutzomyia longipalpis, capturados no foco de leishmaniose visceral na ilha de Sao Luis, Maranhao, sendo encontradas 1,8% com infeccao natural por promastigotas.

IntroductionThis study explored the extent to which an interactive computer play system, Bootle Blast, supports motor learning in a clinical context and examined clinicians’ perceptions of their therapeutic role in the system’s use as an intervention tool.MethodsIn this observational sequential explanatory mixed methods study, five children with cerebral palsy [mean age 9.4 years (SD, 0.5), Gross Motor Function Classification System Levels I–III] used Bootle Blast during a single video-recorded therapy session with their treating clinicians (physical therapists, occupational therapists, and therapy assistants). Children played one Bootle Blast mini game independently (without clinician involvement) before clinicians carried out therapy sessions with the game as per usual care. The type and extent of motor learning strategies (MLS) delivered by Bootle Blast and clinicians were rated from video recordings by a trained assessor using the 22-item Motor Learning Strategies Rating Instrument. Semi-structured interviews with clinicians were conducted to gain insights into MLS use and clinicians’ perceived role during Bootle Blast use. Interviews were audio recorded, transcribed verbatim, and analyzed independently by two researchers using thematic analysis. Quantitative and qualitative data were merged and reported using narrative and joint display approaches.ResultsBootle Blast provided eight MLS, with clinicians adding or enhancing another eight. Four themes reflected clinicians’ perspectives: (1) Bootle Blast disguises therapy as play, (2) clinicians give Bootle Blast the human touch; (3) home use of Bootle Blast is promising; and (4) Bootle Blast is not always the right fit but some shortcomings could be addressed. Agreement was found for nine MLS and disagreement for four MLS when quantitative and qualitative findings were merged.DiscussionBootle Blast delivers several MLS as part of game play and clinicians can enhance and provide additional MLS to suit the child's needs/abilities. Further game refinements that were identified in this study may optimize its clinical use.

Abstract Background An English version of the Patient Perception of Patient-Centeredness (PPPC) scale was recently revised, and it is necessary to test this instrument in different primary care populations. Aim This study aimed to assess the validity and reliability of a Chinese version of the PPPC scale. Design A mixed method was used in this study. The Delphi method was used to collect qualitative and quantitative data to address the content validity of the PPPC scale by calculating the Content Validity Index, Content Validity Ratio, the adjusted Kappa, and the Item Impact Score. Confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) were used to assess the construct validity of the PPPC scale through a cross-sectional survey. The internal consistency was also assessed. Setting/participants In the Delphi consultation, seven experts were consulted through a questionnaire sent by email. The cross-sectional survey interviewed 188 outpatients in Guangzhou city and 108 outpatients in Hohhot City from community health service centers or stations face-to-face. Results The 21 items in the scale were relevant to their component. The Item-level Content Validity Index for each item was higher than 0.79, and the average Scale-level content validity index was 0.97 in each evaluation round. The initial proposed 4-factor CFA model did not fit adequately. Still, we found a 3-factor solution based on our EFA model and the validation via the CFA model (model fit: $${\chi }^{2}=294.573$$ χ 2 = 294.573 , P

Abstract A core pathophysiologic feature underlying many respiratory diseases is multiciliated cell dysfunction, leading to inadequate mucociliary clearance. Due to the prevalence and highly variable etiology of mucociliary dysfunction in respiratory diseases, it is critical to understand the mechanisms controlling multiciliogenesis that may be targeted to restore functional mucociliary clearance. Multicilin, in a complex with E2F4, is necessary and sufficient to drive multiciliogenesis in airway epithelia, however this does not apply to all cell types, nor does it occur evenly across all cells in the same cell population. In this study we further investigated how co-factors regulate the ability of Multicilin to drive multiciliogenesis. Combining data in mouse embryonic fibroblasts and human bronchial epithelial cells, we identify RBL2 as a repressor of the transcriptional activity of Multicilin. Knockdown of RBL2 in submerged cultures or phosphorylation of RBL2 in response to apical air exposure, in the presence of Multicilin, allows multiciliogenesis to progress. These data demonstrate a dynamic interaction between RBL2 and Multicilin that regulates the capacity of cells to differentiate and multiciliate. Identification of this mechanism has important implications for facilitating MCC differentiation in diseases with impaired mucociliary clearance.

