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Abstract: Mutations in the small Rho-family guanosine triphosphate hydrolase RAC2, critical for actin cytoskeleton remodeling and intracellular signal transduction, are associated with neonatal severe combined immunodeficiency (SCID), infantile neutrophilic disorder resembling leukocyte adhesion deficiency (LAD), and later-onset combined immune deficiency (CID). We investigated 54 patients (23 previously reported) from 37 families yielding 15 novel RAC2 missense mutations, including one present only in homozygosity. Data were collected from referring physicians and literature reports with updated clinical information. Patients were grouped by presentation: neonatal SCID (n = 5), infantile LAD-like disease (n = 5), or CID (n = 44). Disease correlated to RAC2 activity: constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID. Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients; myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes. Among 42 patients with CID with clinical data, upper and lower respiratory infections and viral infections were common. Twenty-three distinct RAC2 mutations, including 15 novel variants, were identified. Using heterologous expression systems, we assessed downstream effector functions including superoxide production, p21-activated kinase 1 binding, AKT activation, and protein stability. Confocal microscopy showed altered actin assembly evidenced by membrane ruffling and macropinosomes. Altered protein localization and aggregation were observed. All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence. Most mutants produced elevated superoxide; mutations unable to support superoxide formation were associated with bacterial infections. RAC2 mutations cause a spectrum of immune dysfunction, ranging from early onset SCID to later-onset combined immunodeficiencies depending on RAC2 activity. This trial was registered at www.clinicaltrials.gov as #NCT00001355 and #NCT00001467.

Background: Preeclampsia (PE), new-onset hypertension (HTN), and organ dysfunction during the second half of pregnancy, is associated with an increase in inflammatory immune cells, including T helper 17 (Th17) cells. Studies have demonstrated that mitochondrial (mt) dysfunction is important in the pathogenesis of PE though causative factors have yet to be fully identified. Although Th17 cells, natural killer (NK) cells, and mt dysfunction contribute to HTN in the reduced uterine perfusion pressure (RUPP) rat model, the role of Th17 cells or IL-17 in mt dysfunction is unknown. Therefore, we hypothesize that RUPP stimulated Th17 cells cause HTN and mt dysfunction, which is alleviated with the blockade of IL-17., Methods: On gestational day 12 (GD12), RUPP Th17 cells were transferred into normal pregnant (NP) Sprague Dawley rats. A subset of NP + RUPPTh17 rats received IL-17RC (100 pg/day) on GD14-19. Blood pressure (MAP), NK cells, and mt function were measured on GD19 in all groups., Results: MAP increased in response to NP + RUPP Th17 compared to NP rats and was lowered with IL-17RC. Circulating and placental NK cells increased with NP + RUPP Th17 compared to NP and were lowered with IL-17RC. Renal mtROS increased in NP + RUPP Th17 compared to NP and was normalized with IL-17RC. Similar to PE women, placental mtROS decreased in NP + RUPP Th17 and was normalized with IL-17RC., Conclusion: Our results indicate that IL-17RC inhibition normalizes HTN, NK cell activation, and multi-organ mt dysfunction caused by Th17 cells stimulated in response to placental ischemia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Clinical decisions about Heart Failure (HF) are frequently based on measurements of left ventricular ejection fraction (LVEF), relying mainly on echocardiography measurements for evaluating structural and functional abnormalities of heart disease. As echocardiography is not available in primary care, this means that HF cannot be detected on initial patient presentation. Instead, physicians in primary care must rely on a clinical diagnosis that can take weeks, even months of costly testing and clinical visits. As a result, the opportunity for early detection of HF is lost., Methods and Results: The standard 12-Lead ECG provides only limited diagnostic evidence for many common heart problems. ECG findings typically show low sensitivity for structural heart abnormalities and low specificity for function abnormalities, e.g., systolic dysfunction. As a result, structural and functional heart abnormalities are typically diagnosed by echocardiography in secondary care, effectively creating a diagnostic gap between primary and secondary care. This diagnostic gap was successfully reduced by an AI solution, the Cardio-HART™ (CHART), which uses Knowledge-enhanced Neural Networks to process novel bio-signals. Cardio-HART reached higher performance in prediction of HF when compared to the best ECG-based criteria: sensitivity increased from 53.5% to 82.8%, specificity from 85.1% to 86.9%, positive predictive value from 57.1% to 70.0%, the F-score from 56.4% to 72.2%, and area under curve from 0.79 to 0.91. The sensitivity of the HF-indicated findings is doubled by the AI compared to the best rule-based ECG-findings with a similar specificity level: from 38.6% to 71%., Conclusion: Using an AI solution to process ECG and novel bio-signals, the CHART algorithms are able to predict structural, functional, and valve abnormalities, effectively reducing this diagnostic gap, thereby allowing for the early detection of most common heart diseases and HF in primary care., Competing Interests: Declaration of competing interest Istvan Kecskes disclosure: research director at UVA Research Corp., no other industry connections. Other authors have no financial or personal relationships with other people or organizations that could inappropriately influence their work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Although several different contouring instructional programs are available to radiation oncologists and trainees, very little is known about which methods and resources benefit learners most, and whether some learners may need alternate forms of instruction. This study aimed to determine the factors that were predictors of learners' success in anatomy, radiology, and contouring education., Methods and Materials: Participants in the online and face-to-face Anatomy and Radiology Contouring (ARC) Bootcamp completed pre- and postintervention evaluations that assessed anatomy/radiology knowledge, contouring skills, self-confidence, and spatial ability. Baseline factors were assessed as predictors of outcomes across multiple educational domains., Results: One hundred and eighty (face-to-face: n = 40; online: n = 140) participants enrolled in the ARC Bootcamp, and 57 (face-to-face: n = 30; online: n = 27) participants completed both evaluations. Of the participants enrolled, 37% were female, and most were radiation oncology residents (62%). In the anatomy/radiology knowledge testing, all