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The proliferation of deepfakes and visual misinformation coupled with the fast-paced nature of social media has prompted an increased need for media literacy skills among emerging citizens. The unit activity detailed in this article overviews a media literacy framework for engaged citizenship and presents media literacy strategies that emerging citizens can use when confronted with mis/disinformation on social media. The approaches include SIFT and a four-step process for debunking misinformation. As students participate in this media literacy unit activity, which is focused on debunking deepfakes and halting the spread of mis/disinformation, they acquire tools for discerning truth and learning how to think critically before responding to and advancing the spread of misinformation. Courses: The unit activity is relevant for courses that address digital media, fake news, mass media and society, media literacy, and misinformation, including Digital Media, Fake News and Misinformation, Media Studies, Media Literacy, Political Communication, Rhetoric and Pop Culture, and Visual Communication. Objectives: This activity will enable students to (1) differentiate between disinformation, misinformation, and fake news in relevant media content; (2) identify and analyze examples of deepfakes, misinformation, and disinformation; (3) summarize and apply the 5 As of Media Literacy framework to a current event; and (4) employ media literacy strategies, including SIFT and a debunking approach, to respond to and halt the spread of visual misinformation on social media.

Abstract Introduction The health of the United Kingdom workforce is key; approximately 186 million days are lost to sickness each year. Obesity and type 2 diabetes (T2D) remain major global health challenges. The aim of this retrospective service evaluation was to assess the impact of a digitally enabled, time‐restricted eating (TRE) intervention (Roczen Program, Reset Health Ltd) on weight and other health‐related outcomes. Methods This service evaluation was conducted in people living with overweight/obesity, with 89% referred from public sector employers. Participants were placed on a TRE, low‐carbohydrate, moderate protein plan delivered by clinicians and mentors with regular follow up, dietary guidance, goal setting, feedback, and social support. Results A total of 660 members enrolled and retention was 41% at 12 months. The majority were female (73.2%), 58.9% were of White ethnicity, with a mean (SD) age of 47.5 years (10.1), and a body mass index of 35.0 kg/m2 (5.7). Data were available for 82 members at 12‐month. At 12‐month, members mean actual and percentage weight loss was −9.0 kg (7.0; p

Abstract High‐fat diet (HFD) and exercise remodel skeletal muscle mitochondria. The electron transfer flavoproteins (ETF) transfer reducing equivalents from β‐oxidation into the electron transfer system. Exercise may stimulate the synthesis of ETF proteins to increase lipid respiration. We determined mitochondrial remodeling for lipid respiration through ETF in the context of higher mitochondrial abundance/capacity seen in female mice. We hypothesized HFD would be a greater stimulus than exercise to remodel ETF and lipid pathways through increased protein synthesis alongside increased lipid respiration. Female C57BL/6J mice (n = 15 per group) consumed HFD or low‐fat diet (LFD) for 4 weeks then remained sedentary (SED) or completed 8 weeks of treadmill training (EX). We determined mitochondrial lipid respiration, RNA abundance, individual protein synthesis, and abundance for ETFα, ETFβ, and ETF dehydrogenase (ETFDH). HFD increased absolute and relative lipid respiration (p = 0.018 and p = 0.034) and RNA abundance for ETFα (p = 0.026), ETFβ (p = 0.003), and ETFDH (p = 0.0003). HFD increased synthesis for ETFα and ETFDH (p = 0.0007 and p = 0.002). EX increased synthesis of ETFβ and ETFDH (p = 0.008 and p = 0.006). Higher synthesis rates of ETF were not always reflected in greater protein abundance. Greater synthesis of ETF during HFD indicates mitochondrial remodeling which may contribute higher mitochondrial lipid respiration through enhanced ETF function.

Abstract Despite the reported association between diurnal variations in ambulatory blood pressure (BP) and elevated cardiovascular disease risk, little is known regarding the effects of isometric resistance training (IRT), a practical BP-lowering intervention, on ambulatory BP and morning BP surge (MBPS). Thus, we investigated whether (i) IRT causes reductions in ambulatory BP and MBPS, in young normotensives, and (ii) if there are any sex differences in these changes. Twenty normotensive individuals (mean 24-h SBP = 121 ± 7, DBP = 67 ± 6 mmHg) undertook 10-weeks of bilateral-leg IRT (4 × 2-min/2-min rest, at 20% maximum voluntary contraction (MVC) 3 days/week). Ambulatory BP and MBPS (mean systolic BP (SBP) 2 h after waking minus the lowest sleeping 1 h mean SBP) was measures pre- and post-training. There were significant reductions in 24-h ambulatory SBP in men (− 4 ± 2 mmHg, P = 0.0001) and women (− 4 ± 2 mmHg, P = 0.0001) following IRT. Significant reductions were also observed in MBPS (− 6 ± 8 mmHg, p = 0.044; − 6 ± 7 mmHg, P = 0.019), yet there were no significant differences between men and women in these changes, and 24-h ambulatory diastolic BP remained unchanged. Furthermore, a significant correlation was identified between the magnitude of the change in MBPS and the magnitude of changes in the mean 2-h SBP after waking for both men and women (men, r = 0.89, P = 0.001; women, r = 0.74, P = 0.014). These findings add further support to the idea that IRT, as practical lifestyle intervention, is effective in significantly lowering ambulatory SBP and MBPS and might reduce the incidence of adverse cardiovascular events that often occur in the morning.

