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Suppression of tumorigenicity 2 (ST2) has important cardiovascular prognostic value in community patients; however, previous analyses have utilized non-sex specific cut-off values. We assessed whether sex-specific ST2 cut-off values would improve the prognostic utility of ST2 in the asymptomatic community.A total of 2042 participants underwent clinical assessment and echocardiographic evaluation. Baseline measurements of high sensitivity troponin, natriuretic peptides and ST2 were obtained in 1681 individuals. ST2, cardiac biomarkers and associated co-morbidities were evaluated by sex-specific ST2 quartile analysis. ST2 concentrations were also analysed as dichotomous variables defined as being above the sex-specific cut-off for each the outcomes of heart failure (HF), major adverse cardiac event (MACE) and mortality.Median ST2 concentration was 29.4 ng/mL in male subjects and 24.1 ng/mL in female subjects. Higher ST2 concentrations were associated with incident HF (These data suggest that sex-specific cut-offs, greater than non-sex specific cut-offs, significantly impact the prognostic value of the biomarker ST2 in the asymptomatic community cohort.Clinical SignificanceSuppression of tumorigenicity 2 (ST2) is a biomarker which has known associations with heart failure (HF), major adverse cardiac events (MACEs) and mortality in the general population.Recent data support the concept of sex-specific cut off values and individualized approaches based on sex to predict cardiovascular disease. Given the difference in pathobiology between the sexes, the fact that such approaches improve risk stratification is understandable. Thus, when sex-specific treatments are developed, this may similarly lead to improved outcomes.The use of sex-specific ST2 cut-off values significantly improved the prognostic value in predicting HF, MACE, and mortality in an asymptomatic community. This prognostication was particularly strong for HF with preserved ejection fraction and remained clinically significant following adjustment for cardiac co-morbidities and other traditional cardiac biomarkers (NTproBNP and hscTnI).

Key points Ambient cold exposure is often regarded as a promising anti-obesity treatment in mice. However, most preclinical studies aimed at treating obesity via cold-induced thermogenesis have been confounded by sub-thermoneutral housing temperatures. Therefore, the ability of ambient cold to combat diet-induced obesity in mice housed under humanized thermoneutral conditions is currently unknown. Moreover, mammals such as mice are rarely exposed to chronic ambient cold without reprieve, yet mice are often subjected to experimental conditions of chronic rather than intermittent cold exposure (ICE), despite ICE being more physiologically relevant. Having addressed these issues herein, we provide novel evidence that thermoneutral housing uncouples the effects of ICE on glucose and energy homeostasis suggesting that ICE, despite improving glucose tolerance, is not an effective obesity treatment when mice are housed under humanized thermoneutral conditions. Abstract This study examined whether a physiologically relevant model of ambient cold exposure, intermittent cold exposure (ICE), could ameliorate the metabolic impairments of diet-induced obesity in male and female mice housed under humanized thermoneutral conditions. Male and female C57BL/6J mice housed at thermoneutrality (29 °C) were fed a low-fat diet (LFD) or high-fat diet (HFD) for 6 weeks before being weight matched into groups that remained unperturbed (CTRL) or underwent ICE for four weeks (4 °C for 60 min/day; 5 days/week) while being maintained on their respective diets. ICE induced rapid and persistent hyperphagia exacerbating rather than attenuating HFD-induced obesity over time. These ICE-induced increases in adiposity were found to be energy intake dependent via pair-feeding. Despite exacerbating HFD-induced obesity, ICE improved glucose tolerance, independent of diet, in a sex-specific manner. The effects of ICE on glucose tolerance were not attributed to improvements in whole-body insulin tolerance, tissue specific insulin action, nor to differences in markers of hepatic insulin clearance or pancreatic beta cell proliferation. Instead, ICE increased serum concentrations of insulin and C-peptide in response to glucose, suggesting that ICE may improve glucose tolerance by potentiating pancreatic glucose-stimulated insulin secretion. These data suggest that ICE, despite improving glucose tolerance, is not an effective obesity treatment in mice housed under humanized conditions. Greg L. McKie is a third year PhD Candidate in the Human Health and Nutritional Sciences Department at the University of Guelph, where he works under the supervision of Dr. David C. Wright. Greg's dissertation focuses on the effects of environmental perturbations, such as aerobic exercise and ambient cold exposure, on adipose tissue metabolism, specifically as it relates to promoting non-shivering thermogenesis under translationally relevant thermoneutral conditions. This article is a follow up to Greg's first PhD study, also published in The Journal of Physiology, which demonstrated that housing temperature affects the acute and chronic metabolic adaptations to aerobic exercise in mice. This article is protected by copyright. All rights reserved.

Visual Abstract, Highlights • Among subjects at risk for heart failure (Stage A and B), the minor C allele of the B-type natriuretic peptide (BNP) genetic variant rs198389 is associated with higher circulating levels of BNP. • Rs198389 C allele is also associated with lower risk of hypertension, new onset of left ventricular systolic dysfunction, and major adverse cardiovascular events. • These data support the role of BNP genetic testing and BNP-based therapy for the prevention of heart failure., Summary B-type natriuretic peptide (BNP) possesses blood-pressure–lowering, antifibrotic, and aldosterone-suppressing properties. In Stage A and B heart failure, the carriers of the minor C allele of the BNP genetic variant rs198389 have higher circulating levels of BNP and are at decreased risk of hypertension, new-onset left ventricular systolic dysfunction, and hospitalization for major adverse cardiovascular events. Future studies are warranted to investigate the role of BNP genetic testing and BNP-based therapy in the prevention of heart failure.

Aims The primary aim of this study was to evaluate the efficacy of distension arthrography in the treatment of adhesive capsulitis of the shoulder. The secondary aim was to assess which patient and procedural factors predicted the recurrence of symptoms after the procedure. Methods All patients referred to our shoulder clinic over a ten-year period, between 2008 and 2018, with a clinical diagnosis of capsulitis and symptoms persisting for more than six months, were offered treatment with a distension arthrogram. All procedures were performed by one of five musculoskeletal radiologists, with a combination of steroid, local anaesthetic, and a distention volume of 10 ml, 30 ml, or 50 ml. Patient demographics, procedural details, recurrence of symptoms, and the need for further intervention were evaluated. Results A total of 2,432 distension arthrograms were performed during the study period. The mean time between arthrography and analysis was 5.4 years (SD 4.4; 1 to 11). Recurrent symptoms occurred in 184 cases (7.6%), all of whom had a repeat distension arthrogram at a median of nine months (interquartile range (IQR) 6.0 to 15.3). The requirement for further intervention for persistent symptoms following arthrography was significantly associated with diabetes (p < 0.001) and bilateral capsulitis (p < 0.001). The volume of distension, either with air or saline, showed a dose-dependent advantage. Distension of 50 ml versus 30 ml showed a significantly decreased odds ratio for recurrence of 2.2 (95% confidence interval (CI) 1.6 to 3.0; p < 0.001). Capsule rupture (p = 0.615) or steroid dose (p = 0.275) did not significantly affect the rate of recurrence. There were no infections or neurovascular injuries. Following the second distension arthrogram, the symptoms resolved in 137 cases (74.5%) with no further intervention being required. An arthroscopic capsular release was ultimately required in 41 cases, comprising 1.7% of the entire cohort. Conclusion We found a low rate of repeat intervention following distension arthrography in patients with adhesive capsulitis of the shoulder, at long term follow-up. Greater volumes of distension are associated with lower rates of recurrence independent of capsule rupture. Cite this article: Bone Joint J 2020;102-B(5):606–610.