quartiles (based on baseline performance) improved numerically; however, the largest improvements occurred in learners with the lowest baseline scores (P < .001). At the end of the Bootcamp, learners with lower-performing scores did not reach the level of learners with the highest baseline scores (Bonferroni-corrected P < .001). Regarding the contouring assessment, improvements were only evident for the participants with lower-performing baseline scores (P < .05). Spatial anatomy skills, as measured by the spatial anatomy task, were correlated to contouring ability. Overall, the greatest improvements were seen for learners in postgraduate year 1 to 3, those with no previous rotation experience in a given discipline, and those who attended from other programs (ie, medical physics residents and medical students)., Conclusions: The ARC Bootcamp improved all levels of performers' anatomy and radiology knowledge but only lower-performers' contouring ability. The course alone does not help lower-performing learners reach the abilities of higher-performers. The ARC Bootcamp tends to be most beneficial for participants with less radiation oncology experience. Curriculum modifications can be made to help support ARC Bootcamp participants with lower performing scores., (Copyright © 2022 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Auditory deficits are increasingly recognised following aneurysmal subarachnoid haemorrhage (aSAH) and are thought to be of central rather than peripheral origin. Central hearing impairment, also known as auditory processing disorder (APD), often coexists with cognitive deficits and it is thought that APD has both auditory and cognitive elements. The aim of this study was to assess auditory outcome following aSAH and its relationship with cognition. A retrospective case-controlled study design was employed with aSAH cases and matched controls identified from the UK Biobank. Auditory and cognitive outcomes were assessed using the digit triplet test (DTT) and a test of psychomotor reaction time, respectively. Best DTT score was compared between cases and controls using the t-test. A regression-based mediation analysis was performed to assess whether cognition mediated auditory outcome. 270 aSAH patients with auditory outcomes were identified with an average follow-up of 106 months. A matched control cohort of 1080 individuals was also identified. The aSAH cohort had significantly impaired best DTT scores compared to matched controls (p = 0.002). Cognition significantly mediated auditory outcome following aSAH, accounting for 9.8% of the hearing impairment after aSAH. In conclusion significant hearing impairment follows aSAH. The deficit is bilateral and non-progressive. There is a link with cognitive deficit, pointing to a central rather than peripheral source, in keeping with an auditory processing disorder. All aSAH patients should be asked about hearing difficulty at follow-up and when present it should be investigated with peripheral and central auditory assessments, as well as cognitive tests., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Artificial intelligence (AI) and variant prioritization tools for genomic variant analysis are being rapidly developed for use in clinical diagnostic testing. However, their clinical utility and reliability are currently limited. Therefore, we performed a validation of a commercial AI tool (Moon) and a comprehensive reanalysis of previously collected clinical exome sequencing cases using an open-source variant prioritization tool (Exomiser) and the now-validated AI tool to test their feasibility in clinical diagnostics., Methods: A validation study of Moon was performed with 29 positive cases determined by previous manual analysis. After validation, reanalysis was performed on 80 previously manually analyzed nondiagnostic exome cases using Moon. Finally, a comparison between Moon and Exomiser was completed regarding their ability to identify previously completed positive cases and to identify new positive cases., Results: Moon correctly selected the causal variant(s) in 97% of manually analyzed positive cases and identified 7 new positive cases. Exomiser correctly identified the causal gene in 85% of positive cases and agreed with Moon by ranking the new gene in its top 10 list 43% of the time., Conclusion: The use of AI in diagnostic laboratories greatly enhances exome sequencing analysis by reducing analysis time and increasing the diagnostic rate., Competing Interests: Conflict of Interest All authors are employees of the Knight Diagnostic Laboratories. The authors declare no other conflicts of interest., (Copyright © 2021 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Background: As new treatments and technologies have been introduced in radiation oncology, the clinical roles of radiation therapists (RTs) have expanded. However, there are few formal learning opportunities for RTs. An online, anatomy, radiology and contouring bootcamp (ARC Bootcamp) originally designed for medical residents was identified as a prospective educational tool for RTs. The purpose of this study was to evaluate an RT edition of the ARC Bootcamp on knowledge, contouring, and confidence, as well as to identify areas for future modification., Methods: Fifty licensed RTs were enrolled in an eight-week, multidisciplinary, online RT ARC Bootcamp. Contouring practice was available throughout the course using an online contouring platform. Outcomes were evaluated using a pre-course and post-course multiple-choice quiz (MCQ), contouring evaluation and qualitative self-efficacy and satisfaction survey., Results: Of the fifty enrolled RTs, 30 completed the course, and 26 completed at least one of the post-tests. Nineteen contouring dice similarity coefficient (DSC) scores were available for paired pre- and post-course analysis. RTs demonstrated a statistically significant increase in mean DSC scoring pooled across all contouring structures (mean ± SD improvement: 0.09 ± 0.18 on a scale from 0 to 1, p=0.020). For individual contouring structures, 3/15 reached significance in contouring improvement. MCQ scores were available for 26 participants and increased after RT ARC Bootcamp participation with a mean ± SD pre-test score of 18.6 ± 4.2 (46.5%); on a 40-point scale vs. post-test score of 24.5 ± 4.3 (61.4%) (p < 0.001). RT confidence in contouring, anatomy knowledge and radiographic identification improved after course completion (p < 0.001). Feedback from RTs recommended more contouring instruction, less in-depth anatomy review and more time to complete the course., Conclusions: The RT ARC Bootcamp was an effective tool for improving anatomy and radiographic knowledge among RTs. The course demonstrated improvements in contouring and overall confidence. However, only approximately half of the enrolled RTs completed the course, limiting statistical power. Future modifications will aim to increase relevance to RTs and improve completion rates., (Copyright © 2021. Published by Elsevier Inc.)

