Foot and ankle problems in children and young people: a population-based cohort study.

The aim of this research was to describe the epidemiology, presentation and healthcare use in primary care for foot and ankle problems in children and young people (CYP) across England. We undertook a population-based cohort study using data from the Clinical Practice Research Datalink Aurum database, a database of anonymised electronic health records from general practices across England. Data was accessed for all CYP aged 0-18 years presenting to their general practitioner between January 2015 and December 2021 with a foot and/or ankle problem. Consultation rates were calculated and used to estimate numbers of consultations in an average practice. Hierarchical Poisson regression estimated relative rates of consultations across sociodemographic groups and logistic regression evaluated factors associated with repeat consultations. A total of 416,137 patients had 687,753 foot and ankle events, of which the majority were categorised as "musculoskeletal" (34%) and "unspecified pain" (21%). Rates peaked at 601 consultations per 10,000 patient-years among males aged 10-14 years in 2018. An average practice might observe 132 (95% CI 110 to 155) consultations annually. Odds for repeat consultations were higher among those with pre-existing diagnoses including juvenile arthritis (OR 1.73, 95% CI 1.48 to 2.03).    Conclusions: Consultations for foot and ankle problems were high among CYP, particularly males aged 10 to 14 years. These data can inform service provision to ensure CYP access appropriate health professionals for accurate diagnosis and treatment. What is Known: • Foot and ankle problems can have considerable impact on health-related quality of life in children and young people (CYP). • There is limited data describing the nature and frequency of foot and ankle problems in CYP. What is New: • Foot and ankle consultations were higher in English general practice among CYP aged 10 to 14 years compared to other age groups, and higher among males compared to females. • The high proportion of unspecified diagnoses and repeat consultations suggests there is need for greater integration between general practice and allied health professionals in community-based healthcare settings.

Genome-wide analyses of XRN1-sensitive targets in osteosarcoma cells identify disease-relevant transcripts containing G-rich motifs.

XRN1 is a highly conserved exoribonuclease which degrades uncapped RNAs in a 5'-3' direction. Degradation of RNAs by XRN1 is important in many cellular and developmental processes and is relevant to human disease. Studies in D. melanogaster demonstrate that XRN1 can target specific RNAs, which have important consequences for developmental pathways. Osteosarcoma is a malignancy of the bone and accounts for 2% of all pediatric cancers worldwide. Five-year survival of patients has remained static since the 1970s and therefore furthering our molecular understanding of this disease is crucial. Previous work has shown a down-regulation of XRN1 in osteosarcoma cells; however, the transcripts regulated by XRN1 which might promote osteosarcoma remain elusive. Here, we confirm reduced levels of XRN1 in osteosarcoma cell lines and patient samples and identify XRN1-sensitive transcripts in human osteosarcoma cells. Using RNA-seq in XRN1-knockdown SAOS-2 cells, we show that 1178 genes are differentially regulated. Using a novel bioinformatic approach, we demonstrate that 134 transcripts show characteristics of direct post-transcriptional regulation by XRN1. Long noncoding RNAs (lncRNAs) are enriched in this group, suggesting that XRN1 normally plays an important role in controlling lncRNA expression in these cells. Among potential lncRNAs targeted by XRN1 is HOTAIR, which is known to be up-regulated in osteosarcoma and contributes to disease progression. We have also identified G-rich and GU motifs in post-transcriptionally regulated transcripts which appear to sensitize them to XRN1 degradation. Our results therefore provide significant insights into the specificity of XRN1 in human cells which are relevant to disease.

A cross-sectional assessment of frailty, falls and perceptions of ageing in people living with HIV using an mHealth platform.