Fam151b is a mammalian homologue of the C. elegans menorin gene, which is involved in neuronal branching. The International Mouse Phenotyping Consortium (IMPC) aims to knock out every gene in the mouse and comprehensively phenotype the mutant animals. This project identified Fam151b homozygous knock-out mice as having retinal degeneration. We show they have no photoreceptor function from eye opening, as demonstrated by a lack of electroretinograph (ERG) response. Histological analysis shows that during development of the eye the correct number of cells are produced and that the layers of the retina differentiate normally. However, after eye opening at P14, Fam151b mutant eyes exhibit signs of retinal stress and rapidly lose photoreceptor cells. We have mutated the second mammalian menorin homologue, Fam151a, and homozygous mutant mice have no discernible phenotype. Sequence analysis indicates that the FAM151 proteins are members of the PLC-like phosphodiesterase superfamily. However, the substrates and function of the proteins remains unknown.

Summary: Impaired cardiorenal response to acute saline volume expansion in preclinical systolic dysfunction (PSD) may lead to symptomatic heart failure. The objective was to determine if combination phosphodiesterase-V inhibition and exogenous B-type natriuretic peptide (BNP) administration may enhance cardiorenal response. A randomized double-blinded, placebo-controlled study was conducted in 21 subjects with PSD and renal dysfunction. Pre-treatment with tadalafil and subcutaneous BNP resulted in improved cardiac function, as evidenced by improvement in ejection fraction, left atrial volume index, and left ventricular end-diastolic volume. However, there was reduced renal response with reduction in renal plasma flow, glomerular filtration rate, and urine flow. (Tadalafil and Nesiritide as Therapy in Pre-clinical Heart Failure; NCT01544998) Key Words: B-type natriuretic peptide, cardiorenal, heart failure, nesiritide, phosphodiesterase inhibition, systolic dysfunction

Background Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients’ clinical phenotypes and analyse the differential clinical course. Methods We performed a hierarchical cluster analysis based on Ward’s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients’ prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P < .001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27–3.62; HR 3.42, 95%CI 2.72–4.31; HR 2.79, 95%CI 2.32–3.35), and Cluster 1 (HR 1.88, 95%CI 1.48–2.38; HR 2.50, 95%CI 1.98–3.15; HR 2.09, 95%CI 1.74–2.51) reported a higher risk for the three outcomes respectively. Conclusions In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes.

Increased body iron stores and inflammation in adipose tissue have been implicated in the pathogenesis of insulin resistance (IR) and type 2 diabetes mellitus. However, the underlying basis of these associations are unclear. In order to assess this, we studied how IR and associated inflammation in adipose tissue developed in the presence of increased body iron stores. Male hepcidin knock-out (Hamp1-/-) mice, which have increased body iron stores, and wild-type (WT) mice were fed a high-fat diet (HFD) for 12 and 24 weeks. Development of IR and metabolic parameters linked to this, insulin signaling in tissue, and inflammation and iron-related parameters in visceral adipose tissue were studied in these animals. HFD-feeding resulted in impaired glucose tolerance in both genotypes of mice. In response to the HFD for 24 weeks, Hamp1-/- mice gained less body weight and developed less IR than corresponding WT mice. This was associated with less lipid accumulation in the liver and decreased inflammation and lipolysis in the adipose tissue in the knock-out mice, than in the WT animals. Fewer macrophages infiltrated the adipose tissue in the knockout mice than in wild-type mice, with these macrophages exhibiting a predominantly anti-inflammatory (M2-like) phenotype. These observations suggest a novel role of hepcidin (central regulator of systemic iron homeostasis) in the development of inflammation in adipose tissue and insulin resistance, in response to a high-fat diet.CLINICAL PERSPECTIVESElevated body iron stores and inflammation in adipose tissue have been implicated in the pathogenesis of insulin resistance (IR) and type 2 diabetes mellitus. However, the underlying molecular mechanisms linking them are unclear.In response to high-fat diet (HFD)-feeding (to induce IR), mice that lacked hepcidin (Hamp1-/-) (and hence had elevated body iron stores) gained less body weight and developed less insulin resistance than wild-type (WT) mice. Inflammation and infiltration of macrophages into adipose tissue of HFD-fed Hamp1-/- mice were less than in WT mice, with the macrophages exhibiting an anti-inflammatory M2-like phenotype.These findings suggest a novel role of iron and hepcidin in HFD-induced inflammation in adipose tissue and development of insulin resistance. They raise the possibility that modulation of body iron may represent a potential way to inhibit these processes.

IMPORTANCE: Heart failure (HF) with preserved ejection fraction (HFpEF) is common, is frequently associated with ventricular wall thickening, and has no effective therapy. Transthyretin amyloid cardiomyopathy (ATTR-CM) can cause the HFpEF clinical phenotype, has highly effective therapy, and is believed to be underrecognized. OBJECTIVE: To examine the prevalence of ATTR-CM without and with systematic screening in patients with HFpEF and ventricular wall thickening. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study assessed ATTR-CM prevalence in 1235 consecutive patients in southeastern Minnesota with HFpEF both without (prospectively identified cohort study) and with (consenting subset of cohort study, n = 286) systematic screening. Key entry criteria included validated HF diagnosis, age of 60 years or older, ejection fraction of 40% or greater, and ventricular wall thickness of 12 mm or greater. In this community cohort of 1235 patients, 884 had no known ATTR-CM, contraindication to technetium Tc 99m pyrophosphate scanning, or other barriers to participation in the screening study. Of these 884 patients, 295 consented and 286 underwent scanning between October 5, 2017, and March 9, 2020 (community screening cohort). EXPOSURES: Medical record review or technetium Tc 99m pyrophosphate scintigraphy and reflex testing for ATTR-CM diagnosis. MAIN OUTCOMES AND MEASURES: The ATTR-CM prevalence by strategy (clinical diagnosis or systematic screening), age, and sex. RESULTS: A total of 1235 patients participated in the study, including a community cohort (median age, 80 years; interquartile range, 72-87 years; 630 [51%] male) and a community screening cohort (n = 286; median age, 78 years; interquartile range, 71-84 years; 149 [52%] male). In the 1235 patients in the community cohort without screening group, 16 patients (1.3%; 95% CI, 0.7%-2.1%) had clinically recognized ATTR-CM. The prevalence was 2.5% (95% CI, 1.4%-4.0%) in men and 0% (95% CI, 0.0%-0.6%) in women. In the 286 patients in the community screening cohort, 18 patients (6.3%; 95% CI, 3.8%-9.8%) had ATTR-CM. Prevalence increased with age from 0% in patients 60 to 69 years of age to 21% in patients 90 years and older (P

Brittle cornea syndrome (BCS) is a rare recessive condition characterised by extreme thinning of the cornea and sclera. BCS results from loss-of-function mutations in the poorly understood genes ZNF469 or PRDM5. In order to determine the function of ZNF469 and to elucidate pathogenic mechanisms, we used genome editing to recapitulate a human ZNF469 BCS mutation in the orthologous mouse gene Zfp469. Ophthalmic phenotyping showed that homozygous Zfp469 mutation causes significant central and peripheral corneal thinning arising from reduced stromal thickness. Expression of key components of the corneal stroma in primary keratocytes from Zfp469BCS/BCS mice is affected, including decreased Col1a1 and Col1a2 expression. This alters the collagen type I/collagen type V ratio and results in collagen fibrils with smaller diameter and increased fibril density in homozygous mutant corneas, correlating with decreased biomechanical strength in the cornea. Cell-derived matrices generated by primary keratocytes show reduced deposition of collagen type I, offering an in vitro model for stromal dysfunction. Work remains to determine whether modulating ZNF469 activity will have therapeutic benefit in BCS or in conditions such as keratoconus in which the cornea thins progressively. This article has an associated First Person interview with the first author of the paper., Summary: A mouse model of brittle cornea syndrome was created to elucidate molecular mechanisms underlying the pathology of this rare connective tissue disorder in which extremely thin corneas rupture, causing irreversible blindness.