In 2013, the WHO recommended that all member states aim to reduce population salt intake by 30% by 2025. The year 2019 represents the midpoint, making it a critical time to assess countries' progress towards this target. This review aims to identify all national salt reduction initiatives around the world in 2019, and to quantify countries' progress in achieving the salt reduction target. Relevant data were identified through searches of peer-reviewed and gray literature, supplemented with responses from prefilled country questionnaires sent to known country leads of salt reduction or salt champions, WHO regional representatives, and international experts to request further information. Core characteristics of each country's strategy, including evaluations of program impact, were extracted and summarized. A total of 96 national salt reduction initiatives were identified, representing a 28% increase in the number reported in 2014. About 90% of the initiatives were multifaceted in approach, and 60% had a regulatory component. Approaches include interventions in settings (n= 74), food reformulation (n = 68), consumer education (n = 50), front-of-pack labeling (n = 48), and salt taxation (n = 5). Since 2014, there has been an increase in the number of countries implementing each of the approaches, except consumer education. Data on program impact were limited. There were 3 countries that reported a substantial decrease (>2 g/day), 9 that reported a moderate decrease (1-2 g/day), and 5 that reported a slight decrease (<1 g/day) in the mean salt intake over time, but none have yet met the targeted 30% relative reduction in salt intake from baseline. In summary, there has been an increase in the number of salt reduction initiatives around the world since 2014. More countries are now opting for structural or regulatory approaches. However, efforts must be urgently accelerated and replicated in other countries and more rigorous monitoring and evaluation of strategies is needed to achieve the salt reduction target., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background: COVID-19 has caused unprecedented restrictions, significantly affecting the most vulnerable groups in society, such as those with a disability., Objective: The aim of the study was to investigate the effects of COVID-19 lockdown restrictions on physical activity and mental health of children and young adults with physical and/or intellectual disabilities., Methods: The study was a cross-sectional design. Parents/carers completed an electronic survey in the UK between June-July 2020 on behalf of their child. Through Likert scales and free-text questions, the survey asked about physical activity levels and mental health during lockdown compared to before, access to specialist facilities and equipment to aid with physical activity, and the short- and long-term concerns around ongoing lockdown restrictions., Results: Generally, respondents reported negative effects of lockdown restrictions, with 61% reporting a reduction in physical activity levels and over 90% reporting a negative impact on mental health (including poorer behaviour, mood, fitness and social and learning regression). Many respondents cited a lack of access to specialist facilities, therapies and equipment as reasons for this, and raised concerns about the long-term effects of this lack of access on their child's mental health and physical activity levels., Conclusions: The survey highlights the negative impact of the COVID-19 lockdown on the physical activity levels and mental health of children and young adults with disabilities and highlights the importance of addressing the needs of the disabled community as restrictions are eased., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Biotherapeutics have revolutionized our ability to treat life-threatening diseases. Despite clinical success, the use of biotherapeutics has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs). The multifactorial nature of immunogenicity has prevented a standardized approach for assessing this and each of the assessment methods developed so far does not exhibit high enough reliability to be used alone, due to limited predictiveness. This prompted the Roche Pharma Research and Early Development (pRED) Immunogenicity Working Group to establish an internal preclinical immunogenicity toolbox of in vitro/in vivo approaches and accompanying guidelines for a harmonized assessment and management of immunogenicity in early development. In this article, the complex factors influencing immunogenicity and their associated clinical ramifications are discussed to highlight the importance of an end-to-end approach conducted from lead optimization to clinical candidate selection. We then examine the impact of the resulting lead candidate categorization on the design and implementation of a multi-tiered ADA/immunogenicity assay strategy prior to phase I (entry into human) through early clinical development. Ultimately, the Immunogenicity Toolbox ensures that Roche pRED teams are equipped to address immunogenicity in a standardized manner, paving the way for lifesaving products with improved safety and efficacy., Competing Interests: Declarations of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: the following authors (KBF, KH, GS, CMD, JB, MFF, KGS, CS, TS, AD) declare to be paid employees of Roche Pharmaceutical Research and Early Development. NC declares to be a paid employee of F. Hoffmann-La Roche AG., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy associated with chronic inflammation, mitochondrial (mt) dysfunction and fetal demise. Natural Killer cells (NK cells) are critical for the innate immune response against tumors or infection by disrupting cellular mt function and causing cell death. Although NK cells can be stimulated by Tumor necrosis factor alpha (TNF-α), we don't know the role of TNF-α on NK cell mediated mt dysfunction during PE. Our objective was to determine if mechanisms of TNF-α induced hypertension included activation of NK cells and multi-organ mt dysfunction during pregnancy. Pregnant rats were divided into 2 groups: normal pregnant (NP) (n = 18) and NP + TNF-α (n = 18). On gestational day 14, TNF-α (50 ng/ml) was infused via mini-osmotic pump and on day 18, carotid artery catheters were inserted. Blood pressure (MAP) and samples were collected on day 19. TNF-α increased MAP (109 ± 2 vs 100 ± 2, p < 0.05), circulating cytolytic NK cells (0.771 ± 0.328 vs.0.008 ± 0.003% gated, <0.05) and fetal reabsorptions compared to NP rats. Moreover, TNF-α caused mtROS in the placenta (12976 ± 7038 vs 176.9 ± 68.04% fold, p < 0.05) and in the kidney (2191 ± 1027 vs 816 ± 454.7% fold, p < 0.05) compared to NP rats. TNF-α induced hypertension is associated fetal demise, activation of NK cells and multi-organ mt dysfunction which could be mechanisms for fetal demise and hypertension. Understanding of the mechanisms by which TNF-α causes pathology is important for the use of anti-TNF-α therapeutic agents in pregnancies complicated by PE., (Copyright © 2021 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Adolescents and young adults, aged 13-24 years, are disproportionately affected by HIV in the United States. Youth with HIV (YHIV) face many psychosocial and structural challenges resulting in poor clinical outcomes including lower rates of medication adherence and higher rates of uncontrolled