Abstract High dietary fat intake induces significant whole‐body and skeletal muscle adaptations in mice, including increased capacity for fat oxidation and mitochondrial biogenesis. The impact of a diet that is high in fat and simple sugars (i.e., western diet [WD]), particularly on regulation of skeletal muscle mitochondrial function, is less understood. The purpose of the current study was to determine physiologic adaptations in mitochondrial respiratory capacity in skeletal muscle during short‐term consumption of WD, including if adaptive responses to WD‐feeding are modified by concurrent exercise training or may be sex‐specific. Male and female C57BL/6J mice were randomized to consume low‐fat diet (LFD) or WD for 4 weeks, with some WD‐fed mice also performing concurrent treadmill training (WD + Ex). Group sizes were n = 4–7. Whole‐body metabolism was measured using in‐cage assessment of food intake and energy expenditure, DXA body composition analysis and insulin tolerance testing. High‐resolution respirometry of mitochondria isolated from quadriceps muscle was used to determine skeletal muscle mitochondrial respiratory function. Male mice fed WD gained mass (p

Abstract Background Anterior cruciate ligament (ACL) and meniscus tears are common knee injuries. Despite the high rate of post-traumatic osteoarthritis (PTOA) following these injuries, the contributing factors remain unclear. In this study, we characterized the immune cell profiles of normal and injured joints at the time of ACL and meniscal surgeries. Methods Twenty-nine patients (14 meniscus-injured and 15 ACL-injured) undergoing ACL and/or meniscus surgery but with a normal contralateral knee were recruited. During surgery, synovial fluid was aspirated from both normal and injured knees. Synovial fluid cells were pelleted, washed, and stained with an antibody cocktail consisting of fluorescent antibodies for cell surface proteins. Analysis of immune cells in the synovial fluid was performed by polychromatic flow cytometry. A broad spectrum immune cell panel was used in the first 10 subjects. Based on these results, a T cell-specific panel was used in the subsequent 19 subjects. Results Using the broad spectrum immune cell panel, we detected significantly more total viable cells and CD3 T cells in the injured compared to the paired normal knees. In addition, there were significantly more injured knees with T cells above a 500-cell threshold. Within the injured knees, CD4 and CD8 T cells were able to be differentiated into subsets. The frequency of total CD4 T cells was significantly different among injury types, but no statistical differences were detected among CD4 and CD8 T cell subsets by injury type. Conclusions Our findings provide foundational data showing that ACL and meniscus injuries induce an immune cell-rich microenvironment that consists primarily of T cells with multiple T helper phenotypes. Future studies investigating the relationship between immune cells and joint degeneration may provide an enhanced understanding of the pathophysiology of PTOA following joint injury.

Drawing on challenges I experienced when teaching a political communication course, I designed an upper-level undergraduate course with the objective of developing students’ civic competence and democratic engagement. The major class assignment, which is the focal point of this best practices essay, was a four-step collaborative voter mobilization project designed and executed by undergraduate students. I use research, classroom conversations, and student observations to discuss four best practices for encouraging students to participate in electoral politics: (a) fostering political efficacy, (b) peer-to-peer learning, (c) experiential learning, and (d) learning through reflection. This essay breaks a four-step collaborative voting mobilization project down into easily implementable steps for those seeking to inculcate attitudes and behaviors that foster democratic engagement whether that be in schools, universities, or within the broader community.

Abstract Migratory birds time their migration based on cues that signal resource availability for reproduction. However, with climate change, the timing of seasonal events may shift, potentially inhibiting the ability of some species to use them as accurate cues for migration. We studied the relationship between phenological shifts and reproduction by long‐ and short‐distance migratory songbirds—Bobolinks (Dolichonyx oryzivorus) and Savannah Sparrows (Passerculus sandwichensis). Our study population breeds in hayfields and pastures in Vermont, USA, where farmers are also changing management activities in response to climate change. From 2002 to 2019, we monitored nest initiation dates to quantify correlations with environmental factors and the timing of nest initiation. We collected historical and projected precipitation and temperature data for the breeding grounds, and their respective wintering and stopover sites, the North Atlantic Oscillation (NAO) and the El Niño Southern Oscillation (ENSO). We predicted that winter conditions experienced by the short‐distance migrant, the Savannah Sparrow, but not the long‐distance migrant, the Bobolink, would explain the timing and success of nesting, however that this timing would be misaligned with changes in agricultural practices by hay farmers. Nest initiation dates did not show significant directional change for either species, but did vary among years. Interannual variation in Savannah Sparrow nest initiation dates was best explained by the interaction between precipitation on the breeding grounds and average wintering site (Wilmington, North Carolina). For Bobolinks, interannual variation in nest initiation dates was best explained by the interaction between breeding ground precipitation and average temperature in their fall stopover site (Barquisimieto, Venezuela). However, first haying dates in Vermont advanced by ~10 days over 18 years. These results suggest that the conflict between the timing of hay harvests and grassland songbird reproduction will increase, further threatening population processes for these species, as early harvests notably decrease annual productivity.