BackgroundSynchronous collaboration as defined by a simultaneous encounter between primary care providers (PCPs), patients, and neurologists may improve access to neurologic expertise, care value, and satisfaction of PCPs and patients. We examined a series of synchronous collaborations and report outcomes, PCP satisfaction, downstream utilization, and illustrative case examples.MethodsWithin an outpatient collaborative primary care–neurology care model, we implemented synchronous video consultations from a central hub to satellite clinics while increasing availability of synchronous telephone and face-to-face collaboration. PCP experience was assessed by a postcollaboration survey. Individual cases were summarized. Clinical and utilization outcomes were assessed by a neurologist immediately after and by follow-up chart review.ResultsA total of 58 total synchronous collaborations were performed: 30 by telephone (52%), 18 face to face (31%), and 10 by video (17%) over 27 clinic half-days. The most frequent outcomes as assessed by the neurologist were reassurance of the PCP (23/58; 40%) and patient (22/59; 38%), and the neurologist changed the treatment plan (23/58; 40%). A subsequent face-to-face consultation was completed in 15% (6/58) of patients initially assessed by telephone or video. Test utilization was avoided in 40% (23/58). Unintended utilization occurred 9% (5/58). Most PCPs were very satisfied with the ease of access, quality of care, and reported high likelihood of subsequent use. PCPs perceived similar or less time spent during synchronous vs asynchronous collaboration and neurologist usually altered the testing (87.8%) and treatment plan (95.2%).ConclusionsSynchronous collaboration between neurologists and PCPs may improve timely access to neurologic expertise, downstream utilization, and PCP satisfaction.

Background The anterior cingulate cortex (ACC) is a key structure of the pain processing network. Several structural and functional alterations of this brain area have been found in migraine. In addition, altered serotonergic neurotransmission has been repeatedly implicated in the pathophysiology of migraine, although the exact mechanism is not known. Thus, our aim was to investigate the relationship between acute increase of brain serotonin (5-HT) level and the activation changes of the ACC using pharmacological challenge MRI (phMRI) in migraine patients and healthy controls. Methods Twenty-seven pain-free healthy controls and six migraine without aura patients participated in the study. All participant attended to two phMRI sessions during which intravenous citalopram, a selective serotonin reuptake inhibitor (SSRI), or placebo (normal saline) was administered. We used region of interest analysis of ACC to compere the citalopram evoked activation changes of this area between patients and healthy participants. Results Significant difference in ACC activation was found between control and patient groups in the right pregenual ACC (pgACC) during and after citalopram infusion compared to placebo. The extracted time-series showed that pgACC activation increased in migraine patients compared to controls, especially in the first 8–10 min of citalopram infusion. Conclusions Our results demonstrate that a small increase in 5-HT levels can lead to increased phMRI signal in the pregenual part of the ACC that is involved in processing emotional aspects of pain. This increased sensitivity of the pgACC to increased 5-HT in migraine may contribute to recurring headache attacks and increased stress-sensitivity in migraine.

Scaphoid non-union develops in 10% of scaphoid fractures. There is sparse literature on fixation methods other than screws. We compared union rates following fixation of scaphoid non-union using screw fixation and a novel method of plate fixation. Retrospective study. Union rates were assessed at 3 months post-operatively by a musculoskeletal radiologist. 15 patients underwent screw fixation and 15 underwent plate fixation. 86% union rate with screw fixation and 72% plate fixation united. There was no significant difference. Screw fixation and plate fixation in our institution both provide union rates that are consistent with the literature.

Little research has investigated relationships among heterosexual African, Caribbean, and Black (ACB) youth and the factors that influence their behavior and the behavioral expectations they have of their sexual partners. This study identifies influential factors of behavioral expectations, and how this behavior shapes vulnerability for human immunodeficiency virus. This article draws on data from the POWER project in Windsor, Canada. Six focus groups were held and attended by 26 ACB youth, and data were analyzed following thematic analysis guidelines. ACB youth adhered to gender roles prescribed through cultural heritage and religion. Gender inequality persists among young ACB youth, and sociopolitical history is hypothesized to shape normative gender roles, influencing relationship behaviors.

Purpose: To explore experiences of care at the Royal Children's Hospital Gender Service (RCHGS). Methods: A total of 114 parents and 52 patients of the RCHGS completed an experience of care survey. Results: Most participants highly rated elements of the family-centered care and multidisciplinary team at RCHGS. The majority were satisfied with the RCHGS (parents: 88%, patients: 92%) and would recommend the service (parents: 95%, patients: 89%). Reductions in distress after participation in RCHGS were noted. Wait time was an area of dissatisfaction. Ideas for improvement concerned information giving, family support provision, and improving access to care. Conclusion: This study affirms the multidisciplinary family-centered model used at RCHGS.

Cystic fibrosis (CF) is a genetic disorder associated with vascular endothelial dysfunction. Nitric oxide (NO) plays a major role in maintaining vascular function, and tetrahydrobiopterin (BH4) is a critical determinant of NO bioavailability. Thus the purpose of this study was to investigate the effects of oral administration of BH4 on endothelial function in patients with CF. Twenty-nine patients with CF (18 ± 8 yr old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received a 5 mg/kg dose of oral BH4 (BH4-5; n = 17) or a 20 mg/kg dose of oral BH4 (BH4-20; n = 12). On a separate visit, a subset of patients from each group was retested following a placebo (PLC; n = 9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function, and a plasma sample was obtained before and 3 h after treatment. Cultured endothelial cells were treated with plasma to assess NO bioavailability. Baseline FMD was lower in patients compared with controls (5.7 ± 3.4 vs. 8.4 ± 3.5%, respectively, P = 0.005). No change in FMD was observed following PLC or BH4-5 (∆FMD: −0.8 ± 1.9% and −0.5 ± 2.5%; P = 0.273 and 0.132, respectively). Treatment with BH4-20, however, resulted in significant improvements in FMD (∆FMD: 1.1 ± 1.4%) compared with BH4-5 ( P = 0.023) and PLC ( P = 0.017). Moreover, BH4-20 significantly decreased endothelial cell superoxide production and increased NO production. These data suggest that a single oral dose of BH4 at 20 mg/kg improves vascular endothelial function in patients with CF, likely via increased endothelial NO synthase coupling. These findings support the hypothesis that loss of BH4 bioactivity contributes, in part, to endothelial dysfunction in patients with CF. NEW & NOTEWORTHY For the first time, the present study documents that a single dose of oral BH4 can improve vascular endothelial function in patients with cystic fibrosis (CF), and our in vitro data suggest this is via decreasing uncoupled nitric oxide. These data provide insight into the important role of BH4 bioactivity in vascular dysfunction and provide the foundation for further investigation into the chronic effects of BH4 treatment in patients with CF.

Background The General Paediatric Service at our Hospital is extremely busy, often with more than 70 inpatients under the team each day during months of peak activity and over 40 new acute telephone referrals from Primary Care daily. The number of children attending acute services at the hospital has been increasing annually and the Emergency Department will often have more than 300 attendances in 24 hours in winter months. This activity level means there is a significant pressure on inpatient beds and effective patient flow through the hospital is essential. During the ongoing COVID19 pandemic, there has been pressure on acute NHS services, which has driven the need for new innovative ways of working. Objectives We aimed to ensure that all acute referrals to the General Paediatric Service were triaged via telephone by a senior paediatric clinician (registrar or consultant). The primary aim of this service was to ensure that children were streamed to the appropriate location, to be seen by the appropriate team at the appropriate time. Secondary aims included improving the interface with primary care and instigating pre-hospital management for patients streamed into outpatient services. Methods A General Paediatric telephone triage was introduced, operating for 12 hours each day (9am–9pm) 7 days per week. This service was staffed by senior paediatric clinicians and received calls from GP surgeries, NHS24 and COVID assessment centres. The clinician delivering the service discussed all acute referrals with referring clinician and was able to offer immediate advice with regard to most appropriate management. Data from each acute referral received including the outcome of the call was collected prospectively. Results Data has been collected for 2834 acute referrals to our Paediatric Telephone Triage service from its establishment in March 2020. Of these calls, 57% (1627) had been seen in a face-to-face consultation with their GP prior to referral. We found that following telephone triage with referring clinician acute attendance and assessment was not required in 972/2834 (34%) cases. In 447/2834 (16%) cases it was felt that the child did not require assessment in secondary care at all and the GP was provided with advice in relation to ongoing management. In 128/2834 (4.5%) referrals the child was streamed into General Paediatric clinic (including utilisation of rapid access and urgent telephone consultations). The remaining calls resulted in patients being seen in primary care facilities (including COVID assessment centres) or being streamed to other specialities within the hospital. Conclusions Implementing a telephone-based triage service for paediatrics has reduced unnecessary unscheduled care attendances. Primary Care access to a senior paediatric clinician by telephone has had a positive impact on the number of children being referred for acute assessment. Utilisation of Rapid Access Clinics and urgent Telephone Consultations can help ensure that children are seen in a timely fashion and help reduce pressure on front door services.