While psychotherapy incorporating equine interaction (PIE) has proven to be a viable therapeutic intervention, it is not a common mental health service found on college campuses. Nevertheless, with the rise of mental health challenges on campuses after the COVID-19 pandemic, a need for effective therapeutic solutions is warranted. Therefore, the objective of this study was to determine the effect of a collegiate recovery community (CRC) PIE program for substance abuse disorder (SUD) compared to that of traditional cognitive behavioral therapy (CBT) and to determine whether physiological synchronization occurs between the human and horse during the therapy process. College-aged adults were recruited during the COVID-19 pandemic for two types of short-term SUD therapeutic interventions, CRC-PIE and CBT. Both groups completed a self-reporting survey assessing emotional safety. Vital signs measurements for human and horse participants within the CRC-PIE were collected prior to and after the first and last therapeutic sessions. Results concluded that although emotional safety did not improve significantly for PIE participants by the last therapy session (p = 0.85), emotional safety scores were significantly different between therapy types, with lower post-therapy scores for PIE (p = 0.04). As for physiological measures for PIE participants, respiratory rates (Human: p = 0.01; Horse: p = 0.01) and pain rating scores (Human: p = 0.03; Horse: p = 0.01) significantly decreased post-therapy and a strong positive correlation (R = 0.73, R2 = 0.53) associated with vital signs was observed between humans and horses. This human–horse physiological synchronization during the therapeutic intervention suggests that the horse may be a viable tool within campus CRC programs for the development of therapeutic alliances within the therapy process.

Effective teaching requires an educational environment that promotes learning, and yet, developing such an environment can be challenging within today’s agricultural-based classroom for educators due to the trend to a more virtual teaching format and less hands-on learning. Animal interaction, particularly equine activities, has been shown to assist educators in the development of an emotionally safe environment for promoting learning. However, research is lacking as to whether the interaction with the animal needs to be direct or indirect within the collegiate educational environment to observe benefits. Therefore, the objective of this study was to determine the impact of equine interaction, both direct and indirect, within an educational environment on the emotional safety and learning for the college student within the agricultural-based classroom. Three course types were observed within the agricultural-based educational environment that included courses with no equine interaction (Group A) and courses with equine interaction, both direct (Group B) and indirect (Group C) interaction with the horse. Indirect interaction included items such as observation of equine handling via a video or gaining knowledge from reading online materials, but not engaging in direct, hands-on activities with the horse. Development of emotional safety within the students enrolled within these courses was measured using a self-reporting emotional safety evaluation. Due to the structure of the scale, a decrease in emotional safety indicated a positive change. Learning, both development of semantic and procedural memory, was measured using a student-completed knowledge examination and an instructor-completed skill evaluation, respectively. While significant improvement in emotional safety was not observed within any of the course types, a weak negative correlation was found between emotional safety and semantic memory for students enrolled in equine courses, both direct (R = −0.55, R2 = 0.28) and indirect (R = −0.25, R2 = 0.06) interaction, finding as emotional safety scores lowered to the ideal range that knowledge improved. In addition, students within equine courses showed semantic memory development in specific areas of equine sciences (Group B: Grooming/Tacking, p = 0.03; Group C: Equine Behavior, p = 0.04) and direct equine interaction resulted in development of equine-based procedural memory in all four skill areas measured within the study (p = 0.00). As such, learning is promoted through equine interaction, whether direct or indirect interaction, within the agricultural-based classroom, suggesting that both forms of equine interaction can be a valuable educational tool for the instructor within the collegiate setting.

Abstract Aims To review the contemporary international literature on nurse preceptor competencies and map the components and their descriptors. Review Methods A mapping review. Data Sources Articles reporting evidence‐based and validated Registered Nurse (RN) preceptor competencies published between 2013 and 2022 were identified. Open access databases such as PubMed and Google Scholar and the library healthcare databases Scopus and CINAHL were searched. The authors collaborated at each review stage that included screening, article selection, tabulation, mapping and preparation of findings. Results Seven quantitative studies were included. Three were based on existing nurse preceptor competency data sets and four were purposely developed using collaborative research methods. Each study validated findings through a survey of nurse stakeholders. Three key competencies shared across all studies were ‘facilitating teaching’, ‘being a role model’ and ‘evaluating student's performance’. The number of competency categories ranged from three to 10 and the accompanying item descriptors from 9 to 83. Although terminology describing data sets was inconsistent, similarity was seen across competency domains. Conclusion The contemporary nursing preceptor role is considered an emerging specialist education role. The results offer a set of validated preceptor competency descriptors, applicable to practice, that provide insight into ways employers may recruit, support and retain nurse preceptors. Implications for the Profession The mapped results provide a concise summary of nurse preceptor competency research internationally that can inform further development of RN preceptors. Impact This review addresses the lack of consensus around nursing preceptor competencies for clinical supervision of undergraduate nursing students. Seven competency domains were identified describing key preceptor role capabilities. The domains Facilitator’, ‘Role model’ and ‘Evaluator’ featured across the included studies: ‘More than 300 competency descriptors were reported’. Our review results could better prepare RN preceptors for their important role. Employers of RN preceptors could use the results to design performance competencies that may enhance nursing preceptorship. Reporting Method This review adheres to the PRISMA‐ScR EQUATOR guidelines as the recommended reporting method for mapping reviews.