Measurement(s) progesterone receptor • isoform Technology Type(s) affinity purification method • stable isotope labeling by amino acids in cell culture Factor Type(s) progestin presence • biological replicate Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.14179040

Abstract Background Bipolar disorder (BD) is associated with excess and premature cardiovascular mortality. Elevated blood pressure (BP) is a leading contributor to cardiovascular risk. However, few studies have examined BP in BD in comparison to other psychiatric disorders. Furthermore, the association between BP and mood instability is not presently clear despite increasing interest in repurposing existing antihypertensive medications as possible novel BD treatments. Thus we examined BP differences between BD and borderline personality disorder (BPD), a disorder with a similar symptom profile through chronic mood instability. Methods A total of 106 adults (38 BD, 25 BPD, and 43 healthy controls), evaluated in the Automated Monitoring of Symptom Severity (AMoSS) study, completed a week-long home blood pressure monitoring assessment and ecological momentary assessment of mood. We examined group-wise differences in mean BP and BP variability and their association with mood instability. Results BD individuals had a significantly wider resting pulse pressure (40.8 ± 7.4, mmHg) compared to BPD (35.7 ± 5.3, mmHg, P = 0.03) and control participants (37.3 ± 6.3, mmHg, P = 0.036). Systolic BP was negatively associated with sad mood instability, and all measures of mean BP (systolic, diastolic, and mean arterial pressure) were negatively associated with positive mood instability. Conclusions This study demonstrates BP differences between BD and healthy and clinical controls that are within a normotensive range. Early pulse pressure widening may be a modifiable pathophysiological feature of BD that confers later cardiovascular risk. BP may be an important transdiagnostic predictor of mood instability and a potential explicit treatment target.

Background Perfectionism, low self-esteem and external locus of control are psychological constructs linked to insomnia, anxiety and depression. Examining how these constructs impact mental health and serve as risk factors for the development of clinically significant symptoms may help direct psychological support resources and preventative measures for university students. Aims To longitudinally examine associations between the aforementioned psychological constructs and symptoms of insomnia, anxiety and depression in a large representative sample of first-year university students. Method Electronic surveys including validated measures of the predictors and outcomes were emailed to all first-year undergraduate students at entry to a major Canadian university, and followed up on at conclusion of the academic year. Results Compared with healthy sleepers, students screening positive for insomnia had lower self-esteem, higher self-evaluative perfectionism and increased external locus of control (all P < 0.001). Self-evaluative perfectionism (standardised β = 0.13, P < 0.01), self-esteem (β = −0.30, P < 0.001) and external locus of control (β = 0.07, P = 0.02) measured at entry were significantly associated with insomnia symptoms at follow-up. Insomnia symptoms at entry were strong predictors of symptoms of depression (β = 0.15, P < 0.001) and anxiety (β = 0.16, P < 0.001) at follow-up, even after controlling for baseline symptoms of those disorders. Conclusions Perfectionism, low self-esteem and external locus of control may predispose the development of insomnia symptoms in university students. In turn, insomnia symptoms appear to be robust predictors for depressive and anxiety symptoms. Sleep may be an important prevention target in university students.

Abstract Background Obesity and insulin dysregulation (ID) predispose horses to laminitis. Determination of management practices or phenotypic markers associated with ID may benefit animal welfare. Objectives Determine ID status of a population of Finnhorses using an oral sugar test (OST) and compare phenotypes and management factors between ID and non‐ID Finnhorses. Animals One hundred twenty‐eight purebred Finnhorses ≥3 years of age. Methods Owners were recruited using an online questionnaire regarding signalment, history, feeding, and exercise of their horses. Selected contributing stables within a predefined area were visited. Phenotypic markers of obesity and the weight of each horse were recorded. After fasting overnight, horses received 0.45 mL/kg corn syrup PO. Serum samples before and at 60 and 90 minutes after syrup administration were analyzed for insulin by chemiluminescent assay. Horses met ID criteria if insulin concentrations were ≥33 μIU/mL at T0, ≥66 μIU/mL at T60 or T90 or some combination thereof. Associations between phenotypic markers, feeding and exercise variables, and ID were examined using mixed effects logistic regression modeling. Results Several phenotypic markers of obesity were significant on univariable analysis but in the final multivariable model, only obesity (body condition score ≥8) was associated with ID (P = .04). Over half of the horses (60% [95% confidence interval (CI), 51%‐68%]) were considered overweight or obese whereas 16% (95% CI, 10%‐23%) were classified as having ID. Conclusions and Clinical Importance Because obesity is associated with ID in cold‐blooded type horses, objective monitoring of phenotypic markers by owners may be beneficial for health outcomes.