OBJECTIVE: To evaluate frailty, falls and perceptions of ageing among clinically stable individuals with HIV, engaged with remote healthcare delivered via a novel smartphone application. METHODS: This was a multi-centre European cross-sectional, questionnaire-based sub-study of EmERGE participants. Frailty was assessed using the five-item FRAIL scale. Present criteria were summed and categorized as follows: 0, robust; 1-2, pre-frail; 3-5, frail. Falls history and EQ-5D-5L quality of life measure were completed. Participants were asked their felt age and personal satisfaction with ageing. RESULTS: A total of 1373 participated, with a mean age of 45 (± 9.8) years. Frailty was uncommon at 2%; 12.4% fell in the previous year, 58.8% of these recurrently. Mood symptoms and pain were prevalent, at 43.3% and 31.8%, respectively. Ageing satisfaction was high at 76.4%, with 74.6% feeling younger than their chronological age; the mean felt age was 39.3 years. In multivariable analysis, mood symptoms and pain were positively associated with frailty, falls and ageing dissatisfaction. An increase in pain severity and mood symptoms were respectively associated with 34% and 63% increased odds of pre-frailty/frailty. An increment in pain symptoms was associated with a 71% increase in odds of falling. Pain was associated with ageing poorly, as were mood symptoms, with odds of dissatisfaction increasing by 34% per increment in severity. CONCLUSIONS: Although uncommon, frailty, falls and ageing dissatisfaction were seen in a younger cohort with medically stable HIV infection using a remote care model, promoting screening as advocated by European guidelines. These were more common in those with pain or mood symptoms, which should be proactively managed in clinical care and explored further in future research.

TLR9 expression in chronic lymphocytic leukemia identifies a promigratory subpopulation and novel therapeutic target.

Chronic lymphocytic leukemia (CLL) remains incurable despite B-cell receptor-targeted inhibitors revolutionizing treatment. This suggests that other signaling molecules are involved in disease escape mechanisms and resistance. Toll-like receptor 9 (TLR9) is a promising candidate that is activated by unmethylated cytosine guanine dinucleotide-DNA. Here, we show that plasma from patients with CLL contains significantly more unmethylated DNA than plasma from healthy control subjects (P < .0001) and that cell-free DNA levels correlate with the prognostic markers CD38, ß2-microglobulin, and lymphocyte doubling time. Furthermore, elevated cell-free DNA was associated with shorter time to first treatment (hazard ratio, 4.0; P = .003). We also show that TLR9 expression was associated with in vitro CLL cell migration (P < .001), and intracellular endosomal TLR9 strongly correlated with aberrant surface expression (sTLR9; r = 0.9). In addition, lymph node-derived CLL cells exhibited increased sTLR9 (P = .016), and RNA-sequencing of paired sTLR9hi and sTLR9lo CLL cells revealed differential transcription of genes involved in TLR signaling, adhesion, motility, and inflammation in sTLR9hi cells. Mechanistically, a TLR9 agonist, ODN2006, promoted CLL cell migration (P < .001) that was mediated by p65 NF-κB and STAT3 transcription factor activation. Importantly, autologous plasma induced the same effects, which were reversed by a TLR9 antagonist. Furthermore, high TLR9 expression promoted engraftment and rapid disease progression in a NOD/Shi-scid/IL-2Rγnull mouse xenograft model. Finally, we showed that dual targeting of TLR9 and Bruton's tyrosine kinase (BTK) was strongly synergistic (median combination index, 0.2 at half maximal effective dose), which highlights the distinct role for TLR9 signaling in CLL and the potential for combined targeting of TLR9 and BTK as a more effective treatment strategy in this incurable disease.

Correction: Spelling Errors and Shouting Capitalization Lead to Additive Penalties to Trustworthiness of Online Health Information: Randomized Experiment With Laypersons.

[This corrects the article DOI: 10.2196/15171.].

Functional redundancy between RAP1 isoforms in murine platelet production and function.