AIMS In pre-clinical models of acute myocardial infarction (MI), mature B cells mobilise inflammatory monocytes into the heart, leading to increased infarct size and deterioration of cardiac function, whilst anti-CD20 antibody mediated depletion of B cells limits myocardial injury and improves cardiac function. Rituximab is a monoclonal anti-CD20 antibody targeted against human B cells. However, its use in cardiovascular disease is untested and is currently contraindicated. Therefore, we assessed the safety, feasibility and pharmacodynamic effect of rituximab given to patients with acute ST elevation MI (STEMI). METHODS AND RESULTS RITA-MI was a prospective, open-label, dose-escalation, single-arm, phase 1/2a clinical trial, which tested rituximab administered as a single intravenous dose in patients with STEMI within 48 hours of symptom onset. Four escalating doses (200, 500, 700 and 1000 mg) were used. The primary endpoint was safety, whilst secondary endpoints were changes in circulating immune cell subsets including B cells, and cardiac and inflammatory biomarkers. [NCT : 03072199]. A total of 24 patients were dosed. Rituximab appeared well tolerated. Seven serious adverse events were reported, none of which were assessed as being related to the rituximab infusion. Rituximab caused a mean 96.3% (95% CI 93.8-98.8%) depletion of circulating B cells within 30 mins of starting the infusion. Maximal B cell depletion was seen at day 6, which was significantly lower than baseline for all doses (p

PurposeAlbinism is a clinically and genetically heterogeneous condition. Despite analysis of the nineteen known genes, ∼30% patients remain unsolved. We aimed to identify new genes involved in albinism.MethodsWe sequenced a panel of genes with known or predicted involvement in melanogenesis in 230 unsolved albinism patients.ResultsWe identified variants in theDopachrome tautomerase(DCT) gene in two patients. One was compound heterozygous for a 14 bp deletion in exon 9 and c.118T>A p.(Cys40Ser). The second was homozygous for c.183C>G p.(Cys61Trp). Both patients had mild hair and skin hypopigmentation, and classical ocular features. CRISPR/Cas9 was used in C57BL/6J mice to create mutations identical to the missense mutations carried by the patients, along with one loss-of-function indel mutation. When bred to homozygosity the three mutations revealed hypopigmentation of the coat, milder for Cys40Ser compared to Cys61Trp or the frameshift mutation. Histological analysis identified significant hypopigmentation of the retinal pigmented epithelium (RPE) indicating that defective RPE melanogenesis could be associated with eye and vision defects.DCTloss of function in zebrafish embryos elicited hypopigmentation both in melanocytes and RPE cells.ConclusionsDCTis the gene for a new type of oculocutaneous albinism that we propose to name OCA8.

Background Sexual health, wellbeing, and function are important parts of a person's identity. Chronic diseases, such as kidney failure can alter, impair, and profoundly, affect sexual wellbeing and function. Objective To conduct a scoping review of studies about renal nurses' practice and attitudes towards sexual health, wellbeing, and function in people with kidney failure receiving haemodialysis. Methods Using Arksey and O'Malley's framework, seven databases were searched (CINAHL, MEDLINE, EMBASE, OvidPsycINFO, Scopus, Cochrane library, and JBI library). The search included studies published in English from January 2009 to January 2020. Results Four studies met the review criteria (two cross-sectional surveys and two qualitative). Role confusion in discussing sexual issues, lack of training, and education in addressing sexual concerns, personal, and workplace related barriers were four factors that emerged from the review of the studies. This review identified that renal nurses were uncomfortable and hesitant in initiating discussions about sexual health, wellbeing, and function with people receiving haemodialysis. Conclusion Renal nurses experience role confusion about whose responsibility it is to initiate and discuss sexual concerns with patients, as well as who's role is it to conduct sexual health assessments. Work related and personal barriers impeded nurses' practice regarding sexual health, wellbeing, and function. Nurses working in renal units need knowledge and practical training about how to initiate and address sexual concerns in those affected by kidney disease.

External ventricular drainage (EVD) may be used for therapeutic cerebrospinal fluid (CSF) drainage to control intracranial pressure (ICP) after traumatic brain injury (TBI). However, there is currently uncertainty regarding the optimal timing for EVD insertion. This study aims to compare patient outcomes for patients with early and late EVD insertion. Following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, MEDLINE/EMBASE/Scopus/Web of Science/Cochrane Central Register of Controlled Trials were searched for published literature involving at least 10 severe TBI (sTBI) patients from their inception date to December 2019. Outcomes assessed were mortality, functional outcome, ICP control, length of stay, therapy intensity level, and complications. Twenty-one studies comprising 4542 sTBI patients with an EVD were included; 19 of the studies included patients with an early EVD, and two studies had late EVD placements. The limited number of studies, small sample sizes, imbalance in baseline characteristics between the groups and poor methodological quality have limited the scope of our analysis. We present the descriptive statistics highlighting the current conflicting data and the overall lack of reliable research into the optimal timing of EVD. There is a clear need for high quality comparisons of early vs. late EVD insertion on patient outcomes in sTBI.

OBJECTIVES Because the mortality rate is very low in thoracic surgery, its use as a quality discriminator is limited. Acute kidney injury (AKI) is a candidate measure because it is associated with increased rates of morbidity and mortality and is partly preventable. The incidence of AKI after thoracic surgery is not well documented. We conducted an audit to determine the incidence and outcomes of AKI. This audit became a pilot project, and the results indicate the feasibility of a larger study. METHODS Retrospective data on renal function post-thoracic surgery were collected at a tertiary cardiothoracic unit over 12 months. Renal impairment was classified according to the Kidney Disease Improving Global Outcomes criteria. RESULTS Of 568 patients (mean = 59 ± SD 18; 38% women), AKI was diagnosed in 86 (15.1%) within 72 h post-thoracic surgery based on the Kidney Disease Improving Global Outcomes staging system (stage 1, n = 55; stage 2, n = 25; stage 3, n = 6). Significant differences were found in postoperative length of stay (3 vs 5 days; P CONCLUSIONS The incidence of AKI after thoracic surgery was 15.1%. AKI was associated with longer hospital stays and was more likely in ≥60-year-old patients after open surgery than after VATS. Reducing AKI could improve patient outcomes. We propose that AKI may be a useful quality measure in thoracic surgery. We are developing a multicentre audit based on this approach.