Substance use disorder has become an epidemic in the young adult population across the United States, and these numbers rose during the COVID-19 pandemic. Psychotherapy incorporating equine interaction has emerged to show promise in the mental health community as a complementary form of therapy for this age group and offered a viable treatment option during the pandemic due to the outdoor nature of the treatment environment. However, research concerning its use within a residential treatment program was lacking. The objective of this study was to evaluate the efficacy of psychotherapy incorporating equine interaction in a residential treatment program during the COVID-19 pandemic for developing an emotionally safe environment for learning for young adults. Participants (ages 18–25 years) were those in a substance abuse residential treatment program utilizing psychotherapy incorporating equine interaction during the COVID-19 pandemic. Participants were involved in weekly equine therapy for 2–7 weeks. Participants were divided according to length of stay at the residential facility and participation level with equine interactive activities. Assessment of emotional safety and long-term memory development was performed at the beginning and end of the treatment program. The development of memories centered around equine information that was covered during the treatment program. Semantic memory was assessed using a self-reporting knowledge exam and procedural memory was assessed using a skill evaluation. Emotional safety was determined using a self-reporting survey instrument. Paired t-tests determined significant improvement in emotional safety (p = 0.02) and semantic (p = 0.01) and procedural (p = 0.00) memory for all participants by the end of the program. The one-way analysis of variance indicated length of stay and participation level were not significant indicators of emotional safety (length of stay: p = 0.91, participation level: p = 0.98) and semantic (length of stay: p = 0.09, participation level: p = 0.60) and procedural (length of stay: p = 0.25, participation level: p = 0.09) memory development. These results suggest psychotherapy incorporating equine interaction was an efficient complementary therapeutic intervention for developing emotional safety and encouraging learning in a young-adult residential addiction treatment program during the COVID-19 pandemic.

During the 2021 (n = 15) and 2022 (n = 13) summers, we measured the total and dissolved (

BackgroundDespite the Canadian healthcare system's commitment to equity, evidence for disparate access to primary care (PC) providers exists across individual social identities/positions. Intersectionality allows us to reflect the realities of how social power shapes healthcare experiences at an individual's interdependent and intersecting social identities/positions. The objectives of this study were to determine: (1) the extent to which intersections can be used classify those who had/did not have a PC provider; (2) the degree to which each social identity/position contributes to the ability to classify individuals as having a PC provider; and (3) predicted probabilities of having a PC provider for each intersection.Methods and findingsUsing national cross-sectional data from 241,445 individuals in Canada aged ≥18, we constructed 320 intersections along the dimensions of gender, age, immigration status, race, and income to examine the outcome of whether one had a PC provider. Multilevel analysis of individual heterogeneity and discriminatory accuracy, a multi-level model using individual-level data, was employed to address intersectional objectives. An intra-class correlation coefficient (ICC) of 23% (95%CI: 21-26%) suggests that these intersections could, to a very good extent, explain individual variation in the outcome, with age playing the largest role. Not all between-intersection variance in this outcome could be explained by additive effects of dimensions (remaining ICC: 6%; 95%CI: 2-16%). The highest intersectional predicted probability existed for established immigrant, older South Asian women with high income. The lowest intersectional predicted probability existed for recently immigrated, young, Black men with low income.ConclusionsDespite a "universal" healthcare system, our analysis demonstrated a substantial amount of inequity in primary care across intersections of gender, age, immigration status, race, and income.

SARS-CoV-2 infection remains a major public health concern, particularly for the aged and those individuals with co-morbidities at risk for developing severe COVID-19. Understanding the pathogenesis and biomarkers associated with responses to SARS-CoV-2 infection remain critical components in developing effective therapeutic approaches, especially in cases of severe and long-COVID-19. In this study blood plasma protein expression was compared in subjects with mild, moderate, and severe COVID-19 disease. Evaluation of an inflammatory protein panel confirms upregulation of proteins including TNFβ, IL-6, IL-8, IL-12, already associated with severe cytokine storm and progression to severe COVID-19. Importantly, we identify several proteins not yet associated with COVID-19 disease, including mesothelin (MSLN), that are expressed at significantly higher levels in severe COVID-19 subjects. In addition, we find a subset of markers associated with T-cell and dendritic cell responses to viral infection that are significantly higher in mild cases and decrease in expression as severity of COVID-19 increases, suggesting that an immediate and effective activation of T-cells is critical in modulating disease progression. Together, our findings identify new targets for further investigation as therapeutic approaches for the treatment of SARS-CoV-2 infection and prevention of complications of severe COVID-19.