HIV. The Johns Hopkins Intensive Primary Care clinic, a longstanding HIV care program in Baltimore, Maryland, cares for 76 YHIV (aged 13-24 years). The multidisciplinary team provides accessible, evidenced-based, culturally sensitive, coordinated and comprehensive patient and family-centered HIV primary care. However, the ability to provide these intensive, in-person services was abruptly disrupted by the necessary institutional, state, and national coronavirus disease 2019 (COVID-19) mitigation strategies. As most of our YHIV are from marginalized communities (racial/ethnic, sexual, and gender minorities) with existing health and social inequities that impede successful clinical outcomes and increase HIV disparities, there was heightened concern that COVID-19 would exacerbate these inequities and amplify the known HIV disparities. We chronicle the structural and logistic approaches that our team has taken to proactively address the social determinants of health that will be negatively impacted by the COVID-19 pandemic, while supporting YHIV to maintain medication adherence and viral suppression., (Copyright © 2020 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Women with preeclampsia (PE) have increased mean arterial pressure (MAP), natural killer (NK) cells, reactive oxygen species (ROS), and agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA). AT1-AA's administered to pregnant rodents produces a well-accepted model of PE. However, the role of NK cells and mitochondrial reactive oxygen species (mtROS) in AT1-AA mediated hypertension during pregnancy is unknown. We hypothesize that AT1-AA induced model of PE will exhibit elevated MAP, NK cells, and mtROS; while inhibition of the AT1-AA binding to the AT1R would be preventative. Pregnant rats were divided into 4 groups: normal pregnant (NP) (n = 5), NP + AT1-AA inhibitory peptide (NP +'n7AAc') (n = 3), NP + AT1-AA infused (NP + AT1-AA) (n = 10), and NP + AT1-AA +'n7AAc' (n = 8). Day 13, rats were surgically implanted with mini-pumps infusing either AT1-AA or AT1-AA +'n7AAc'. Day 19, tissue and blood was collected. MAP was elevated in AT1-AA vs. NP (119 ± 1 vs. 102 ± 2 mmHg, p < 0.05) and this was prevented by 'n7AAc' (108 ± 3). There was a 6 fold increase in renal activated NK cells in AT1-AA vs NP (1.2 ± 0.4 vs. 0.2 ± 0.1% Gated, p = 0.05) which returned to NP levels in AT1-AA +'n7AAc' (0.1 ± 0.1% Gated). Renal mtROS (317 ± 49 vs. 101 ± 13% Fold, p < 0.05) was elevated with AT1-AA vs NP and was decreased in AT1-AA +'n7AAc' (128 ± 16, p < 0.05). In conclusion, AT1-AA's increased MAP, NK cells, and mtROS which were attenuated by AT1-AA inhibition, thus highlighting new mechanisms of AT1-AA and the importance of drug therapy targeted to AT1-AAs in hypertensive pregnancies., (Copyright © 2018 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Objective: To examine the validity of the Children's Eating Behavior Questionnaire (CEBQ) through the associations of its 3 subscale scores (food responsiveness, slowness in eating, and satiety responsiveness) with body mass index (BMI)., Design: Cross-sectional study of baseline data from a clinic-based obesity prevention and control randomized controlled trial., Participants: Latino pediatric patients (n = 295) aged 5-11 years from a federally qualified health center in San Diego County, CA, with BMI percentiles ranging from 75.5 to 99.0., Main Outcome Measure: Child BMI-for-age percentile computed using the standardized program for the 2000 Centers for Disease Control and Prevention growth charts., Analysis: Principal components analysis and multivariate linear regressions., Results: Principal components analysis showed a factor structure relatively similar to that of the original 3 CEBQ subscales, with acceptable internal consistency and between-subscale correlations. Analyses demonstrated the validity of the 3 subscales: child BMI was positively associated with food responsiveness (β = .336; P ≤ .001) and negatively associated with slowness in eating (β = -.209; P ≤ .001) and satiety responsiveness (β = -.211; P ≤ .001)., Conclusions and Implications: The 14-item CEBQ scale may be useful for assessing obesogenic eating behaviors of Latino children. Further study is needed to replicate these findings., (Copyright © 2017 Society for Nutrition Education and Behavior. Published by Elsevier Inc. All rights reserved.)

Introduction: As the therapeutic options in the management of type 2 diabetes increase, there is an increase confusion among health care professionals, thus leading to the phenomenon of therapeutic inertia. This is the failure to escalate or de-escalate treatment when the clinical need for this is required. It has been studied extensively in various settings, however, it has never been reported in any studies focusing solely on primary care physicians with an interest in diabetes. This group is increasingly becoming the focus of managing complex diabetes care in the community, albeit with the support from specialists., Methods: In this retrospective audit, we assessed the prevalence of the phenomenon of therapeutic inertia amongst primary care physicians with an interest in diabetes in UK. We also assessed the predictive abilities of various patient level characteristics on therapeutic inertia amongst this group of clinicians., Results: Out of the 240 patients reported on, therapeutic inertia was judged to have occurred in 53 (22.1%) of patients. The full model containing all the selected variables was not statistically significant, p=0.59. So the model was not able to distinguish between situations in which therapeutic inertia occurred and when it did not occur. None of the patient level characteristics on its own was predictive of therapeutic inertia., Conclusion: Therapeutic inertia was present only in about a fifth of patient patients with diabetes being managed by primary care physicians with an interest in diabetes., (Copyright © 2017 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

Because of the aging of the intensive care unit (ICU) population and an improvement in survival rates after ICU hospitalization, an increasing number of older adults are suffering from long-term impairments because of critical illness, known as post-intensive care syndrome (PICS). This article focuses on PICS-related cognitive, psychological, and physical impairments and the impact of ICU hospitalization on families and caregivers. The authors also describe innovative models of care for PICS and what roles geriatric psychiatrists could play in the future of this rapidly growing population., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Low rates of cardiovascular preventive therapy with statin medications is a significant public health problem in Canada. There is a pressing need for public health interventions to increase the use of statin medications, especially among high-risk patients. In this article, we present the results of a quality assurance pilot program to provide laboratory-reported Framingham Risk Score (FRS) to physicians. This work was performed in a mixed urban and rural setting in southern Alberta. We provided FRSs and, for high-risk patients, statin treatment recommendations in conjunction with laboratory lipid panel requests. Adhesive labels were supplied to primary care physicians, and space was provided for information necessary for the calculation of the FRS by a laboratory