Background People with personality disorder experience long waiting times for access to psychological treatments, resulting from a limited availability of long-term psychotherapies and a paucity of evidence-based brief interventions. Mentalisation-based treatment (MBT) is an efficacious therapeutic modality for personality disorder, but little is known about its viability as a short-term treatment. Aims We aimed to evaluate mental health, client satisfaction and psychological functioning outcomes before and after a 10-week group MBT programme as part of a stepped-care out-patient personality disorder service. Method We examined routinely collected pre–post treatment outcomes from 176 individuals (73% female) aged 20–63 years, attending a dedicated out-patient personality disorder service, who completed MBT treatment. Participants completed assessments examining mentalising capacity, client satisfaction, emotional reactivity, psychiatric symptom distress and social functioning. Results Post-MBT outcomes suggested increased mentalising capacity (mean difference 5.1, 95% CI 3.4–6.8, P < 0.001) and increased client satisfaction with care (mean difference 4.3, 95% CI 3.3–5.2, P < 0.001). Post-MBT emotional reactivity (mean difference −6.3, 95% CI −8.4 to −4.3, P < 0.001), psychiatric symptom distress (mean difference −5.2, 95% CI −6.8 to −3.7, P < 0.001) and impaired social functioning (mean difference −0.7, 95% CI −1.2 to −0.3, P = 0.002) were significantly lower than pre-treatment. Improved mentalising capacity predicted improvements in emotional reactivity (β = −0.56, P < 0.001) and social functioning (β = −0.35, P < 0.001). Conclusions Short-term MBT as a low-intensity treatment for personality disorder was associated with positive pre–post treatment changes in social and psychological functioning. MBT as deployed in this out-patient service expands access to personality disorder treatment.

Objectives To investigate the perceptions, attitudes, behaviours and potential barriers to effective obesity care in the UK using data collected from people with obesity (PwO) and healthcare professionals (HCPs) in the Awareness, Care, and Treatment In Obesity maNagement–International Observation (ACTION-IO) study.Design UK’s PwO (body mass index of ≥30 kg/m2 based on self-reported height and weight) and HCPs who manage patients with obesity completed an online survey.Results In the UK, 1500 PwO and 306 HCPs completed the survey. Among the 47% of PwO who discussed weight with an HCP in the past 5 years, it took a mean of 9 years from the start of their struggles with weight until a discussion occurred. HCPs reported that PwO initiated 35% of weight-related discussions; PwO reported that they initiated 47% of discussions. Most PwO (85%) assumed full responsibility for their own weight loss. The presence of obesity-related comorbidities was cited by 76% of HCPs as a top criterion for initiating weight management conversations. The perception of lack of interest (72%) and motivation (61%) in losing weight was reported as top reasons by HCPs for not discussing weight with a patient. Sixty-five per cent of PwO liked their HCP bringing up weight during appointments. PwO reported complex and varied emotions following a weight loss conversation with an HCP, including supported (36%), hopeful (31%), motivated (23%) and embarrassed (17%). Follow-up appointments were scheduled for 19% of PwO after a weight discussion despite 62% wanting follow-up.Conclusions The current narrative around obesity requires a paradigm shift in the UK to address the delay between PwO struggling with their weight and discussing weight with their HCP. Perceptions of lack of patient interest and motivation in weight management must be challenged along with the blame culture of individual responsibility that is prevalent throughout society. While PwO may welcome weight-related conversations with an HCP, they evoke complex feelings, demonstrating the need for sensitivity and respect in these conversations.Trial registration number NCT03584191.

Abstract Background Gene expression-based profiling has been used to identify biomarkers for different breast cancer subtypes. However, this technique has many limitations. IsomiRs are isoforms of miRNAs that have critical roles in many biological processes and have been successfully used to distinguish various cancer types. Biomarker isomiRs for identifying different breast cancer subtypes has not been investigated. For the first time, we aim to show that isomiRs are better performing biomarkers and use them to explain molecular differences between breast cancer subtypes. Results In this study, a novel method is proposed to identify specific isomiRs that faithfully classify breast cancer subtypes. First, as a null hypothesis method we removed the lowly expressed isomiRs from small sequencing data generated from diverse breast cancers types. Second, we developed an improved mutual information-based feature selection method to calculate the weight of each isomiR expression. The weight of isomiR measures the importance of a given isomiR in classifying breast cancer subtypes. The improved mutual information enables to apply the dataset in which the feature is continuous data and label is discrete data; whereby, the traditional mutual information cannot be applied in this dataset. Finally, the support vector machine (SVM) classifier is applied to find isomiR biomarkers for subtyping. Conclusions Here we demonstrate that isomiRs can be used as biomarkers in the identification of different breast cancer subtypes, and in addition, they may provide new insights into the diverse molecular mechanisms of breast cancers. We have also shown that the classification of different subtypes of breast cancer based on isomiRs expression is more effective than using published gene expression profiling. The proposed method provides a better performance outcome than Fisher method and Hellinger method for discovering biomarkers to distinguish different breast cancer subtypes. This novel technique could be directly applied to identify biomarkers in other diseases.