Summary: Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.

IntroductionCarbon dioxide (CO2) is a critical biological signal that is noxious to many animals at high concentrations. The earthworm Dendrobaena veneta lives in subterranean burrows containing high levels of CO2 and respires through its skin. Despite the ecological and agricultural importance of earthworms, relatively little is known about how they make decisions in their environment, including their response to elevated levels of CO2.MethodsTo examine CO2 detection in this species, we designed the exudate assay, in which we placed an earthworm in a sealed container, exposed it to varying concentrations of CO2 for one minute, and recorded the amount of exudate secreted. Because earthworms excrete exudate in response to noxious stimuli, we hypothesized that the amount of exudate produced was proportional to the amount of irritation. We repeated these experiments after treatment with several blockers for molecules with potential involvement in CO2 detection, including carbonic anhydrases, guanylate cyclase, TRPA1, ASICs, and OTOP channels. We also confirmed the presence of homologous transcripts for each of these gene families in an epithelial transcriptome for D. veneta. Additionally, since organisms often detect CO2 levels indirectly by monitoring the conversion to carbonic acid (a weak acid), we used the exudate assay to evaluate aversion to additional weak acids (formic acid, acetic acid, and propionic acid).ResultsEarthworms excreted significantly more exudate in response to CO2 in a dosage-dependent manner, and this response was muted by the general carbonic anhydrase inhibitor acetazolamide, the carbonic anhydrase IX/XII inhibitor indisulam, the calcium channel blocker ruthenium red, the sodium channel blocker amiloride, and the acid-sensing ion channel blocker diminazene aceturate.DiscussionThese data provide evidence of the role of carbonic anhydrase and epithelial sodium channels in earthworm CO2 detection, establish that, similar to other subterranean-dwelling animals, earthworms are extremely tolerant of CO2, and contribute to our understanding of the mechanisms used by earthworms to detect and react to weak acids in their environment.

Transitional care to cardiac rehabilitation during the pandemic was a complex process for older adults, with additional challenges for decision-making and participation. This study aimed to explore the perspectives of older adults and health providers on transitional care from the hospital to cardiac rehabilitation, focusing on patient participation in decision-making. A qualitative exploratory design was used. Semi-structured interviews were conducted with 15 older adults and 6 healthcare providers. Document analysis and reflexive journaling were used to support triangulation of findings. Six themes emerged from the data, related to insufficient follow-up from providers, the importance of patients’ emotional and psychological health and the support provided by family members, the need for information tailored to patients’ needs and spaces for participation in decision-making, as well as challenges during COVID-19, including delayed medical procedures, rushed discharge and isolating hospital stays. The findings of this study indicated a number of potential gaps in the provision of transitional care services as reported by older adults who had a cardiovascular event, often during the first few weeks post hospital discharge.

A sizable portion of the United States’ population lives in a rural setting. Coupled with a limited number of infectious diseases providers, this has created a need for innovative practice models to deliver outpatient antimicrobial therapy and clinical monitoring in rural settings. This article reviews existing literature regarding outpatient parenteral antimicrobial therapy in rural settings and explores existing barriers and potential solutions that may be of assistance to providers looking to provide these services.

Abstract Background Prior to the pandemic, Canada lagged behind other Organisation for Economic Cooperation and Development countries in the uptake of virtual care. The onset of COVID-19, however, resulted in a near-universal shift to virtual primary care to minimise exposure risks. As jurisdictions enter a pandemic recovery phase, the balance between virtual and in-person visits is reverting, though it is unlikely to return to pre-pandemic levels. Our objective was to explore Canadian family physicians’ perspectives on the rapid move to virtual care during the COVID-19 pandemic, to inform both future pandemic planning for primary care and the optimal integration of virtual care into the broader primary care context beyond the pandemic. Methods We conducted semi-structured interviews with 68 family physicians from four regions in Canada between October 2020 and June 2021. We used a purposeful, maximum variation sampling approach, continuing recruitment in each region until we reached saturation. Interviews with family physicians explored their roles and experiences during the pandemic, and the facilitators and barriers they encountered in continuing to support their patients through the pandemic. Interviews were audio-recorded, transcribed, and thematically analysed for recurrent themes. Results We identified three prominent themes throughout participants’ reflections on implementing virtual care: implementation and evolution of virtual modalities during the pandemic; facilitators and barriers to implementing virtual care; and virtual care in the future. While some family physicians had prior experience conducting remote assessments, most had to implement and adapt to virtual care abruptly as provinces limited in-person visits to essential and urgent care. As the pandemic progressed, initial forays into video-based consultations were frequently replaced by phone-based visits, while physicians also rebalanced the ratio of virtual to in-person visits. Medical record systems with integrated capacity for virtual visits, billing codes, supportive clinic teams, and longitudinal relationships with patients were facilitators in this rapid transition for family physicians, while the absence of these factors often posed barriers. Conclusion Despite varied experiences and preferences related to virtual primary care, physicians felt that virtual visits should continue to be available beyond the pandemic but require clearer regulation and guidelines for its appropriate future use.