information system. In total, 16 physicians from 4 different clinics participated in the pilot program. Data were collected from October 25, 2014-November 5, 2015, during which time 1266 patients had FRSs from the laboratory. Three hundred twenty-four individuals were identified as high risk for coronary heart disease (≥ 20% 10-year risk) and received a recommendation for treatment with a statin medication in the laboratory result report. These individuals had a 26% relative and a 6.4% absolute increase in statin prescriptions compared with before the pilot program. The laboratory-based provision of FRSs with statin treatment recommendations for high-risk individuals has the potential to significantly increase the use of statin drugs., (Copyright © 2017 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Incidental ovarian cysts are frequently detected on imaging. Despite published follow-up consensus statements, there remains variability in radiologist follow-up recommendations and clinician practice patterns. The aim of this study was to evaluate if collaborative ovarian cyst management recommendations and a radiologist decision support tool can improve adherence to follow-up recommendations., Methods: Gynecologic oncologists and abdominal radiologists convened to develop collaborative institutional recommendations for the management of incidental, asymptomatic simple ovarian cysts detected on ultrasound, CT, and MRI. The recommendations were developed by modifying the published consensus recommendations developed by the Society of Radiologists in Ultrasound on the basis of local practice patterns and the experience of the group members. A less formal process involved the circulation of the published consensus recommendations, followed by suggestions for revisions and subsequent consensus, in similar fashion to the ACR Incidental Findings Committee II. The recommendations were developed by building on the published work of experienced groups to provide the authors' medical community with a set of recommendations that could be endorsed by both the Department of Gynecology and the Department of Radiology to provide supportive guidance to the clinicians who manage incidental ovarian cysts. The recommendations were integrated into a radiologist decision support tool accessible from the dictation software. Nine months after tool launch, institutional review board approval was obtained, and radiology reports mentioning ovarian cysts in the prior 34 months were retrospectively reviewed. For cysts detected on ultrasound, adherence rates to Society of Radiologists in Ultrasound recommendations were calculated for examinations before tool launch and compared with adherence rates to the collaborative institutional recommendations after tool launch. Additionally, electronic medical records were reviewed to determine the follow-up chosen by the clinician., Results: For cysts detected on ultrasound, radiologist adherence to recommendations improved from 50% (98 of 197) to 80% (111 of 139) (P < .05). Overmanagement decreased from 34% (67 of 197) to 10% (14 of 139) (P < .05). A recommendation was considered "overmanaged" if the radiologist recommended follow-up when it was not indicated or if the recommended follow-up time was at a shorter interval than indicated. Clinician adherence to radiologist recommendations showed statistically nonsignificant improvement from 49% (36 of 73) to 57% (27 of 47) (P = .5034)., Conclusions: Management recommendations developed through collaboration with clinicians may help standardize follow-up of ovarian cysts and reduce overutilization., (Copyright © 2016 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Background: Implantable cardioverter defibrillators (ICDs) reduce mortality in patients with ischaemic cardiomyopathy at high risk of ventricular arrhythmias (VA). However, the current indication for ICD prescription needs improvement. Telomere and telomerase in leucocytes have been shown to associate with biological ageing and pathogenesis of cardiovascular diseases. We hypothesised that leucocyte telomere length, load-of-short telomeres and/or telomerase activity are associated with VA occurrence in ischaemic cardiomyopathy patients., Methods and Results: 90 ischaemic cardiomyopathy patients with primary prevention ICDs were recruited. 35 had received appropriate therapy from the ICD for potentially-fatal VA while the remaining 55 patients had not. No significant differences in baseline demographic data relevant to telomere biology were seen between the two groups. There was no significant difference in the age and sex adjusted mean telomere length analysed by qPCR between the groups (p=0.88). In contrast, the load-of-short telomeres assessed by Universal-STELA method and telomerase activity by TRAP assay were both higher in patients who had appropriate ICD therapy and were significantly associated with incidence of ICD therapy (p=0.02, p=0.02). ROC analyses demonstrated that the sensitivity and specificity of these telomere dynamics in predicting potentially-fatal VA was higher than the current gold-standard - left ventricular ejection fraction (AUC 0.82 versus 0.47)., Conclusion: The load-of-short telomeres and telomerase activity had a significant association with ICD therapy (for VA) in ischaemic cardiomyopathy patients. These biomarkers should be tested in prospective studies to assess their clinical utility in predicting VA after myocardial infarction and guiding primary prevention ICD prescription., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: To develop and test the utility of a domain-specific physical activity efficacy scale in adolescents for predicting physical activity behaviour., Design: Two independent studies were conducted. Study 1 examined the psychometric properties of a newly constructed Domain-Specific Physical Activity Efficacy Questionnaire (DSPAEQ) and study 2 tested the utility of the scale for predicting leisure- and school-time physical activity., Methods: In study 1, descriptive physical activity data were used to generate scale items. The scales factor structure and internal consistency were tested in a sample of 272 adolescents. A subsequent sample of Canadian ( N = 104) and New Zealand ( N = 29) adolescents, was recruited in study 2 to explore the scale's predictive validity using a subjective measure of leisure- and school-time physical activity., Results: A principle axis factor analysis in study 1 revealed a 26-item, five-factor coherent and interpretable solution; representative of leisure and recreation, household, ambulatory, transportation, and school physical activity efficacy constructs, respectively. The five-factor solution explained 81% of the response variance. In study 2 the domain-specific efficacy model explained 16% and 1% of leisure- and school-time physical activity response variance, respectively, with leisure time physical activity efficacy identified as a unique and significant contributor of leisure-time physical activity., Conclusion: Study 1 provides evidence for the tenability of a five factor DSPEAQ, while study 2 shows that the DSPEAQ has utility in predicting domain-specific physical activity. This latter finding underscores the importance of scale correspondence between the behavioral elements (leisure-time physical activity) and cognitive assessment of those elements ( leisure-time physical activity efficacy ).