RAP GTPases, important regulators of cellular adhesion, are abundant signaling molecules in the platelet/megakaryocytic lineage. However, mice lacking the predominant isoform, RAP1B, display a partial platelet integrin activation defect and have a normal platelet count, suggesting the existence of a RAP1-independent pathway to integrin activation in platelets and a negligible role for RAP GTPases in megakaryocyte biology. To determine the importance of individual RAP isoforms on platelet production and on platelet activation at sites of mechanical injury or vascular leakage, we generated mice with megakaryocyte-specific deletion (mKO) of Rap1a and/or Rap1b Interestingly, Rap1a/b-mKO mice displayed a marked macrothrombocytopenia due to impaired proplatelet formation by megakaryocytes. In platelets, RAP isoforms had redundant and isoform-specific functions. Deletion of RAP1B, but not RAP1A, significantly reduced α-granule secretion and activation of the cytoskeleton regulator RAC1. Both isoforms significantly contributed to thromboxane A2 generation and the inside-out activation of platelet integrins. Combined deficiency of RAP1A and RAP1B markedly impaired platelet aggregation, spreading, and clot retraction. Consistently, thrombus formation in physiological flow conditions was abolished in Rap1a/b-mKO, but not Rap1a-mKO or Rap1b-mKO, platelets. Rap1a/b-mKO mice were strongly protected from experimental thrombosis and exhibited a severe defect in hemostasis after mechanical injury. Surprisingly, Rap1a/b-mKO platelets were indistinguishable from controls in their ability to prevent blood-lymphatic mixing during development and hemorrhage at sites of inflammation. In summary, our studies demonstrate an essential role for RAP1 signaling in platelet integrin activation and a critical role in platelet production. Although important for hemostatic/thrombotic plug formation, platelet RAP1 signaling is dispensable for vascular integrity during development and inflammation.

Spelling Errors and Shouting Capitalization Lead to Additive Penalties to Trustworthiness of Online Health Information: Randomized Experiment With Laypersons.

BACKGROUND: The written format and literacy competence of screen-based texts can interfere with the perceived trustworthiness of health information in online forums, independent of the semantic content. Unlike in professional content, the format in unmoderated forums can regularly hint at incivility, perceived as deliberate rudeness or casual disregard toward the reader, for example, through spelling errors and unnecessary emphatic capitalization of whole words (online shouting). OBJECTIVE: This study aimed to quantify the comparative effects of spelling errors and inappropriate capitalization on ratings of trustworthiness independently of lay insight and to determine whether these changes act synergistically or additively on the ratings. METHODS: In web-based experiments, 301 UK-recruited participants rated 36 randomized short stimulus excerpts (in the format of information from an unmoderated health forum about multiple sclerosis) for trustworthiness using a semantic differential slider. A total of 9 control excerpts were compared with matching error-containing excerpts. Each matching error-containing excerpt included 5 instances of misspelling, or 5 instances of inappropriate capitalization (shouting), or a combination of 5 misspelling plus 5 inappropriate capitalization errors. Data were analyzed in a linear mixed effects model. RESULTS: The mean trustworthiness ratings of the control excerpts ranged from 32.59 to 62.31 (rating scale 0-100). Compared with the control excerpts, excerpts containing only misspellings were rated as being 8.86 points less trustworthy, those containing inappropriate capitalization were rated as 6.41 points less trustworthy, and those containing the combination of misspelling and capitalization were rated as 14.33 points less trustworthy (P<.001 for all). Misspelling and inappropriate capitalization show an additive effect. CONCLUSIONS: Distinct indicators of incivility independently and additively penalize the perceived trustworthiness of online text independently of lay insight, eliciting a medium effect size.

Determining the accuracy of zero-flux and ingestible thermometers in the peri-operative setting.

Accurately monitoring peri-operative core temperature is a cornerstone of good practice. Relatively invasive devices such as oesophageal temperature probes and pulmonary artery catheters facilitate this, but are inappropriate for many patients. There remains a need for accurate monitors of core temperature that can be used in awake patients. This study compared the accuracy of two core temperature thermometers that can be used for this purpose: the 3M Bair Hugger™ Temperature Monitoring System Zero Flux Thermometer and the CorTempR™ Wireless Ingestible Temperature Sensor. Readings were compared with the oesophageal probe, the current intraoperative standard. Thirty patients undergoing elective surgical procedures under general anaesthesia were recruited. The ingestible sensor was ingested prior to induction of anaethesia, and post induction, the zero-flux electrode attached above the right eyebrow and oesophageal probe inserted. During surgery, the temperature on each device was recorded every minute. Measurements were compared using Bland-Altman analysis. The ingestible sensor experienced interference from use of diathermy and fluoroscopy in the operating theatre, rendering 39% of its readings unusable. These were removed from analysis. With remaining readings the bias compared with oesophageal probe was + 0.42 °C, with 95% limits of agreement - 2.4 °C to 3.2 °C. 75.4% of readings were within ± 0.5 °C of the OTP reading. The bias for the zero flux electrode compared to oesophageal probe was + 0.02 °C with 95% limits of agreement - 0.5 °C to 0.5 °C. 97.7% of readings were within ± 0.5 °C of the oesophageal probe. The study findings suggest the zero-flux thermometer is sufficiently accurate for clinical use, whereas the ingestible sensor is not.Trial registration The study was registered at http://www.clinicaltrials.gov , NCT Number: NCT02121574.