Utah Lake is unusual due to its large surface area, shallow depth, phosphorus-rich sediments, and well-mixed, unstratified waters. This creates conditions where water column phosphorous concentrations tend toward equilibrium, with lake sediments containing high concentrations of geologic phosphorus. To help understand the potential impact of phosphorous load reductions, we computed a time history of phosphorus mass in the lake using state and federal records of lake volume, dissolved phosphorus concentrations, and outflow. We show that historically, Utah Lake phosphorus concentrations have remained stable over time, in the range of 0.02 to 0.04 mg/L, despite large changes in lake volume and internal phosphorus mass. We performed sorption calculations using data from the literature, demonstrating that it would take unrealistically large load changes to alter water column phosphorus concentrations under sorption processes. The sorption model produces results consistent with historical data that show relatively constant phosphorous concentrations despite large lake volume changes. We show, through several lines of evidence, that water column phosphorus concentrations are insensitive to external loads. Phosphorous load reduction is unlikely to have a significant effect on phosphorus concentrations in Utah Lake and, by extension, in other sorption-dominated shallow lakes with phosphorus-rich sediment.

Outpatient parenteral antimicrobial therapy (OPAT) has been widely used in clinical practice for many decades because of its associated cost savings, reductions in inpatient hospital days, and decreases in hospital-associated infections. Despite this long history, evolving practice patterns and new drug delivery devices continue to present challenges as well as opportunities for clinicians when designing appropriate outpatient antimicrobial regimens. One such change is the increasing use of extended and continuous infusion (CI) of antimicrobials to optimize the achievement of pharmacokinetic and pharmacodynamic targets. Elastomeric devices are also becoming increasingly popular in OPAT, including for the delivery of CI. In this article, we review the clinical evidence for CI in OPAT, as well as practical considerations of patient preferences, cost, and antimicrobial stability.

Human lung function is intricately linked to blood flow and breathing cycles, but it remains unknown how these dynamic cues shape human airway epithelial biology. Here we report a state-of-the-art protocol for studying the effects of dynamic medium and airflow as well as stretch on human primary airway epithelial cell differentiation and maturation, including mucociliary clearance, using an organ-on-chip device. Perfused epithelial cell cultures displayed accelerated maturation and polarization of mucociliary clearance, and changes in specific cell-types when compared to traditional (static) culture methods. Additional application of airflow and stretch to the airway chip resulted in an increase in polarization of mucociliary clearance towards the applied flow, reduced baseline secretion of interleukin-8 and other inflammatory proteins, and reduced gene expression of matrix metalloproteinase (MMP) 9, fibronectin, and other extracellular matrix factors. These results indicate that breathing-like mechanical stimuli are important modulators of airway epithelial cell differentiation and maturation and that their fine-tuned application could generate models of specific epithelial pathologies, including mucociliary (dys)function.

Abstract Background The onset of the COVID-19 pandemic necessitated a rapid shift in primary health care from predominantly in-person to high volumes of virtual care. The pandemic afforded the opportunity to conduct a deep regional examination of virtual care by family physicians in London and Middlesex County, Ontario, Canada that would inform the foundation for virtual care in our region post-pandemic. Objectives: (1) to determine volumes of in-person and virtual family physicians visits and characteristics of the family physicians and patients using them during the early COVID-19 pandemic; (2) to determine how virtual visit volumes changed over the pandemic, compared to in-person; and (3) to explore family physicians’ experience in virtual visit adoption and implementation. Methods We conducted a concurrent mixed-methods study of family physicians from March to October 2020. The quantitative component examined mean weekly number of total, in-person and virtual visits using health administrative data. Differences in outcomes according to physician and practice characteristics for pandemic periods were compared to pre-pandemic. The qualitative study employed Constructivist Grounded Theory, conducting semi-structured family physicians interviews; analyzing data iteratively using constant comparative analysis. We mapped themes from the qualitative analysis to quantitative findings. Results Initial volumes of patients decreased, driven by fewer in-person visits. Virtual visit volumes increased dramatically; family physicians described using telephone almost entirely. Rural family physicians reported video connectivity issues. By early second wave, total family physician visit volume returned to pre-pandemic volumes. In-person visits increased substantially; family physicians reported this happened because previously scarce personal protective equipment became available. Patients seen during the pandemic were older, sicker, and more materially deprived. Conclusion These results can inform the future of virtual family physician care including the importance of continued virtual care compensation, the need for equitable family physician payment models, and the need to attend to equity for vulnerable patients. Given the move to virtual care was primarily a move to telephone care, the modality of care delivery that is acceptable to both family physicians and their patients must be considered.