Introduction: Atrial natriuretic peptide (ANP) plays an important role in blood pressure (BP) regulation via the second messenger cGMP. ANP also induces lipolysis by increasing plasma levels of non-esterified fatty acids (NEFA). MANP is a new Mayo Clinic designed ANP analog consisting of the native ANP with a novel 12-amino-acid C-terminus extension. In experimental models, MANP is more potent than ANP in reducing BP and inducing natriuresis. These actions are mediated by the activation of the pGC-A receptor and generation of cGMP. To date, the BP pressure lowering, cGMP generating and lipolytic actions of MANP remain unexplored along with its safety and tolerability in subjects with hypertension (HTN) associated with metabolic disease. Hypothesis: In subjects with HTN, obesity and metabolic syndrome (MS), MANP administration is safe, well tolerated, activates cGMP and exerts BP lowering and lipolytic properties. Methods: Double-blind, placebo-control clinical trial in 22 subjects (17 receiving MANP) with HTN, obesity and MS involving a single subcutaneous (SQ) injection of MANP (2.5 μg/Kg) or placebo. Subjects were monitored and cardiovascular, cGMP and metabolic parameters were collected during 24 hours after the injection. Results: In all subjects, MANP was safe and well-tolerated with no serious adverse side effects. MANP increased mean cGMP plasma levels after 30 minutes (delta: 4.8 ± 2.0 pmol/mL, p=0.02) and 1 hour (delta: 2.9 ±1.3 pmol/mL, p=0.03) when compared to baseline. Six hours after MANP injection systolic BP decreased by 5.7 ± 2.9 mmHg (p=0.06) whereas subjects receiving placebo had no decrease in blood pressure values compared to baseline. During fasting period, one hour after the administration of MANP, NEFA plasma levels increased by 108.2 ± 37.4 μM (p=0.01). Conclusions: In subjects with HTN, obesity and MS, SQ MANP is safe, well tolerated and activates the pGC-A receptor as measured by a significant increase in the second messenger cGMP. Subjects receiving MANP showed a borderline significant decrease in systolic BP and a significant increase in NEFA circulating levels supporting anti-hypertensive and lipolytic properties. Our findings support MANP as a potential novel therapy for HTN associated with metabolic disease.

Mindfulness-Based-Cognitive-Therapy (MBCT) reduces vulnerability for relapse into depression by helping individuals to counter tendencies to engage in maladaptive repetitive patterns of thinking and respond more compassionately to negative self-judgment. However, little is known about the neural correlates underlying these effects. To elucidate these correlates, we investigated fMRI brain activation during a task eliciting feelings of blaming oneself or others. Sixteen participants in remission from major depressive disorder (MDD) completed fMRI assessments before and after MBCT, alongside self-reported levels of self-compassion, mindfulness, and depression symptoms. Analyses of self-blame versus other-blame contrasts showed a reduction in activation in the bilateral dorsal anterior cingulate/medial superior frontal gyrus after MBCT compared to baseline. Further, exploratory analyses showed that increases in self-kindness after MBCT correlated with reduced activation in the posterior cingulate cortex (PCC)/precuneus in self-blame versus rest contrasts. These findings suggest that MBCT is associated with a reduction in activations in cortical midline regions to self-blame which may be mediated by increasing self-kindness. However, this is a small, uncontrolled study with 16 participants and therefore our results will need confirmation in a controlled study.

PURPOSE: Exercise intolerance, evaluated by O(2) consumption, predicts mortality in Cystic Fibrosis (CF). People with CF exhibit skeletal muscle dysfunctions that may contribute to an imbalance between O(2) delivery and utilization. Sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, increases blood flow and improves O(2) consumption, although the exact mechanisms in CF have yet to be elucidated. Thus, we hypothesized that exercise intolerance in CF is limited primarily by an impaired skeletal muscle O(2) utilization, and sildenafil improves exercise tolerance in CF by addressing this mismatch between O(2) demand and extraction. METHODS: Fifteen individuals with mild-to-moderate CF and eighteen healthy controls completed an incremental exercise test and measurements of gaseous exchange, chronotropic response, hemodynamics, and O(2) extraction and utilization. People with CF also completed a four-week-treatment with sildenafil with a subsequent follow-up evaluation after treatment. RESULTS: Skeletal muscle O(2) extraction and utilization during exercise were reduced in people with CF when compared to controls. Exercise capacity in our CF population was minimally limited by hemodynamic or chronotopic responses, while peripheral O(2) extraction was more closely associated with exercise capacity. The study also demonstrated that four weeks of sildenafil improved skeletal muscle O(2) utilization during exercise to similar values observed in healthy individuals. CONCLUSIONS: Individuals with mild to moderate CF exhibit exercise intolerance secondary to a reduction in O(2) utilization by the exercising skeletal muscle. The present study demonstrated that four weeks of sildenafil treatment improves the capacity of the skeletal muscle to utilize O(2) more efficiently during exercise. Findings from the present study highlight the importance of targeting skeletal muscle O(2) utilization to improve exercise tolerance in CF.

Objective To validate an artificial intelligence–augmented electrocardiogram (AI-ECG) algorithm for the detection of preclinical left ventricular systolic dysfunction (LVSD) in a large community-based cohort. Methods We identified a randomly selected community-based cohort of 2041 subjects age 45 years or older in Olmsted County, Minnesota. All participants underwent a study echocardiogram and ECG. We first assessed the performance of the AI-ECG to identify LVSD (ejection fraction ≤40%). After excluding participants with clinical heart failure, we further assessed the AI-ECG to detect preclinical LVSD among all patients (n=1996) and in a high-risk subgroup (n=1348). Next we modelled an imputed screening program for preclinical LVSD detection where a positive AI-ECG triggered an echocardiogram. Finally, we assessed the ability of the AI-ECG to predict future LVSD. Participants were enrolled between January 1, 1997, and September 30, 2000; and LVSD surveillance was performed for 10 years after enrollment. Results For detection of LVSD in the total population (prevalence, 2.0%), the area under the receiver operating curve for AI-ECG was 0.97 (sensitivity, 90%; specificity, 92%); in the high-risk subgroup (prevalence 2.7%), the area under the curve was 0.97 (sensitivity, 92%; specificity, 93%). In an imputed screening program, identification of one preclinical LSVD case would require 88.3 AI-ECGs and 8.7 echocardiograms in the total population and 65.7 AI-ECGs and 5.5 echocardiograms in the high-risk subgroup. The unadjusted hazard ratio for a positive AI-ECG for incident LVSD over 10 years was 2.31 (95% CI, 1.32 to 4.05; P=.004). Conclusion Artificial intelligence–augmented ECG can identify preclinical LVSD in the community and warrants further study as a screening tool for preclinical LVSD.

A cross-section correlational study was conducted to evaluate the overall quality of life in young adults (AYAs) diagnosed with cancer, and the impact of health-related and non-health-related factors on their quality of life. Fifty-six AYA cancer survivors were recruited to elicit the impact of biological function (cancer type and comorbidity), symptoms, functional status, general perception of health status, gender, and characteristics of the environment on quality of life. Participants experienced higher than average quality of life. Symptoms, functional status, and general perception of health status were significant predictors of quality of life in this group of AYAs diagnosed with cancer. In delivering quality cancer care, nurses must be able to thoroughly assess symptom status, AYA cancer survivors’ perception of their health status, and functioning in order to implement supportive measures to help improve their quality of life.

A 13-year-old girl presented to the emergency department with acute onset of chest pain, nausea and tremor. The patient denied drug ingestion, and urine toxicology was negative. ECG demonstrated sinus tachycardia, prolonged QTc (541 ms) and ST depression. Laboratory testing demonstrated metabolic acidosis, hypokalaemia, hypophosphataemia and hyperglycaemia. She was commenced on continuous cardiac monitoring and treated with intravenous fluids and electrolyte replacement. Presenting features and laboratory abnormalities resolved within 48 hours. The National Poisons Information Service and Clinical Biochemistry were integral to her management, advising the clinical team on the likeliest aetiology. Five weeks after discharge, urine toxicology, using mass spectrometry, identified clenbuterol. Clenbuterol is an oral β2-agonist with anabolic and lipolytic effects that is misused as a performance and image enhancing drug. Clinicians must be aware of the increasing availability of these drugs and their potential for causing harm in children and adolescents.