Objectives: We examined the association between anticholinergic medication exposure and subsequent cognitive and physical function in patients with delirium superimposed on dementia during rehabilitation. We also examined length of stay and discharge disposition by anticholinergic medication exposure., Design: In this secondary analysis we used control group data from an ongoing randomized clinical trial., Setting/participants: Participants with delirium and dementia were enrolled at admission to post-acute care. These 99 participants had a mean age of 86.11 (±6.83) years; 67.6% were women; 98% were Caucasian; and 33% were positive for at least one APOE e4 allele., Measures: We obtained daily measures of cognitive and physical function using: Digit Span; memory, orientation and attention items from the Montreal Cognitive Assessment; CLOX; the Confusion Assessment Method; and the Barthel Index. Anticholinergic medication exposure was measured weekly using the Anticholinergic Cognitive Burden Scale., Results: Using multilevel models for time we found that greater use of clinically relevant anticholinergic medications in the previous week reduced cognitive and physical function, as measured by Digit Span Backwards and the Barthel index, in the current week. There was no effect of anticholinergic medication use on delirium severity, and APOE status did not moderate any outcomes. Greater use of clinically relevant anticholinergic medications was related to longer length of stay but not discharge disposition., Conclusions: For vulnerable older adults, anticholinergic exposure represents a potentially modifiable risk factor for poor attention, working memory, physical function, and greater length of stay during rehabilitation., (Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: This study explored whether longer provider delays (between first presentation and treatment) were associated with later stage and poorer survival in women with symptomatic breast cancer., Methods: Data from 850 women with symptomatic breast cancer were linked with the Scottish Cancer Registry; Death Registry; and hospital discharge dataset. Logistic regression and Cox survival analyses with restricted cubic splines explored relationships between provider delays, stage and survival, with sequential adjustment for patient and tumour factors., Results: Although confidence intervals were wide in both adjusted analyses, those with the shortest provider delays had more advanced breast cancer at diagnosis. Beyond approximately 20 weeks, the trend suggests longer delays are associated with more advanced stage, but is not statistically significant. Those with symptomatic breast cancer and the shortest presentation to treatment time (within 4 weeks) had the poorest survival. Longer time to treatment was not significantly associated with worsening mortality., Conclusions: Poor prognosis patients with breast cancer are being triaged for rapid treatment with limited effect on outcome. Prolonged time to treatment does not appear to be strongly associated with poorer outcomes for patients with breast cancer, but the power of this study to assess the effect of very long delays (>25 weeks) was limited. Efforts to reduce waiting times are important from a quality of life perspective, but tumour biology may often be a more important determinant of stage at diagnosis and survival outcome., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Accurate blood pressure measurement is critical to properly identify and treat individuals with hypertension. In 2005, the Canadian Hypertension Education Program produced a revised algorithm to be used for the diagnosis of hypertension. Subsequent annual reviews of the literature have identified 2 major deficiencies in the current diagnostic process. First, auscultatory measurements performed in routine clinical settings have serious accuracy limitations that have not been overcome despite great efforts to educate health care professionals over several years. Thus, alternatives to auscultatory measurements should be used. Second, recent data indicate that patients with white coat hypertension must be identified earlier in the process and in a systematic manner rather than on an ad hoc or voluntary basis so they are not unnecessarily treated with antihypertensive medications. The economic and health consequences of white coat hypertension are reviewed. In this article evidence for a revised algorithm to diagnose hypertension is presented. Protocols for home blood pressure measurement and ambulatory blood pressure monitoring are reviewed. The role of automated office blood pressure measurement is updated. The revised algorithm strongly encourages the use of validated electronic digital oscillometric devices and recommends that out-of-office blood pressure measurements, ambulatory blood pressure monitoring (preferred), or home blood pressure measurement, should be performed to confirm the diagnosis of hypertension., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Arsenic is a class I human carcinogen that has been identified as the second most important global health concern in groundwater supplies after contamination by pathogenic organisms. Hydrogeological assessments have shown naturally occurring arsenic to be widespread in groundwater across the northeastern United States and eastern Canada. Knowledge of arsenic risk exposure among private well users in these arsenic endemic areas has not yet been fully explored but research on water quality perceptions indicates a consistent misalignment between public and scientific assessments of environmental risk. This paper evaluates knowledge of arsenic risk exposure among a demographic cross-section of well users residing in 5 areas of Nova Scotia assessed to be at variable risk (high-low) of arsenic occurrence in groundwater based on water sample analysis. An integrated knowledge-to-action (KTA) methodological approach is utilized to comprehensively assess the personal, social and local factors shaping perception of well water contaminant risks and the translation of knowledge into routine water testing behaviors. Analysis of well user survey data (n=420) reveals a high level of confidence in well water quality that is unrelated to the relative risk of arsenic exposure or homeowner adherence to government testing recommendations. Further analysis from the survey and in-depth well user interviews (n=32) finds that well users' assessments of risk are influenced by personal experience, local knowledge, social networks and convenience of infrastructure rather than by formal information channels, which are largely failing to reach their target audiences. Insights from interviews with stakeholders representing government health and environment agencies (n=15) are used to reflect on the institutional barriers that mediate the translation of scientific knowledge into public awareness and stewardship behaviors. The utilization of local knowledge brokers, community-based networks and regulatory incentives to improve risk knowledge and support routine testing among private well users is discussed., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Recently, intradialytic hypertension was reported to be associated with increased mortality for hemodialysis patients. To determine whether volume status plays a role in dialysis-associated hypertension, we prospectively audited 531 patients that had volume assessments measured by multiple-frequency bioelectrical impedance during their midweek dialysis session. Mean pre- and postdialysis weights were 73.2 vs 71.7 kg, and systolic blood pressures (SBPs) 140.5 vs. 130.3 mm Hg, respectively. Patients were divided into groups based on a fall in SBP of 20 mm Hg or more (32%), an increased SBP of 10 mm Hg or more (18%), and a stable group (50%). There were no differences in patient demographics, dialysis prescriptions, predialysis weight, total body (TBW), and extracellular (ECW) and intracellular water (ICW). However, the change in weight was significantly less in the increased blood pressure group (1.01 kg vs. stable 1.65, and 1.7 hypotensive). The ratio of ECW to TBW was significantly higher in the increased blood pressure group, particularly post dialysis (39.1 vs. stable 38.7% and fall in blood pressure group 38.7%). ECW overhydration was significantly greater in the increased blood pressure group post dialysis (0.7 (0.17 to 1.1) vs. stable 0.39 (-0.2 to 0.95) and fall in blood pressure group 0.38 (-0.19 to 0.86) liter). We found that patients who had increased blood pressure post dialysis had greater hydration status, particularly ECW. Thus, patients who increase their blood pressure post dialysis should have review of target weight, consideration of lowering the post-dialysis weight, and may benefit from increasing dialysis session time or frequency.