Abstract Obese and overweight children are at risk of developing nonalcoholic fatty liver disease (NAFLD), which can lead to steatohepatitis, cirrhosis, and liver transplantation. Neuropsychiatric conditions affect an increasing proportion of children and often require neuropsychiatric medications (NPMs) that are associated with weight gain and/or drug‐induced liver injury. We sought to evaluate the role that the extended use of NPMs play in pediatric NAFLD. Medical chart review was conducted for 260 patients with NAFLD (NPM = 77, non‐NPM = 183) seen in the Liver Care Center at Children’s Mercy Hospital between 2000 and 2016. Outcome measures included body mass index (BMI) percentile, BMI z‐score, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and gamma glutamyltransferase, and were collected at diagnosis, 6–18 month follow‐up, and 18–36 months. Controlling for race and metformin, there was a significant increase over time in BMI z‐score (p

Abstract Background Effective deployment of AI tools in primary health care requires the engagement of practitioners in the development and testing of these tools, and a match between the resulting AI tools and clinical/system needs in primary health care. To set the stage for these developments, we must gain a more in-depth understanding of the views of practitioners and decision-makers about the use of AI in primary health care. The objective of this study was to identify key issues regarding the use of AI tools in primary health care by exploring the views of primary health care and digital health stakeholders. Methods This study utilized a descriptive qualitative approach, including thematic data analysis. Fourteen in-depth interviews were conducted with primary health care and digital health stakeholders in Ontario. NVivo software was utilized in the coding of the interviews. Results Five main interconnected themes emerged: (1) Mismatch Between Envisioned Uses and Current Reality—denoting the importance of potential applications of AI in primary health care practice, with a recognition of the current reality characterized by a lack of available tools; (2) Mechanics of AI Don’t Matter: Just Another Tool in the Toolbox– reflecting an interest in what value AI tools could bring to practice, rather than concern with the mechanics of the AI tools themselves; (3) AI in Practice: A Double-Edged Sword—the possible benefits of AI use in primary health care contrasted with fundamental concern about the possible threats posed by AI in terms of clinical skills and capacity, mistakes, and loss of control; (4) The Non-Starters: A Guarded Stance Regarding AI Adoption in Primary Health Care—broader concerns centred on the ethical, legal, and social implications of AI use in primary health care; and (5) Necessary Elements: Facilitators of AI in Primary Health Care—elements required to support the uptake of AI tools, including co-creation, availability and use of high quality data, and the need for evaluation. Conclusion The use of AI in primary health care may have a positive impact, but many factors need to be considered regarding its implementation. This study may help to inform the development and deployment of AI tools in primary health care.

In 2017 February, the blazar OJ 287 underwent a period of intense multiwavelength activity. It reached a new historic peak in the soft X-ray (0.3–10 keV) band, as measured by the Swift X-ray Telescope. This event coincides with a very-high-energy (VHE) γ -ray outburst that led VERITAS to detect emission above 100 GeV, with a detection significance of 10 σ (from 2016 December 9 to 2017 March 31). The time-averaged VHE γ -ray spectrum was consistent with a soft power law (Γ = −3.81 ± 0.26) and an integral flux corresponding to ∼2.4% that of the Crab Nebula above the same energy. Contemporaneous data from multiple instruments across the electromagnetic spectrum reveal a complex flaring behavior, primarily in the soft X-ray and VHE bands. To investigate the possible origin of such an event, our study focuses on three distinct activity states: before, during, and after the 2017 February peak. The spectral energy distributions during these periods suggest the presence of at least two nonthermal emission zones, with the more compact one responsible for the observed flare. Broadband modeling results and observations of a new radio knot in the jet of OJ 287 in 2017 are consistent with a flare originating from a strong recollimation shock outside the radio core.

Under non-pathological conditions, human γδ T cells represent a small fraction of CD3+ T cells in peripheral blood (1-10%). They constitute a unique subset of T lymphocytes that recognize stress ligands or non-peptide antigens through MHC-independent presentation. Major human γδ T cell subsets, Vδ1 and Vδ2, expand in response to microbial infection or malignancy, but possess distinct tissue localization, antigen recognition, and effector responses. We hypothesized that differences at the gene, phenotypic, and functional level would provide evidence that γδ T cell subpopulations belong to distinct lineages. Comparisons between each subset and the identification of the molecular determinants that underpin their differences has been hampered by experimental challenges in obtaining sufficient numbers of purified cells. By utilizing a stringent FACS-based isolation method, we compared highly purified human Vδ1 and Vδ2 cells in terms of phenotype, gene expression profile, and functional responses. We found distinct genetic and phenotypic signatures that define functional differences in γδ T cell populations. Differences in TCR components, repertoire, and responses to calcium-dependent pathways suggest that Vδ1 and Vδ2 T cells are different lineages. These findings will facilitate further investigation into the ligand specificity and unique role of Vδ1 and Vδ2 cells in early immune responses.