Background: Trauma registries are known to drive improvements and optimise trauma systems worldwide. This is the first reported comparison of the epidemiology and outcomes at major centres across Australia. Methods: The Australian Trauma Registry was a collaboration of 26 major trauma centres across Australia at the time of this study and currently collects information on patients admitted to these centres who die after injury and/or sustain major trauma (Injury Severity Score (ISS) > 12). Data from 1 July 2016 to 30 June 2017 were analysed. Primary endpoints were risk adjusted length of stay and mortality (adjusted for age, cause of injury, arrival Glasgow coma scale (GCS), shock-index grouped in quartiles and ISS). Results: There were 8423 patients from 24 centres included. The median age (IQR) was 48 (28–68) years. Median (IQR) ISS was 17 (14–25). There was a predominance of males (72%) apart from the extremes of age. Transport-related cases accounted for 45% of major trauma, followed by falls (35.1%). Patients took 1.42 (1.03–2.12) h to reach hospital and spent 7.10 (3.64–15.00) days in hospital. Risk adjusted length of stay and mortality did not differ significantly across sites. Primary endpoints across sites were also similar in paediatric and older adult (>65) age groups. Conclusion: Australia has the capability to identify national injury trends to target prevention and reduce the burden of injury. Quality of care following injury can now be benchmarked across Australia and with the planned enhancements to data collection and reporting, this will enable improved management of trauma victims.

Sexual orientation microaggressions are common on college campuses and can contribute to negative outcomes; yet little is known about their relationship with substance use outcomes. Among a convenience sample of cisgender sexual minority college students (

Cystic fibrosis (CF), characterized by defective CFTR function, is associated with multiple systemic complications, including vascular dysfunction. Sildenafil, a phosphodiesterase type 5 inhibitor, not only enhances nitric oxide (NO) metabolism but has been shown to improve CFTR functionality as well. Thus, sildenafil has been proposed as a therapy to improve vascular health in CF; however, its potential therapeutic role has yet to be determined. We sought to investigate the effect of sildenafil on endothelial function in patients with CF. Patients with CF completed a randomized, double-blind, placebo-controlled, crossover study with an acute dose of sildenafil (50 mg) or placebo followed by a 4-wk open-label extension with sildenafil (20 mg/day). Flow-mediated dilation (FMD) was used to evaluate endothelial function before and after treatments. In addition, phosphorylated endothelial NO synthase (pNOS3) and total NOS3 protein expression was determined from endothelial cells that were exposed to plasma from the patients before and after 4 wk of sildenafil treatment. No changes ( P ≥ 0.110) in endothelial function were observed after the acute dose of sildenafil. However, FMD significantly ( P = 0.029) increased after 4 wk of treatment (∆FMD: 1.5 ± 2.2%). Moreover, pNOS3 protein expression significantly ( P = 0.013) increased after 4 wk of treatment (∆pNOS3: 0.31 ± 0.39 arbitrary units) and was associated ( r = 0.593, P = 0.033) with the change in FMD. These data suggest that 4 wk of sildenafil treatment can improve vascular endothelial function in patients with CF, likely through an increase in NOS3 phosphorylation. NEW & NOTEWORTHY Findings from the present study demonstrate, for the first time, significant improvement of endothelial function in patients with cystic fibrosis treated with sildenafil that is associated with greater phosphorylation of endothelial nitric oxide synthase. These results support the use of sildenafil as a potential novel therapy for this patient population.

Multiple pterygium syndrome (MPS) disorders are a phenotypically and genetically heterogeneous group of conditions characterized by multiple joint contractures (arthrogryposis), pterygia (joint webbing) and other developmental defects. MPS is most frequently inherited in an autosomal recessive fashion but X-linked and autosomal dominant forms also occur. Advances in genomic technologies have identified many genetic causes of MPS-related disorders and genetic diagnosis requires large targeted next generation sequencing gene panels or genome-wide sequencing approaches. Using the Illumina TruSightOne clinical exome assay, we identified a recurrent heterozygous missense substitution in TPM2 (encoding beta tropomyosin) in three unrelated individuals. This was confirmed to have arisen as a de novo event in the two patients with parental samples. TPM2 mutations have previously been described in association with a variety of dominantly inherited neuromuscular phenotypes including nemaline myopathy, congenital fibre-type disproportion, distal arthrogryposis and trismus pseudocamptodactyly, and in a patient with autosomal recessive Escobar syndrome and a nemaline myopathy. The three cases reported here had overlapping but variable features. Our findings expand the range of TMP2-related phenotypes and indicate that de novo TMP2 mutations should be considered in isolated cases of MPS-related conditions.

To investigate the interrelation between economic, marital, and known histopathologic/therapeutic prognostic factors in presentation and survival of patients with lung cancer in nine different ethnic groups. A retrospective review of the SEER database was conducted through the years 2007–2012. Population differences were assessed via chi‐square testing. Multivariable analyses (MVA) were used to detect overall survival (OS) differences in the total population (TP, N = 153,027) and for those patients presenting with Stage IV (N = 70,968). Compared to Whites, Blacks were more likely to present with younger age, male sex, lower income, no insurance, single/widowed partnership, less squamous cell carcinomas, and advanced stage; and experience less definitive surgery, lower OS, and lung cancer‐specific (LCSS) survival. White Hispanics presented with younger age, higher income, lower rates of insurance, single/widowed partnership status, advanced stage, more adenocarcinomas, and lower rates of definitive surgery, but no difference in OS and LCSS than Whites. In the TP and Stage IV populations, MVAs revealed that OS was better or equivalent to Whites for all other ethnic groups and was positively associated with insurance, marriage, and higher income. Blacks presented with more advanced disease and were more likely to succumb to lung cancer, but when adjusted for prognostic factors, they had a better OS in the TP compared to Whites. Disparities in income, marital status, and insurance rather than race affect OS of patients with lung cancer. Because of their presentation with advanced disease, Black and Hispanics are likely to have increased benefit from lung cancer screening.

Background The impact of blood flow regulation and oxidative stress during exercise in cystic fibrosis (CF) has yet to be investigated. Methods A maximal graded exercise test was conducted to determine exercise capacity (VO 2 peak) and peak workload in 14 pediatric patients with mild CF (age 14±3y, FEV 1 93±16 % predicted) and 14 demographically-matched controls. On a separate visit, participants performed submaximal cycling up to 60% of peak workload where brachial artery blood velocity was determined using Doppler ultrasound. Retrograde and antegrade components were further analyzed as indices of blood flow regulation. Results The cumulative AUC for retrograde velocity was lower in patients versus controls (1770±554 vs. 3440±522cm, P =0.038). In addition, an exaggerated oxidative stress response during exercise occurred in patients only ( P =0.004). Conclusion These data suggest that patients with mild CF exhibit impaired blood flow regulation and an exaggerated oxidative stress response to submaximal exercise.

Background Lower serum chloride (Cl) is associated with mortality in heart failure patients and may be more prognostically relevant than sodium. However, the association of hemodynamics and Cl levels is unknown. Methods 438 sequential patients with advanced chronic heart failure (ACHF) underwent invasive hemodynamic assessment with measured serum Cl levels during an evaluation for ACHF. Patients were followed for death, heart transplant (HT), or ventricular assist device placement (VAD). A backwards regression model determined hemodynamic predictors of Cl (removal, P Results In this cohort, the median Cl level was 102 [98–104]meq/L (range 86–113meq/L). Chloride was weakly correlated with FCI (rho 0.12, P=0.01) and MAP (rho 0.21, P 0.05 for all). In the multivariable model, FCI (beta 0.73meq/L/L/min/m 2 , P=0.002) but not RAP (P=0.3) or MAP (P=0.2), remained associated with Cl. Lower Cl was associated with increased risk of death, HT, or VAD placement (HR 0.94/meq/L, 95% CI 0.89–0.99, P=0.01). However, this association was attenuated after additional adjustment for BUN (P=0.27) and PCWP and FCI (0.48). Conclusions Lower FCI, not lower MAP or higher cardiac filling pressures, was associated with lower chloride. Although lower chloride was associated with poor long-term outcomes, this risk attenuates with adjustment for more conventional clinical parameters.