In 2010, unhealthy diets were estimated to be the leading risk for death and disability in Canada and globally. Although important, policies aimed at improving individual's skills in selecting and eating healthy foods has had a limited effect. Policies that create healthy eating environments are strongly recommended but have not yet been effectively and/or broadly implemented in Canada. Widespread adoption of healthy food procurement policies are strongly recommended in this policy statement from the Hypertension Advisory Committee with support from 15 major national health organizations. The policy statement calls on governments to take a leadership role, but also outlines key roles for the commercial and noncommercial sectors including health and scientific organizations and the Canadian public. The policy statement is based on a systematic review of healthy food procurement interventions that found them to be almost uniformly effective at improving sales and purchases of healthy foods. Successful food procurement policies are nearly always accompanied by supporting education programs and some by pricing policies. Ensuring access and availability to affordable healthy foods and beverages in public and private sector settings could play a substantive role in the prevention of noncommunicable diseases and health risks such as obesity, hypertension, and ultimately improve cardiovascular health., (Copyright © 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate and compare perioperative morbidity and mortality in dogs undergoing cervical and thoracolumbar spinal surgery., Study Design: Prospective case series., Animals: 157 dogs undergoing cervical or thoracolumbar spinal surgery., Methods: Data were collected sequentially on canine cases presented from the Neurology Section of the North Carolina State University Veterinary Teaching Hospital for anesthesia and surgery for cervical spinal cord disease. Simultaneously, data were collected on all thoracolumbar spinal surgery cases during the same time period. Data included signalment, drugs administered, surgical approach, disease process, cardiac arrhythmias during anesthesia, and outcome., Results: Data were collected from 164 surgical events in 157 dogs. There were 52 cervical approaches; four dorsal and 48 ventral. All thoracolumbar surgeries were approached dorsolaterally. Four dogs 4/52 (7.6%) undergoing a cervical approach did not survive to discharge. Two dogs (2/8; 25%) underwent atlanto-axial (AA) stabilization and suffered cardiovascular arrest and two dogs (2/38; 5.2%) undergoing cervical ventral slot procedures were euthanized following anesthesia and surgery due to signs of aspiration pneumonia. All dogs undergoing thoracolumbar surgery survived until discharge (112/112). Mortality in dogs undergoing cervical spinal surgery was greater compared with dogs undergoing thoracolumbar spinal surgery (p = 0.009), however, in dogs undergoing decompressive disc surgery, intraoperative death rates were not different between dogs undergoing a cervical compared with thoracolumbar approaches (p = 0.32) nor was there a significant difference in overall mortality (p = 0.07)., Conclusion and Clinical Relevance: Overall, dogs undergoing cervical spinal surgery were less likely to survive until discharge compared with dogs undergoing thoracolumbar spinal surgery. Mortality in dogs undergoing cervical intervertebral disc decompression surgery was no different than for dogs undergoing thoracolumbar intervertebral disc decompression surgery. However, dogs undergoing cervical intervertebral disc decompression surgery should be considered at risk for aspiration pneumonia., (© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)

Background: It is unclear whether blood pressure control varies across the spectrum of atherosclerotic risk., Methods: We used data from nonpregnant adults who had fasted laboratory samples drawn for the 2007-2009 cycle of the Canadian Health Measures Survey (CHMS) or the 2005-2008 US National Health and Nutrition Examination Survey (NHANES)., Results: The 1692 CHMS subjects and 3541 NHANES participants were demographically similar (aged a mean of 45 years), although NHANES participants exhibited higher obesity rates (33.8% vs. 22.2%, P < 0.001). Over 80% of CHMS and NHANES subjects with hypertension had at least 1 other cardiovascular risk factor. As the number of atherosclerotic risk factors increased, hypertension prevalence increased, but blood pressure control rates improved (from 48% among hypertensives with no other risk factors in CHMS to 77% among those with 3 or more risk factors, and from 35% to 53% in NHANES). However, the converse was not true: The distribution of Framingham risk scores for those subjects with "controlled hypertension" was nearly identical to the distribution among those adults with uncontrolled hypertension in both CHMS and NHANES and substantially higher than scores in normotensive subjects., Conclusions: Although control of blood pressure was better in patients with multiple atherosclerotic risk factors, hypertensives with controlled blood pressures exhibited risk-factor profiles similar to those of participants with uncontrolled blood pressures. This suggests the need, in educational messaging and therapy decision making, for an increased focus on total atherosclerotic risk rather than just blood pressure control., (Copyright © 2013 Canadian Cardiovascular Society. All rights reserved.)