IntroductionIn response to viral infection, neutrophils release inflammatory mediators as part of the innate immune response, contributing to pathogen clearance through virus internalization and killing. Pre- existing co-morbidities correlating to incidence to severe COVID-19 are associated with chronic airway neutrophilia. Furthermore, examination of COVID-19 explanted lung tissue revealed a series of epithelial pathologies associated with the infiltration and activation of neutrophils, indicating neutrophil activity in response to SARS-CoV-2 infection.MethodsTo determine the impact of neutrophil-epithelial interactions on the infectivity and inflammatory responses to SARS-CoV-2 infection, we developed a co-culture model of airway neutrophilia. This model was infected with live SARS-CoV-2 virus the epithelial response to infection was evaluated.ResultsSARS-CoV-2 infection of airway epithelium alone does not result in a notable pro-inflammatory response from the epithelium. The addition of neutrophils induces the release of proinflammatory cytokines and stimulates a significantly augmented proinflammatory response subsequent SARS-CoV-2 infection. The resulting inflammatory responses are polarized with differential release from the apical and basolateral side of the epithelium. Additionally, the integrity of the \epithelial barrier is impaired with notable epithelial damage and infection of basal stem cells.ConclusionsThis study reveals a key role for neutrophil-epithelial interactions in determining inflammation and infectivity.

Abstract Background Disruption of alveolar epithelial cell (AEC) differentiation is implicated in distal lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung adenocarcinoma that impact morbidity and mortality worldwide. Elucidating underlying disease pathogenesis requires a mechanistic molecular understanding of AEC differentiation. Previous studies have focused on changes of individual transcription factors, and to date no study has comprehensively characterized the dynamic, global epigenomic alterations that facilitate this critical differentiation process in humans. Results We comprehensively profiled the epigenomic states of human AECs during type 2 to type 1-like cell differentiation, including the methylome and chromatin functional domains, and integrated this with transcriptome-wide RNA expression data. Enhancer regions were drastically altered during AEC differentiation. Transcription factor binding analysis within enhancer regions revealed diverse interactive networks with enrichment for many transcription factors, including NKX2–1 and FOXA family members, as well as transcription factors with less well characterized roles in AEC differentiation, such as members of the MEF2, TEAD, and AP1 families. Additionally, associations among transcription factors changed during differentiation, implicating a complex network of heterotrimeric complex switching in driving differentiation. Integration of AEC enhancer states with the catalog of enhancer elements in the Roadmap Epigenomics Mapping Consortium and Encyclopedia of DNA Elements (ENCODE) revealed that AECs have similar epigenomic structures to other profiled epithelial cell types, including human mammary epithelial cells (HMECs), with NKX2–1 serving as a distinguishing feature of distal lung differentiation. Conclusions Enhancer regions are hotspots of epigenomic alteration that regulate AEC differentiation. Furthermore, the differentiation process is regulated by dynamic networks of transcription factors acting in concert, rather than individually. These findings provide a roadmap for understanding the relationship between disruption of the epigenetic state during AEC differentiation and development of lung diseases that may be therapeutically amenable.

Radiological /nuclear (R/N) mass casualty incidents can potentially expose several hundreds and thousands of humans to substantial doses of ionizing radiation (IR). Timely assessment of radiation dose is critical for making “life-saving” clinical decision for those with exposures to moderate and high doses of radiation. The current biodosimetry techniques are time consuming and laborious making them impractical for mass casualty incidents. Therefore, improvements for the existing techniques and development of new biodosimetry tools are required for rapid individualized dose estimation. This review summarizes some of the ongoing multi-parametric efforts at the REAC/TS Cytogenetic Biodosimetry Laboratory (REAC/TS CBL) to accelerate the radiation dose assessment in exposed individuals.