RNA-seq reveals post-transcriptional regulation of Drosophila insulin-like peptide dilp8 and the neuropeptide-like precursor Nplp2 by the exoribonuclease Pacman/XRN1.

Ribonucleases are critically important in many cellular and developmental processes and defects in their expression are associated with human disease. Pacman/XRN1 is a highly conserved cytoplasmic exoribonuclease which degrades RNAs in a 5'-3' direction. In Drosophila, null mutations in pacman result in small imaginal discs, a delay in onset of pupariation and lethality during the early pupal stage. In this paper, we have used RNA-seq in a genome-wide search for mRNAs misregulated in pacman null wing imaginal discs. Only 4.2% of genes are misregulated ±>2-fold in pacman null mutants compared to controls, in line with previous work showing that Pacman has specificity for particular mRNAs. Further analysis of the most upregulated mRNAs showed that Pacman post-transcriptionally regulates the expression of the secreted insulin-like peptide Dilp8. Dilp8 is related to human IGF-1, and has been shown to coordinate tissue growth with developmental timing in Drosophila. The increased expression of Dilp8 is consistent with the developmental delay seen in pacman null mutants. Our analysis, together with our previous results, show that the normal role of this exoribonuclease in imaginal discs is to suppress the expression of transcripts that are crucial in apoptosis and growth control during normal development.

The roles of the exoribonucleases DIS3L2 and XRN1 in human disease.

RNA degradation is a vital post-transcriptional process which ensures that transcripts are maintained at the correct level within the cell. DIS3L2 and XRN1 are conserved exoribonucleases that are critical for the degradation of cytoplasmic RNAs. Although the molecular mechanisms of RNA degradation by DIS3L2 and XRN1 have been well studied, less is known about their specific roles in the development of multicellular organisms or human disease. This review focusses on the roles of DIS3L2 and XRN1 in the pathogenesis of human disease, particularly in relation to phenotypes seen in model organisms. The known diseases associated with loss of activity of DIS3L2 and XRN1 are discussed, together with possible mechanisms and cellular pathways leading to these disease conditions.

A novel role for the 3'-5' exoribonuclease Dis3L2 in controlling cell proliferation and tissue growth.

In a complex organism, cell proliferation and apoptosis need to be precisely controlled in order for tissues to develop correctly. Excessive cell proliferation can lead to diseases such as cancer. We have shown that the exoribonuclease Dis3L2 is required for the correct regulation of proliferation in a natural tissue within the model organism Drosophila melanogaster. Dis3L2 is a member of a highly conserved family of exoribonucleases that degrade RNA in a 3'-5' direction. We show that knockdown of dis3L2 in the Drosophila wing imaginal discs results in substantial wing overgrowth due to increased cellular proliferation rather than an increase in cell size. Imaginal discs are specified in the embryo before proliferating and differentiating to form the adult structures of the fly. Using RNA-seq we identified a small set of mRNAs that are sensitive to Dis3L2 activity. Of the mRNAs which increase in levels and are therefore potential targets of Dis3L2, we identified 2 that change at the post-transcriptional level but not at the transcriptional level, namely CG2678 (a transcription factor) and pyrexia (a TRP cation channel). We also demonstrate a compensatory effect between Dis3L2 and the 5'-3' exoribonuclease Pacman demonstrating that these 2 exoribonucleases function to regulate opposing pathways within the developing tissue. This work provides the first description of the molecular and developmental consequences of Dis3L2 inactivation in a non-human animal model. The work is directly relevant to the understanding of human overgrowth syndromes such as Perlman syndrome.