Background: Remote monitoring and digital phenotyping harbor potential to aid clinical diagnosis, predict episode course and recognize early signs of mental health crises. Digital communication metrics, such as phone call and short message service (SMS) use may represent novel biomarkers of mood and diagnosis in Bipolar Disorder (BD) and Borderline Personality Disorder (BPD).Materials and Methods: BD (n = 17), BPD (n = 17) and Healthy Control (HC, n = 21) participants used a smartphone application which monitored phone calls and SMS messaging, alongside self-reported mood. Linear mixed-effects regression models were used to assess the association between digital communications and mood symptoms, mood state, trait-impulsivity, diagnosis and the interaction effect between mood and diagnosis.Results: Transdiagnostically, self-rated manic symptoms and manic state were positively associated with total and outgoing call frequency and cumulative total, incoming and outgoing call duration. Manic symptoms were also associated with total and outgoing SMS frequency. Transdiagnostic depressive symptoms were associated with increased mean incoming call duration. For the different diagnostic groups, BD was associated with increased total call frequency and BPD with increased total and outgoing SMS frequency and length compared to HC. Depression in BD, but not BPD, was associated with decreased total and outgoing call frequency, mean total and outgoing call duration and total and outgoing SMS frequency. Finally, trait-impulsivity was positively associated with total call frequency, total and outgoing SMS frequency and cumulative total and outgoing SMS length.Conclusion: These results identify a general increase in phone call and SMS communications associated with self-reported manic symptoms and a diagnosis-moderated decrease in communications associated with depression in BD, but not BPD, participants. These findings may inform the development of clinical tools to aid diagnosis and remote symptom monitoring, as well as informing understanding of differential psychopathologies in BD and BPD.

BackgroundThe immunologic pathways activated during snakebite envenoming (SBE) are poorly described, and their association with recovery is unclear. The immunologic response in SBE could inform a prognostic model to predict recovery. The purpose of this study was to develop pre- and post-antivenom prognostic models comprised of clinical features and immunologic cytokine data that are associated with recovery from SBE. Materials and MethodsWe performed a prospective cohort study in an academic medical center emergency department. We enrolled consecutive patients with Crotalinae SBE and obtained serum samples based on previously described criteria for the Surgical Critical Care Initiative (SC2i)(ClinicalTrials.gov Identifier: NCT02182180). We assessed a standard set of clinical variables and measured 35 unique cytokines using Luminex Cytokine 35-Plex Human Panel pre- and post-antivenom administration. The Patient-Specific Functional Scale (PSFS), a well-validated patient-reported outcome of functional recovery, was assessed at 0, 7, 14, 21 and 28 days and the area under the patient curve (PSFS AUPC) determined. We performed Bayesian Belief Network (BBN) modeling to represent relationships with a diagram composed of nodes and arcs. Each node represents a cytokine or clinical feature and each arc represents a joint-probability distribution (JPD).ResultsTwenty-eight SBE patients were enrolled. Preliminary results from 24 patients with clinical data, 9 patients with pre-antivenom and 11 patients with post-antivenom cytokine data are presented. The group was mostly female (82%) with a mean age of 38.1 (SD ± 9.8) years. In the pre-antivenom model, the variables most closely associated with the PSFS AUPC are predominantly clinical features. In the post-antivenom model, cytokines are more fully incorporated into the model. The variables most closely associated with the PSFS AUPC are age, antihistamines, white blood cell count (WBC), HGF, CCL5 and VEGF. The most influential variables are age, antihistamines and EGF. Both the pre- and post-antivenom models perform well with AUCs of 0.87 and 0.90 respectively.DiscussionPre- and post-antivenom networks of cytokines and clinical features were associated with functional recovery measured by the PSFS AUPC over 28 days. With additional data, we can identify prognostic models using immunologic and clinical variables to predict recovery from SBE.