Opioid-binding protein/cell adhesion molecule-like (OPCML) is a tumor-suppressor gene that is frequently inactivated in ovarian cancer and many other cancers by somatic methylation. We have previously shown that OPCML exerts its suppressor function by negatively regulating a spectrum of receptor tyrosine kinases (RTK), such as ErbB2/HER2, FGFR1, and EphA2, thus attenuating their related downstream signaling. The physical interaction of OPCML with this defined group of RTKs is a prerequisite for their downregulation. Overexpression/gene amplification of EGFR and HER2 is a frequent event in multiple cancers, including ovarian and breast cancers. Molecular therapeutics against EGFR/HER2 or EGFR only, such as lapatinib and erlotinib, respectively, were developed to target these receptors, but resistance often occurs in relapsing cancers. Here we show that, though OPCML interacts only with HER2 and not with EGFR, the interaction of OPCML with HER2 disrupts the formation of the HER2-EGFR heterodimer, and this translates into a better response to both lapatinib and erlotinib in HER2-expressing ovarian and breast cancer cell lines. Also, we show that high OPCML expression is associated with better response to lapatinib therapy in breast cancer patients and better survival in HER2-overexpressing ovarian cancer patients, suggesting that OPCML co-therapy could be a valuable sensitizing approach to RTK inhibitors. Mol Cancer Ther; 16(10); 2246–56. ©2017 AACR.

Background: Exercise intolerance is a common phenotype observed in patients with cystic fibrosis (CF). Treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, has previously been shown to improve exercise capacity (VO2 peak) in other patient populations. Thus, the present study sought to determine the acute and subacute effects of sildenafil on exercise capacity in patients with CF. Methods: The present investigation utilized a randomized, double-blind, placebo-controlled, crossover study with an acute dose of either sildenafil (50 mg) or placebo ( n = 13, age 25 ± 10), followed by a 4 week open-label extension with sildenafil (20 mg, TID; n = 15, age 23 ± 11). A comprehensive evaluation of pulmonary function and a maximal exercise test were each performed at every visit. Results: A significant increase in VO2 peak was observed after the acute sildenafil dose with no changes following placebo (77 ± 13 versus 72 ± 13% predicted; p = 0.033). In addition, after 4 weeks of treatment, patients showed a significant increase in exercise capacity (72 ± 12 versus 75 ± 12% predicted; p = 0.028) and exercise duration (409 ± 98 versus 427 ± 101 s; p = 0.014). A robust correlation ( r = 0.656; p = 0.008) between baseline FEV1 (% predicted) and the change in exercise capacity following 4 weeks of treatment was identified. Conclusions: This proof-of-concept clinical trial demonstrates that sildenafil treatment can improve exercise capacity in patients with CF and that pulmonary function may play an important role in the effectiveness of treatment. Future investigations of sildenafil treatment in patients with CF are certainly warranted.

Half of the people living with HIV have cognitive deficits indicative of HIV-associated neurocognitive disorders (HANDs). With few treatment options, informing patients about a HAND diagnosis is a questionable practice. A sample of 139 people living with HIV were administered gold-standard cognitive tests; scores were used to determine whether they met cognitive criteria for HAND. Participants were informed that they met the criteria for HAND and asked 2 open-ended questions about their reactions to learning this information. Participant responses were recorded verbatim and coded into 3 overarching themes: positive, indifferent, and negative. Positive responses contained subthemes of confirmation, gratitude, desire for improvement, and curiosity. Indifferent responses contained nonreactive responses, apathy, and confusion. Negative responses contained surprise, discontentment, fear, and denial. Although most participants responded positively to feedback about HANDs, others experienced distress. Nurse clinicians should be mindful about informing patients if they have HAND while also educating them about brain health.

Hypoxia is common in many chronic lung diseases. Beyond pulmonary considerations, delivery of oxygen (O2) to the tissues and subsequent O2 utilisation is also determined by other factors including red blood cell mass and iron status; consequently, disruption to these mechanisms provides further physiological strains on an already stressed system. O2 availability influences ventilation, regulates pulmonary blood flow and impacts gene expression throughout the body. Deleterious effects of poor tissue oxygenation include decreased exercise tolerance, increased cardiac strain and pulmonary hypertension in addition to pathophysiological involvement of multiple other organs resulting in progressive frailty. Increasing inspired O2 is expensive, disliked by patients and does not normalise tissue oxygenation; thus, other strategies that improve O2 delivery and utilisation may provide novel therapeutic opportunities in patients with lung disease. In this review, we focus on the rationale and possibilities for doing this by increasing haemoglobin availability or improving iron regulation.

We examined the impact of comorbidities on length of stay and total hospital charges for children and young adults with Crohn's Disease (CD) undergoing surgery.Patients (21 years) were identified with a diagnosis of CD and an intraabdominal surgery in the Kids' Inpatient Database for the years 2006, 2009 and 2012. Length of stay (LOS) and total hospital charges (THC; USD$) were stratified by anemia, anxiety, depression and nutritional deficiency. National estimates were obtained using case weighting and multivariable linear regression was performed.We identified 3224 CD admissions with an intraabdominal surgery. The population was predominantly male, non-Hispanic white, and high school aged. There was an increase in LOS and THC for nutritional deficiency in all study years, and for depression and anemia in specific years. Multivariable linear regression revealed a 3.3-5.5 day increase in LOS associated with a comorbid diagnosis of nutritional deficiency. However, no increase in THC was seen for any comorbidity under evaluation.Behavioral health and, particularly, nutritional status have a significant impact on the care of children and young adults with CD. Nutritional deficiency, anemia, and depression resulted in increased LOS for those undergoing surgery. Improved presurgical management of comorbidities may reduce LOS for these patients.III.

Eating behaviour requires that internal metabolic changes are recognized by the central nervous system which regulates brain responses to food cues. This function may be altered in obesity. The aim of this study was to examine potential differences in neurocognitive responses to visual food cues as a function of metabolic state and weight status. A crossover study with two participant groups was conducted, one group with normal-weight (n = 20) and one group with overweight/obesity (n = 22), who completed a novel battery of neurocognitive tests assessing food-cue elicited behavior in both fasted and fed states. The test battery included a visual-dot probe task (VPT), a stimulus-response compatibility task (SRCT) and an implicit association task (IAT). Results from the VPT showed a significant main effect of metabolic state on attentional bias (F(1,40) = 9.90, p = .003, η2p = .198), with participants in the fasted state showing a significantly greater attentional bias for food stimuli than in the fed state. No significant main effect of metabolic state on approach food bias, assessed via the SRCT, or implicit attitudes to food cues, assessed via the IAT, was found and overall, no difference in neurocognitive processing of food cues was demonstrated between participant groups. In the fed state, attentional bias to food cues decreases in both normal-weight controls and participants with overweight/obesity, indicating that changes in current metabolic state can be reflected in attentional processing of visual food cues independently of weight status. Neurocognitive tasks which can effectively and sensitively identify differences in food cue perception according to changes in metabolic status will be useful tools in exploring more complicated interactions between homeostatic and hedonic drives of food intake.

Oxidative stress and vascular endothelial dysfunction are established characteristics of cystic fibrosis (CF). Oxidative stress may contribute to vascular dysfunction via inhibition of nitric oxide (NO) bioavailability. Purpose. To determine if ingestion of a single antioxidant cocktail (AOC) improves vascular endothelial function in patients with CF. Methods. In 18 patients with CF (age 8-39 y), brachial artery flow-mediated dilation (FMD) was assessed using a Doppler ultrasound prior to and two hours following either an AOC (n=18; 1,000 mg vitamin C, 600 IU vitamin E, and 600 mg α-lipoic acid) or a placebo (n=9). In a subgroup of patients (n=9), changes in serum concentrations of α-tocopherol and lipid hydroperoxide (LOOH) were assessed following AOC and placebo. Results. A significant (p=0.032) increase in FMD was observed following AOC (Δ1.9±3.3%), compared to no change following placebo (Δ−0.8±1.9%). Moreover, compared with placebo, AOC prevented the decrease in α-tocopherol (Δ0.48±2.91 vs. −1.98±2.32 μM, p=0.024) and tended to decrease LOOH (Δ−0.2±0.1 vs. 0.1±0.1 μM, p=0.063). Conclusions. These data demonstrate that ingestion of an antioxidant cocktail can improve vascular endothelial function and improve oxidative stress in patients with CF, providing evidence that oxidative stress is a key contributor to vascular endothelial dysfunction in CF.