Mechanisms of regulation of mature miRNAs.

miRNAs are short RNA molecules of ∼22-nt in length that play important roles in post-transcriptional control of gene expression. miRNAs normally function as negative regulators of mRNA expression by binding complementary sequences in the 3'-UTR of target mRNAs and causing translational repression and/or target degradation. Much research has been undertaken to enhance understanding of the biogenesis, function and targeting of miRNAs. However, until recently, the mechanisms underlying the regulation of the levels of mature miRNAs themselves have been largely overlooked. Although it has generally been assumed that miRNAs are stable molecules, recent evidence indicates that the stability of specific mature miRNAs can be regulated during key cellular and developmental processes in certain cell types. Here we discuss the current knowledge of the mechanisms by which mature miRNAs are regulated in the cell and the factors that contribute to the control of their stability.

The 3'-5' exoribonuclease Dis3 regulates the expression of specific microRNAs in Drosophila wing imaginal discs.

Dis3 is a highly conserved exoribonuclease which degrades RNAs in the 3'-5' direction. Mutations in Dis3 are associated with a number of human cancers including multiple myeloma and acute myeloid leukemia. In this work, we have assessed the effect of a Dis3 knockdown on Drosophila imaginal disc development and on expression of mature microRNAs. We find that Dis3 knockdown severely disrupts the development of wing imaginal discs in that the flies have a "no wing" phenotype. Use of RNA-seq to quantify the effect of Dis3 knockdown on microRNA expression shows that Dis3 normally regulates a small subset of microRNAs, with only 11 (10.1%) increasing in level ≥ 2-fold and 6 (5.5%) decreasing in level ≥ 2-fold. Of these microRNAs, miR-252-5p is increased 2.1-fold in Dis3-depleted cells compared to controls while the level of the miR-252 precursor is unchanged, suggesting that Dis3 can act in the cytoplasm to specifically degrade this mature miRNA. Furthermore, our experiments suggest that Dis3 normally interacts with the exosomal subunit Rrp40 in the cytoplasm to target miR-252-5p for degradation during normal wing development. Another microRNA, miR-982-5p, is expressed at lower levels in Dis3 knockdown cells, while the miR-982 precursor remains unchanged, indicating that Dis3 is involved in its processing. Our study therefore reveals an unexpected specificity for this ribonuclease toward microRNA regulation, which is likely to be conserved in other eukaryotes and may be relevant to understanding its role in human disease.

XRN 5'→3' exoribonucleases: structure, mechanisms and functions.

The XRN family of 5'→3' exoribonucleases is critical for ensuring the fidelity of cellular RNA turnover in eukaryotes. Highly conserved across species, the family is typically represented by one cytoplasmic enzyme (XRN1/PACMAN or XRN4) and one or more nuclear enzymes (XRN2/RAT1 and XRN3). Cytoplasmic and/or nuclear XRNs have proven to be essential in all organisms tested, and deficiencies can have severe developmental phenotypes, demonstrating that XRNs are indispensable in fungi, plants and animals. XRNs degrade diverse RNA substrates during general RNA decay and function in specialized processes integral to RNA metabolism, such as nonsense-mediated decay (NMD), gene silencing, rRNA maturation, and transcription termination. Here, we review current knowledge of XRNs, highlighting recent work of high impact and future potential. One example is the breakthrough in our understanding of how XRN1 processively degrades 5' monophosphorylated RNA, revealed by its crystal structure and mutational analysis. The expanding knowledge of XRN substrates and interacting partners is outlined and the functions of XRNs are interpreted at the organismal level using available mutant phenotypes. Finally, three case studies are discussed in more detail to underscore a few of the most exciting areas of research on XRN function: XRN4 involvement in small RNA-associated processes in plants, the roles of XRN1/PACMAN in Drosophila development, and the function of human XRN2 in nuclear transcriptional quality control. This article is part of a Special Issue entitled: RNA Decay mechanisms.