ABSTRACT Bone homeostasis is a dynamic, multicellular process that is required throughout life to maintain bone integrity, prevent fracture, and respond to skeletal damage. WNT16 has been linked to bone fragility and osteoporosis in human genome wide‐association studies, as well as the functional hematopoiesis of leukocytes in vivo. However, the mechanisms by which WNT16 promotes bone health and repair are not fully understood. In this study, CRISPR‐Cas9 was used to generate mutant zebrafish lacking Wnt16 (wnt16−/−) to study its effect on bone dynamically. The wnt16 mutants displayed variable tissue mineral density (TMD) and were susceptible to spontaneous fractures and the accumulation of bone calluses at an early age. Fractures were induced in the lepidotrichia of the caudal fins of wnt16−/− and WT zebrafish; this model was used to probe the mechanisms by which Wnt16 regulates skeletal and immune cell dynamics in vivo. In WT fins, wnt16 expression increased significantly during the early stages for bone repair. Mineralization of bone during fracture repair was significantly delayed in wnt16 mutants compared with WT zebrafish. Surprisingly, there was no evidence that the recruitment of innate immune cells to fractures or soft callus formation was altered in wnt16 mutants. However, osteoblast recruitment was significantly delayed in wnt16 mutants postfracture, coinciding with precocious activation of the canonical Wnt signaling pathway. In situ hybridization suggests that canonical Wnt‐responsive cells within fractures are osteoblast progenitors, and that osteoblast differentiation during bone repair is coordinated by the dynamic expression of runx2a and wnt16. This study highlights zebrafish as an emerging model for functionally validating osteoporosis–associated genes and investigating fracture repair dynamically in vivo. Using this model, it was found that Wnt16 protects against fracture and supports bone repair, likely by modulating canonical Wnt activity via runx2a to facilitate osteoblast differentiation and bone matrix deposition. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Pituitary pars intermedia dysfunction (PPID) is the most prevalent endocrine disorder of older equids. To date, key research areas likely to have the greatest impact on equine health have not been identified. In human medicine, public and patient involvement is widely used to inform research agendas. This study aimed to engage with veterinary surgeons and horse owners to identify evidence gaps ('uncertainties') and prioritise these into a list of the 10 most important PPID research questions. The James Lind Alliance (JLA) Priority Setting Partnership (PSP) Framework was adapted. Questions about the diagnosis, treatment and prognosis of PPID were gathered via an online survey targeting veterinary surgeons and horse owners with experience of PPID. Thematic analysis was used to form a longlist of collated indicative research questions (CIRQs), defined by the JLA as true 'evidence uncertainties' when not answered by a published, clinically relevant, up-to-date systematic review. In an interim prioritisation survey, questions were ranked by weighted scores creating a shortlist of 25 that were taken forward to the PSP workshop, where participants reached a consensus on the top 10. Useable responses containing ≥1 question were received from 524 respondents (92.6% owners, n = 485; 7.4% veterinary surgeons, n = 39). After screening for relevance, 1,260 individual questions were included in thematic analysis, resulting in 47 CIRQs. Interim prioritisation votes for the CIRQs were received from 360 respondents. The top 10 questions prioritised at the PSP workshop focused on long-term prognosis, diagnostic accuracy, efficacy of pergolide treatment, alternative treatment/management strategies and potential treatment options for poor responders to pergolide. The quantity of questions generated indicates an extensive number of uncertainties regarding the diagnosis, treatment and prognosis of PPID. The top 10 research questions will help to inform key areas for evidence synthesis and knowledge translation, and to direct future research into areas most important to end users involved in caring for and treating animals with PPID.

Abstract The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.

Abstract Regulation of the PI-3 kinase (PI3K)/Akt signalling pathway is essential for maintaining the integrity of fundamental cellular processes, cell growth, survival, death and metabolism, and dysregulation of this pathway is implicated in the development and progression of cancers. Receptor tyrosine kinases (RTKs) are major upstream regulators of PI3K/Akt signalling. The phosphatase and tensin homologue (PTEN), a well characterised tumour suppressor, is a prime antagonist of PI3K and therefore a negative regulator of this pathway. Loss or inactivation of PTEN, which occurs in many tumour types, leads to overactivation of RTK/PI3K/Akt signalling driving tumourigenesis. Cellular PTEN levels are tightly regulated by a number of transcriptional, post-transcriptional and post-translational regulatory mechanisms. Of particular interest, transcription of the PTEN pseudogene, PTENP1, produces sense and antisense transcripts that exhibit post-transcriptional and transcriptional modulation of PTEN expression respectively. These additional levels of regulatory complexity governing PTEN expression add to the overall intricacies of the regulation of RTK/PI-3 K/Akt signalling. This review will discuss the regulation of oncogenic PI3K signalling by PTEN (the regulator) with a focus on the modulatory effects of the sense and antisense transcripts of PTENP1 on PTEN expression, and will further explore the potential for new therapeutic opportunities in cancer treatment.