Abstract Background The prevalence of multimorbidity varies widely due to the lack of consensus in defining multimorbidity. This study aimed to measure the prevalence of multimorbidity in a primary care setting using two definitions of multimorbidity with two different lists of chronic conditions. Methods We conducted a cross-sectional study of 787,446 patients, aged 0 to 99 years, who consulted a family physician between July 2015 to June 2016. Multimorbidity was defined as ‘two or more’ (MM2+) or ‘three or more’ (MM3+) chronic conditions using the Fortin list and Chronic Disease Management Program (CDMP) list of chronic conditions. Crude and standardised prevalence rates were reported, and the corresponding age, sex or ethnic-stratified standardised prevalence rates were adjusted to the local population census. Results The number of patients with multimorbidity increased with age. Age-sex-ethnicity standardised prevalence rates of multimorbidity using MM2+ and MM3+ for Fortin list (25.9, 17.2%) were higher than those for CDMP list (22.0%; 12.4%). Sex-stratified, age-ethnicity standardised prevalence rates for MM2+ and MM3+ were consistently higher in males compared to females for both lists. Chinese and Indians have the highest standardised prevalence rates among the four ethnicities using MM2+ and MM3+ respectively. Conclusions MM3+ was better at identifying a smaller number of patients with multimorbidity requiring higher needs compared to MM2+. Using the Fortin list seemed more appropriate than the CDMP list because the chronic conditions in Fortin’s list were more commonly seen in primary care. A consistent definition of multimorbidity will help researchers and clinicians to understand the epidemiology of multimorbidity better.

Abstract The use of Cannabis sativa, or Hemp, in commercial, recreational, and pharmacological applications is on the rise in the United States and worldwide. Many of these applications have guidelines associated with them dependent on the concentration of cannabinoid molecules that keep the products classified as hemp versus marijuana or that allow the producer to comment on the purity and potency of their product. Herein, we propose a method for homogenization of hemp that results in small particle sizes, uniform samples, and does not alter the cannabinoid concentrations during processing, allowing for optimal and reproducible potency testing. Using a novel “active grinding media” we homogenized commercially available hemp to analyze approximately 100 mg samples of homogenate via sieve analysis and high-performance liquid chromatography to assess the resulting size and potency of the sample when using this methodology. When processing hemp samples with our proposed methodology, we have demonstrated the ability to produce 60.2% of all particles

Purpose: Many cancer survivors experience cancer-related cognitive impairment (CRCI). We conducted a randomized controlled pilot trial of 2 types of yoga practice and evaluated their effects on participants’ objective cognitive function. Methods: Sedentary breast or ovarian cancer survivors were randomized to practice either restorative yoga (with more meditative practice and minimal physical exertion) or vigorous yoga (with considerable physical exertion and minimal meditative practice) in 60-minute supervised sessions 3 times a week for 12 weeks, followed by 12 weeks of home practice. We used the NIH Toolbox Cognition Domain to evaluate participants at baseline, week 12, and week 24. Results: We enrolled 35 participants. For women in the restorative yoga group, overall cognitive function was statistically significantly improved at weeks 12 and 24 compared to baseline ( P = .03 and 0.004; Cohen’s D = 0.3 and 0.5). Fluid cognitive function also significantly improved at weeks 12 and 24 ( P = .02 and 0.0007; Cohen’s D = 0.3 and 0.6), whereas improvements in crystallized cognition were not significant. For women in the vigorous yoga group, significant improvement was only seen in tasks of crystallized cognition at week 24 ( P = .03; Cohen’s D = 0.5). Between-group comparisons showed that at week 24, women in the restorative yoga group had significantly higher scores on fluid cognition tasks. Conclusions: Patients who participated in yoga practice demonstrated improvement in objective cognitive function over time. Restorative yoga may be more effective in improving fluid cognitive function at week 24 when compared to vigorous yoga. These promising findings should be confirmed in definitive studies. Trial registration: Clinicaltrials.gov; NCT02305498 (Date Registered: December 2, 2014)

Abstract Introduction Americans with diabetes are clinically vulnerable to worse COVID‐19 outcomes; thus, insight into how to prevent infection is imperative. Using longitudinal, prospective data from the real‐world iNPHORM study, we identify the intrinsic and extrinsic risk factors of confirmed or probable COVID‐19 in people with type 1 or 2 diabetes. Methods The iNPHORM study recruited 1206 Americans (18–90 years) with insulin‐ and/or secretagogue‐treated type 1 or 2 diabetes from a probability‐based internet panel. Online questionnaires (screener, baseline and 12 monthly follow‐ups) assessed COVID‐19 incidence and various plausible intrinsic and extrinsic factors. Multivariable Cox regression was used to model the rate of COVID‐19 (confirmed or probable). Risk factors were selected using a repeated backwards‐selection ‘voting’ procedure. Results A sub‐sample of 817 iNPHORM participants (type 1 diabetes: 16.9%; age: 52.1 [SD: 14.2] years; female: 50.2%) was analysed between May 2020 and March 2021. During this period, 13.7% reported confirmed or probable COVID‐19. Age, body mass index, number of chronic comorbidities, most recent A1C, past severe hypoglycaemia, and employment status were selected in our final model. Body mass index ≥30 kg/m2 versus