The 5'-3' exoribonuclease Pacman (Xrn1) regulates expression of the heat shock protein Hsp67Bc and the microRNA miR-277-3p in Drosophila wing imaginal discs.

Pacman/Xrn1 is a highly conserved exoribonuclease known to play a critical role in gene regulatory events such as control of mRNA stability, RNA interference and regulation via miRNAs. Although Pacman has been well studied in Drosophila tissue culture cells, the biologically relevant cellular pathways controlled by Pacman in natural tissues are unknown. This study shows that a hypomorphic mutation in pacman (pcm (5)) results in smaller wing imaginal discs. These tissues, found in the larva, are known to grow and differentiate to form wing and thorax structures in the adult fly. Using microarray analysis, followed by quantitative RT-PCR, we show that eight mRNAs were increased in level by>2-fold in the pcm5 mutant wing discs compared with the control. The levels of pre-mRNAs were tested for five of these mRNAs; four did not increase in the pcm (5) mutant, showing that they are regulated at the post-transcriptional level and, therefore, could be directly affected by Pacman. These transcripts include one that encodes the heat shock protein Hsp67Bc, which is upregulated 11.9-fold at the post-transcriptional level and 2.3-fold at the protein level. One miRNA, miR-277-3p, is 5.6-fold downregulated at the post-transcriptional level in mutant discs, suggesting that Pacman affects its processing in this tissue. Together, these data show that a relatively small number of mRNAs and miRNAs substantially change in abundance in pacman mutant wing imaginal discs. Since Hsp67Bc is known to regulate autophagy and protein synthesis, it is possible that Pacman may control the growth of wing imaginal discs by regulating these processes.

Platelet factor XIII-A regulates platelet function and promotes clot retraction and stability.

Background: Factor XIII (FXIII) is an important proenzyme in the hemostatic system. The plasma-derived enzyme activated FXIII cross-links fibrin fibers within thrombi to increase their mechanical strength and cross-links fibrin to fibrinolytic inhibitors, specifically α2-antiplasmin, to increase resistance to fibrinolysis. We have previously shown that cellular FXIII (factor XIII-A [FXIII-A]), which is abundant in the platelet cytoplasm, is externalized onto the activated membrane and cross-links extracellular substrates. The contribution of cellular FXIII-A to platelet activation and platelet function has not been extensively studied. Objectives: This study aims to identify the role of platelet FXIII-A in platelet function. Methods: We used normal healthy platelets with a cell permeable FXIII inhibitor and platelets from FXIII-deficient patients as a FXIII-free platelet model in a range of platelet function and clotting tests. Results: Our data demonstrate that platelet FXIII-A enhances fibrinogen binding to the platelet surface upon agonist stimulation and improves the binding of platelets to fibrinogen and aggregation under flow in a whole-blood thrombus formation assay. In the absence of FXIII-A, platelets show reduced sensitivity to agonist stimulation, including decreased P-selectin exposure and fibrinogen binding. We show that FXIII-A is involved in platelet spreading where a lack of FXIII-A reduces the ability of platelets to fully spread on fibrinogen and collagen. Our data demonstrate that platelet FXIII-A is important for clot retraction where clots formed in its absence retracted to a lesser extent. Conclusion: Overall, this study shows that platelet FXIII-A functions during thrombus formation by aiding platelet activation and thrombus retraction in addition to its antifibrinolytic roles.

The rate of platelet activation determines thrombus size and structure at arterial shear.

BACKGROUND: The response of platelets to activating stimuli and pharmaceutical agents varies greatly within the normal population. Current platelet function tests are used to measure end-point levels of platelet activation without taking the speed at which platelets activate into account, potentially missing vital metrics to characterize platelet reactivity. OBJECTIVES: To identify variability, to agonists and among individuals, in platelet activation kinetics and assess the impact of this on thrombus formation. METHODS: We have developed a bespoke real-time flow cytometry assay and analysis package to measure the rate of platelet activation over time using 2 parameters of platelet activation, fibrinogen binding and P-selectin exposure. RESULTS: The rate of platelet activation varied considerably within the normal population but did not correlate with maximal platelet activation, demonstrating that platelet activation rate is a separate and novel metric to describe platelet reactivity. The relative rate of platelet response between agonists was strongly correlated, suggesting that a central control mechanism regulates the rate of platelet response to all agonists. CONCLUSION: For the first time, we have shown that platelet response rate corresponds to thrombus size and structure, wherein faster responders form larger, more densely packed thrombi at arterial, but crucially not venous, shear. We have demonstrated that the rate of platelet activation is an important metric in stratifying individual platelet responses and will provide a novel focus for the design and development of antiplatelet therapy, targeting high-shear thrombosis without exacerbating bleeding at low shear.