Abstract Bacterial environmental and surgical site infection (SSI) surveillance was implemented from 2011–2016 in a UK Equine Referral Veterinary Hospital and identified 81 methicillin-resistant Staphylococcus aureus (MRSA) isolates. A cluster of MRSA SSIs occurred in early 2016 with the isolates confirmed as ST398 by multilocus sequence typing (MLST), which prompted retrospective analysis of all MRSA isolates obtained from the environment (n = 62), SSIs (n = 13) and hand plates (n = 6) in the past five years. Sixty five of these isolates were typed to CC398 and a selection of these (n = 38) were further characterised for resistance and virulence genes, SCCmec and spa typing. Overall, MRSA was identified in 62/540 (11.5%) of environmental samples, 6/81 of the hand-plates (7.4%) and 13/208 of the SSIs (6.3%). spa t011 was the most frequent (24/38) and Based Upon Repeat Pattern (BURP) analysis identified spa t011 as one of the two group founders of the main spa CC identified across the five years (spa CC011/3423). However, 3 singletons (t073, t786, t064) were also identified suggesting separate introductions into the hospital environment. This long-term MRSA surveillance study revealed multiple introductions of MRSA CC398 in a UK Equine Hospital, identifying an emerging zoonotic pathogen so far only sporadically recorded in the UK.

Study DesignRetrospective, case series.PurposeThe purpose of this study is to determine morbidity, complications, and patient reported outcomes from minimally invasive sacroiliac joint (SIJ) fusion.Overview of LiteratureLumbar back pain emanating from the SIJ can be surgically treated via a percutaneous approach in the appropriately selected patient with minimal morbidity and acceptable functional outcomes.MethodsPatients diagnosed by >2 physical examination maneuvers and subjective relief from a computed tomography–guided lidocaine-bupivacaine-steroid injection underwent SIJ fusion after failing conservative management with a combination of oral anti-inflammatory medications, physical therapy, and pelvic belt stabilization. Perioperative data collected include estimated blood loss (EBL) and operative time. Oswestry disability index, 12-item short form health survey (SF-12), visual analogue score, and functional status were analyzed. All complications were noted.ResultsThe study cohort of 45 cases (69% female) achieved postoperative survey follow-up at 9.9 and 32.3 months. SF-12 physical component summary statistically improved while all other scores were equivalent. Mean EBL and operative time were 22 mL and 36 minutes, respectively. Initial survey showed that 64% of patients discontinued narcotics (29/45), 71% do not use an assistive device (32/45), and 15.6% do not work due to pain (7/45). 73% of patients stated they would have the surgery again (33/45). For the second survey, 65% of patients discontinued narcotics (26/40), 70% did not use an assistive device (28/40), and 17.5% did not work due to pain (7/40). A history of thoracolumbar instrumentation (16/45) did not significantly affect outcomes. Three complications described by screw malposition with neurologic deficit (6.7%) were treated with screw repositioning (1 case) and removal of a single superior implant (2 cases) with time to revision of 2.2 months. All three ultimately had resolution of radicular pain.ConclusionsPercutaneous SIJ fusion offers minimal morbidity and acceptable functional outcomes. While women and those with a prior history of lumbar instrumentation may be at increased risk of having SIJ dysfunction requiring surgical intervention, it was not found to affect postoperative functional outcomes when compared to the non-instrumented group.

Obesity is officially recognised as a chronic disease and a top public health priority by several global societies and healthcare bodies. In some European countries, the majority of the adult population is either overweight or obese, with major implications for patient health and healthcare systems. General practitioners (GPs) are well-placed to tackle this epidemic, yet their engagement with patients is fraught with challenges and barriers. These include time limitations, a lack of evidence base, sensitivities around raising the topic of obesity with patients, inadequate availability of supporting local weight loss services, a lack of training for healthcare professionals (HCPs) on the management of obesity and a limited number of effective therapies. A number of steps need to be implemented to promote engagement between GPs and individuals with obesity. This article provides a European perspective on the obstacles that patients face in accessing healthcare services and discusses a variety of approaches for engaging individuals with obesity and facilitating the management of obesity as a chronic disease.

Challenges with primary care access and overextended providers present opportunities for pharmacists as patient care extenders for chronic disease management. The primary objective was to align primary care pharmacist services with organizational priorities and improve patient clinical outcomes. The secondary objective was to develop a technological strategy for service evaluation. An interdisciplinary workgroup developed primary care pharmacist services focused on improving performance measures and supporting the care team in alignment with ongoing population health initiatives. Pharmacist collaborative practice agreements (CPAs) were developed and implemented. An electronic dashboard was developed to capture service outcome measures. Blood pressure control to

Cardiovascular disease (CVD) is the leading cause of death in the world and our approach to the control and management of CVD mortality is limited. Nattokinase (NK), the most active ingredient of natto, possesses a variety of favourable cardiovascular effects and the consumption of Natto has been linked to a reduction in CVD mortality. Recent research has demonstrated that NK has potent fibrinolytic activity, antihypertensive, anti-atherosclerotic, and lipid-lowering, antiplatelet, and neuroprotective effects. This review covers the major pharmacologic effects of NK with a focus on its clinical relevance to CVD. It outlines the advantages of NK and the outstanding issues pertaining to NK pharmacokinetics. Available evidence suggests that NK is a unique natural compound that possesses several key cardiovascular beneficial effects for patients with CVD and is therefore an ideal drug candidate for the prevention and treatment of CVD. Nattokinase is a promising alternative in the management of CVD.