WOS: 000468732700018, PubMed ID: 31054483, Background and aims: One of the objectives of the ESC-EORP EUROASPIRE V survey is to determine how well European guidelines on the management of dyslipidaemias are implemented in coronary patients. Methods: Standardized methods were used by trained technicians to collect information on 7824 patients from 130 centers in 27 countries, from the medical records and at a visit at least 6 months after hospitalization for a coronary event. All lipid measurements were performed in one central laboratory. Patients were divided into three groups: on high-intensity LDL-C-lowering-drug therapy (LLT), on low or moderate-intensity LLT and on no LLT. Results: At the time of the visit, almost half of the patients were on a high-intensity LLT. Between hospital discharge and the visit, LLT had been reduced in intensity or interrupted in 20.8% of the patients and had been started or increased in intensity in 11.7%. In those who had interrupted LLT or had reduced the intensity, intolerance to LLT and the advice of their physician were reported as the reason why in 15.8 and 36.8% of the cases, respectively. LDL-C control was better in those on a high-intensity LLT compared to those on low or moderate intensity LLT. LDL-C control was better in men than women and in patients with self-reported diabetes. Conclusions: The results of the EUROASPIRE V survey show that most coronary patients have a less than optimal management of LDL-C. More professional strategies are needed, aiming at lifestyle changes and LLT adapted to the need of the individual patient., ESC - EORP; AmgenAmgen; Eli LillyEli Lilly; PfizerPfizer; SanofiSanofi-Aventis; Ferrer; Novo NordiskNovo Nordisk, The EUROASPIRE V survey was carried out under the auspices of the ESC - EORP. Since the start of EORP, the following companies have supported the programme: Amgen, Eli Lilly, Pfizer, Sanofi, Ferrer and Novo Nordisk. The sponsors of the EUROASPIRE surveys had no role in the design, data collection, data analysis, data interpretation, decision to publish, or writing the manuscript.

Aims In recent years, stroke prevention in patients with atrial fibrillation (AF) has radically changed, with increasing use of non-vitamin K antagonist oral anticoagulants (NOACs). Contemporary European data on AF thromboprophylaxis are needed. Methods and results We report 1-year follow-up data from the EURObservational Research Programme in Atrial Fibrillation (EORP-AF) General Long-Term Registry. Outcomes were assessed according to antithrombotic therapy. At 1-year follow-up, 9663 (88.0%) patients had available data for analysis: 586 (6.1%) were not treated with any antithrombotic; 681 (7.0%) with antiplatelets only; 4066 (42.1%) with vitamin K antagonist (VKA) only; 3167 (32.8%) with NOACs only; and 1163 (12.0%) with antiplatelet and oral anticoagulant. At 1-year follow-up, there was a low rate of stroke (0.7%) and any thromboembolic event (TE) (1.2%), while haemorrhagic events occurred in 222 patients (2.3%). Cardiovascular (CV) death and all-cause death occurred in 3.9% and 5.2% of patients, respectively. Cumulative survival for all the three main outcomes considered was highest amongst patients treated only with NOACs (P Conclusion The 1-year follow-up of EORP-AF General Long-Term Registry reported a low occurrence of thromboembolic and haemorrhagic events, although mortality was high. Both VKA and NOACs were associated with a lower risk of all main adverse outcomes. All treatments were associated with a lower risk for CV death and all-cause death.

Aims Guided by predictive characteristics of cardiovascular biomarkers, we explored the clinical implications of a simulated biomarker-guided heart failure (HF) and major adverse cardiovascular events (MACE) prevention strategy in the community. Methods and results In a community cohort (n = 1824), the predictive characteristics for HF and MACE of galectin-3 (Gal-3), ST2, high-sensitivity cardiac troponin I (hscTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro-brain natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP) were established. We performed number needed to screen (NNS) and treat (NNT) with the intervention analyses according to biomarker screening strategy and intervention efficacy in persons with at least one cardiovascular risk factor. In the entire cohort, for both HF and MACE, the predictive characteristics of NT-proBNP and hscTnI were superior to other biomarkers; alone, in a multimarker model, and adjusting for clinical risk factors. An NT-proBNP-guided preventative intervention with an intervention effect size (4-year hazard ratio for intervention in biomarker positive cohort) of ≤0.7 would reduce the global burden of HF by ≥20% and MACE by ≥15%. From this simulation, the NNS to prevent one HF event or MACE in 4 years would be ≤100 with a NNT to prevent one HF event of ≤20 and one MACE of ≤10. Conclusions The predictive characteristics of NT-proBNP and hscTnI for HF or MACE in the community are superior to other biomarkers. Biomarker-guided preventative interventions with reasonable efficacy would compare favourably to established preventative interventions. This data provides a framework for biomarker selection which may inform design of biomarker-guided preventative intervention trials.

Aims We have previously reported that asymptomatic systolic heart failure (HF) is characterized by an impaired renal response to volume expansion due to lack of activation of urinary cGMP which is corrected by subcutaneous (SQ) BNP. In the current study, we sought to define the cardiorenal response to intravascular volume expansion after 12 weeks of SQ BNP therapy. Methods and results We utilized a double-blinded, placebo-controlled study to compare 12 weeks of twice-daily SQ BNP 10 µg/kg (n = 22) or placebo (n = 12) in asymptomatic systolic HF. Subjects underwent two study visits: baseline and after 12 weeks of therapy. At each study visit, echocardiography, renal, and neurohumoral assessments were performed before and after intravascular volume expansion. The primary endpoint was change in urinary sodium excretion in response to volume expansion at 12 weeks, and we observed a greater increase in urinary sodium excretion [166 (77, 290) vs. 15 (−39, 72) mEq/min; P = 0.02] with SQ BNP treatment vs. placebo. Secondary endpoints included change in urine flow and glomerular filtration rate (GFR) in response to volume expansion at 12 weeks. We observed a significant increase in urine flow (P < 0.01) and trend for differential response in GFR (P = 0.08) with SQ BNP treatment vs. placebo. Conclusion Among patients with asymptomatic systolic HF, twice-daily SQ BNP therapy improved the cardiorenal response to volume expansion at 12-week follow-up. Further studies are warranted to determine if these beneficial physiological observations with chronic natriuretic peptide administration translate into a delay in the progression to symptomatic HF.

Objective To evaluate the efficacy of deferiprone (DFP), 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one (CM1) or green tea extract (GTE) in enhancing expression of hepatic hepcidin1 (Hamp1) mRNA and relieving iron overload in β-globin knockout thalassemic mice. Methods The β-globin knockout thalassemic mice were fed with a ferrocene-supplemented diet for 2 months and oral administration of deionized water, DFP (50 mg/kg), CM1 (50 mg/kg), GTE (50 mg epigallocatechin 3-gallate equivalent/kg), GTE along with DFP (50 mg/kg), and GTE along with CM1 (50 mg/kg) every day for 3 months. Levels of hepatic Hamp1 mRNA, plasma non-transferrin bound iron, plasma alanine aminotransferase activity and tissue iron content were determined. Results All chelation treatments could reduce plasma non-transferrin bound iron concentrations. Additionally, hepatic Hamp1 mRNA expression was significantly up-regulated in the mice in a GTE + DFP combined treatment, correlating with a decrease in the plasma alanine aminotransferase activity and tissue iron deposition. Conclusions The GTE + DFP treatment could ameliorate iron overload and liver oxidative damage in non-transfusion dependent β-thalassemic mice, by chelating toxic iron in plasma and tissues, and increasing hepcidin expression to inhibit duodenal iron absorption and iron release from hepatocytes and macrophages in the spleen. There is probably an advantage in giving GTE with DFP when treating patients with iron overload.