Background: Enrollment of patients with lung cancer into clinical trials is required to accelerate the pace of new therapy development and contribute to a better understanding of the biological characteristics of cancer., Methods: We conducted a retrospective chart review of all patients seen by the thoracic medical oncology team at the Vanderbilt Ingram Cancer Center (VICC) from November 2005 to November 2008 to determine the barriers associated with patient enrollment in to clinical trials., Results: One thousand forty-three patient charts were audited: 32% of patients were eligible for enrollment, and 14% enrolled in a study. There were no significant differences in protocol availability or eligibility by sex, smoking status, or age. Patients living further from the cancer center were significantly less likely to have a study protocol available (P = .009), but if a protocol was available they were more likely to be eligible for enrollment (P < .001). Significantly more protocols were available for patients with non-small-cell lung cancer (NSCLC) compared with those who had small-cell lung cancer (SCLC) (63% vs. 48%; P < .001). Patients with advanced disease were more likely to have a protocol available (P < .001) and enter a study (P = .031). The most common reasons for patients not being eligible for enrollment were poor performance status (32%) and presence of comorbid disease (27%). The most common reasons for potentially eligible patients not enrolling in a study included preference for treatment closer to home (49%) and patient refusal (43%)., Conclusion: Additional strategies are required to increase accrual of patients into lung cancer trials, including development of protocols for early-stage disease and modifying eligibility and performance status criteria for this unique patient population., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Increased blood pressure is a leading risk for premature death and disability. The causes of increased blood pressure are intuitive and well known. However, the fundamental basis and means for improving blood pressure control are highly integrated into our complex societal structure both inside and outside our health system and hence require a comprehensive discussion of the pathway forward. A group of Canadian experts was appointed by Hypertension Canada with funding from Public Health Agency of Canada and the Heart and Stroke Foundation of Canada, Canadian Institute for Health Research (HSFC-CIHR) Chair in Hypertension Prevention and Control to draft a discussion Framework for prevention and control of hypertension. The report includes an environmental scan of past and current activities, proposals for key indicators, and targets to be achieved by 2020, and what changes are likely to be required in Canada to achieve the proposed targets. The key targets are to reduce the prevalence of hypertension to 13% of adults and improve control to 78% of those with hypertension. Broad changes in government policy, research, and health services delivery are required for these changes to occur. The Hypertension Framework process is designed to have 3 phases. The first includes the experts' report which is summarized in this report. The second phase is to gather input and priorities for action from individuals and organizations for revision of the Framework. It is hoped the Framework will stimulate discussion and input for its full intended lifespan 2011-2020. The third phase is to work with individuals and organizations on the priorities set in phase 2., (Copyright © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

This paper is a Position Statement from an 'ad hoc' Scientific Review Subcommittee of the PAHO/WHO Regional Expert Group on Cardiovascular Disease Prevention through Dietary Salt Reduction. It is produced in response to requests from representatives of countries of the Pan-American Region of WHO needing clarification on two recent publications casting doubts on the appropriateness of population wide policies to reduce salt intake for the prevention of cardiovascular disease. The paper provides a brief background, a critical appraisal of the recent reports and explanations as why the implications have been mis-interpreted. The paper concludes that the benefits of salt reduction are clear and consistent, and reinforces the recommendations outlined by PAHO/WHO and other organizations worldwide for a population reduction in salt intake to prevent strokes, heart attacks and other cardiovascular events., (Copyright © 2011. Published by Elsevier B.V.)

This review article summarizes the salient literature on the diagnosis and management of endometrial polyps. Electronic resources including Medline, PubMed, CINAHL, The Cochrane Library (including the Cochrane Database of Systematic Reviews), Current Contents, and EMBASE were searched with the MeSH terms including all subheadings and keywords endometrial polyps, abnormal uterine bleeding, polypectomy, polyp management, polyp and diagnosis, and polyp and malignancy. There is a paucity of level I evidence in the literature on the diagnosis and management of this common gynecologic disease. Noninvasive investigations such as transvaginal ultrasonography, with or without the use of 3-dimensional ultrasonography and contrast techniques remain the mainstay of first-line investigation. Hysteroscopic resection is the most effective management for endometrial polyps and allows histologic assessment, whereas blind biopsy or curettage has low diagnostic accuracy and should not be performed. This article will review the cause, epidemiology, clinical presentation, diagnostic investigations, and management of endometrial polyps., (Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.)

Background: The management of cardiovascular risk factors such as hypertension and dyslipidemia is poorly described in many communities, and the benefits associated with tighter control remain unknown. We used data from the 2007 MyHealthCheckup survey to document the treatment gaps and estimated the potential benefits of better adherence to recommended guidelines., Methods: Cardiovascular risk factors, lifestyle habits, and prescribed medications were evaluated among Canadian adults recruited primarily in pharmacies. The Cardiovascular Life Expectancy Model was used to estimate the potential benefits of optimally treating hypertension or dyslipidemia (defined as not smoking, regular physical activity, an acceptable body weight, and maximal medication as needed)., Results: Among 2674 screened individuals, 1266 (47%) were receiving pharmacotherapy for either dyslipidemia or hypertension, including 772 (61%) and 656 (63%), respectively, who remained above treatment targets. Among those above lipid or blood pressure targets, 27% and 22%, respectively, were optimally treated. The average increased life expectancy or life-years gained associated with making appropriate lifestyle changes included 2.2 to 4.7 years from smoking cessation, 0.7 to 1.1 years from regular exercise, and 0.4 to 0.7 years from weight reduction. The life-years gained following better risk factor treatment included maximal pharmacotherapy for elevated blood pressure (0.6-0.8), low-density lipoprotein cholesterol (0.5-0.6), and the ratio of total cholesterol to high-density lipoprotein cholesterol (0.3-0.4). Years of life free of cardiovascular disease would be similarly increased., Conclusions: Better treatment of cardiovascular risk factors could result in a substantial reduction in morbidity and mortality among Canadians. Given current physician prescribing and patient habits, lifestyle modification should be considered a priority before additional medications are prescribed., (Copyright © 2011 Elsevier Inc. All rights reserved.)