This review focuses on current understanding of prenatal, prepubertal and post-pubertal development of the male reproductive system of cattle. The critical developmental events occur during the first 3 to 4 months of gestation and the first ~6 to 9 months after birth. The Wilms Tumor-1 and SRY proteins play critical roles in early development and differentiation of the fetal testis, which in turn drives gestational development of the entire male reproductive system. The hypothalamic–pituitary–gonadal axis matures earlier in the bovine fetus than other domestic species with descent of the testes into the scrotum occurring around the 4th month of gestation. An array of congenital abnormalities affecting the reproductive system of bulls has been reported and most are considered to be heritable, although the mode of inheritance in most cases has not been fully defined. Early postnatal detection of most of these abnormalities is problematic as clinical signs are generally not expressed until after puberty. Development of genomic markers for these abnormalities would enable early culling of affected calves in seedstock herds. The postnatal early sustained increase in lutenising hormone secretion cues the rapid growth of the testes in the bull calf leading to the onset of puberty. There is good evidence that both genetic and environmental factors, in particular postnatal nutrition, control or influence development and maturation of the reproductive system. For example, in Bos taurus genotypes which have had sustained genetic selection pressure applied for fertility, and where young bulls are managed on a moderate to high plane of nutrition puberty typically occurs at 8 to 12 months of age. However, in many Bos indicus genotypes where there has been little selection pressure for fertility and where young bulls are reared on a low plane of nutrition, puberty typically occurs between 15 to 17 months. Our understanding of the control and expression of sexual behavior in bulls is limited, particularly in B. indicus genotypes.

El presente artículo es el resumen de una investigación histórica sobre el fotómetro realizada entorno en diversos centros de investigación extranjeros, bibliotecas y registro de patentes. En este artículo se incorporan en anexos materiales inéditos y que se han solicitado en diversas oficinas de patentes y bibliotecas. El fotómetro es una invención reciente y de orígenes un tanto inciertos y poco estudiados, a pesar de ser una herramienta fundamental en el arsenal del fotógrafo y director de fotografía, puesto que sólo con él se podía determinar la exposición correcta del negativo. La presente investigación plantea subsanar una laguna de la historia del arte, proponemos una cronología de su invención, desde la fundamentación científica hasta la primera instancia de su configuración moderna, incluyendo antecedentes fotográficos primitivos.

The annexin family and S100A associated proteins are important regulators of diverse calcium-dependent cellular processes including cell division, growth regulation and apoptosis. Dysfunction of individual annexin and S100A proteins is associated with cancer progression, metastasis and cancer drug resistance. This manuscript describes the novel finding of differential regulation of the annexin and S100A family of proteins by activation of p53 in breast cancer cells. Additionally, the observed differential regulation is found to be beneficial to the survival of breast cancer cells and to influence treatment efficacy. We have used unbiased, quantitative proteomics to determine the proteomic changes occurring post p14ARF-p53 activation in estrogen receptor (ER) breast cancer cells. In this report we identified differential regulation of the annexin/S100A family, through unique peptide recognition at the N-terminal regions, demonstrating p14ARF-p53 is a central orchestrator of the annexin/S100A family of calcium regulators in favor of pro-survival functions in the breast cancer cell. This regulation was found to be cell-type specific. Retrospective human breast cancer studies have demonstrated that tumors with functional wild type p53 (p53wt) respond poorly to some chemotherapy agents compared to tumors with a non-functional p53. Given that modulation of calcium signaling has been demonstrated to change sensitivity of chemotherapeutic agents to apoptotic signals, in principle, we explored the paradigm of how p53 modulation of calcium regulators in ER+ breast cancer patients impacts and influences therapeutic outcomes.

Abstract The transmembrane metalloprotease‐disintegrin ADAM8 mediates cell adhesion and shedding of ligands, receptors and extracellular matrix components. Here, we report that ADAM8 is abundantly expressed in breast tumors and derived metastases compared to normal tissue, especially in triple‐negative breast cancers (TNBCs). Furthermore, high ADAM8 levels predicted poor patient outcome. Consistently, ADAM8 promoted an aggressive phenotype of TNBC cells in culture. In a mouse orthotopic model, tumors derived from TNBC cells with ADAM8 knockdown failed to grow beyond a palpable size and displayed poor vascularization. Circulating tumor cells and brain metastases were also significantly reduced. Mechanistically, ADAM8 stimulated both angiogenesis through release of VEGF‐A and transendothelial cell migration via β1‐integrin activation. In vivo, treatment with an anti‐ADAM8 antibody from the time of cell inoculation reduced primary tumor burden and metastases. Furthermore, antibody treatment of established tumors profoundly decreased metastases in a resection model. As a non‐essential protein under physiological conditions, ADAM8 represents a promising novel target for treatment of TNBCs, which currently lack targeted therapies and frequently progress with fatal dissemination.