Spelling Errors in Brief Computer-Mediated Texts Implicitly Lead to Linearly Additive Penalties in Trustworthiness.

Background: Spelling errors in documents lead to reduced trustworthiness, but the mechanism for weighing the psychological assessment (i.e., integrative versus dichotomous) has not been elucidated. We instructed participants to rate content of texts, revealing that their implicit trustworthiness judgments show marginal differences specifically caused by spelling errors. Methods: An online experiment with 100 English-speaking participants were asked to rate 27 short text excerpts (∼100 words) about multiple sclerosis in the format of unmoderated health forum posts. In a counterbalanced design, some excerpts had no typographic errors, some had two errors, and some had five errors. Each participant rated nine paragraphs with a counterbalanced mixture of zero, two or five errors. A linear mixed effects model (LME) was assessed with error number as a fixed effect and participants as a random effect. Results: Using an unnumbered scale with anchors of "completely untrustworthy" (left) and "completely trustworthy" (right) recorded as 0 to 100, two spelling errors resulted in a penalty to trustworthiness of 5.91 ± 1.70 (robust standard error) compared to the reference excerpts with zero errors, while the penalty for five errors was 13.5 ± 2.47; all three conditions were significantly different from each other (P < 0.001). Conclusion: Participants who rated information about multiple sclerosis in a context mimicking an online health forum implicitly assigned typographic errors nearly linearly additive trustworthiness penalties. This contravenes any dichotomous heuristic or local ceiling effect on trustworthiness penalties for these numbers of typographic errors. It supports an integrative model for psychological judgments of trustworthiness.

The efficiency of the EmERGE platform for medically stable people living with HIV in Portugal.

Background: The aim of this study was to calculate the cost-effectiveness of the EmERGE Pathway of Care for medically stable people living with HIV in the Hospital Capuchos, Centro Hospitalar Universitário de Lisboa Central (HC-CHLC). The app enables individuals to receive HIV treatment information and communicate with caregivers. Methods: This before-and-after study collected the use of services data 1 year before implementation and after implementation of EmERGE from November 1, 2016, to October 30, 2019. Departmental unit costs were calculated and linked to mean use of outpatient services per patient-year (MPPY). Annual costs per patient-year were combined with primary (CD4 count; viral load) and secondary outcomes (PAM-13; PROQOL-HIV). Results: Five hundred eighty-six EmERGE participants used HIV outpatient services. Annual outpatient visits decreased by 35% from 3.1 MPPY (95% confidence interval [CI]: 3.0-3.3) to 2.0 (95% CI: 1.9-2.1) as did annual costs per patient-year from €301 (95% CI: €288-€316) to €193 (95% CI: €182-€204). Laboratory tests and costs increased by 2%, and radiology investigations decreased by 40% as did costs. Overall annual cost for HIV outpatient services decreased by 5% from €2093 (95% CI: €2071-€2112) to €1984 (95% CI: €1968-€2001); annual outpatient costs decreased from €12,069 (95% CI: €12,047-€12,088) to €11,960 (95% CI: €11,944-€11,977), with 83% of annual cost because of antiretroviral therapy (ART). Primary and secondary outcome measures did not differ substantially between periods. Conclusions: The EmERGE Pathway produced cost savings after implementation-extended to all people living with HIV additional savings are likely to be produced, which can be used to address other needs. Antiretroviral drugs (ARVs) were the main cost drivers and more expensive in Portugal compared with ARV costs in the other EmERGE sites.