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Background: Nowadays the level of physical activity is compromised among all, especially in young adults, which may contribute to early development risk of cardiac disease. Objective: To determine the association of risk of cardiac disease with physical activity among young adults. Methods: A cross-sectional study was conducted from January 2024 to April 2024 at Iqra National University, Peshawar after approval from the ethical committee. A total of n=102 undergraduate male and female students between the age of 18-24 years were included in the study. To determine the physical activity of the participants International Physical Activity Questionnaire - Short Form was used. To evaluate the risk of cardiac disease was observed according to the National Cholesterol Education Program. Results: The mean age and BMI of the n=102 study participants were 23.22±3.4 years and 23.37±5kg/m2 respectively. The risk of cardiac disease was found in n=45(44.1%) while most of the participants (n=33) were moderately and (n=42) highly physically active with a mean METs score of 2881.51±2704.83. Physical activity (PA) is not significantly associated (p=0.44) with the risk of cardiac disease. However, gender showed a strong association (p

Background: Physical activity reduces mortality and prevents many chronic diseases; it can promote healthy cognitive and psychosocial function. It is also important to understand the moderate physical activity affects hemoglobin levels. Objective: To determine the effects of moderate physical activity on HB level, and psychological well-being in females. Methodology: A single-blinded, randomized control trial was conducted on n=30 participants for 6 months. The participants aged 18-25 years were recruited through a non-probability convenient sampling technique and randomly divided into two groups experimental and control group. The data was collected at the baseline after the six weeks of intervention. The outcome measures were Hb level and psychological well-being through the perceived stress scale (PSS). Results: The mean age of study participants was 19.59±1.32 years. While the mean BMI of the participants was 24.22±3.43 kg/m2. The result showed a significant increase in hemoglobin concentrations in the experimental group as compared to the control group (p

Efficient mapping from unmanned aerial platforms cannot rely on aerial triangulation using known ground control points. The cost and time of setting ground control, added to the need for increased overlap between flight lines, severely limits the ability of small VTOL platforms, in particular, to handle mapping-grade missions of all but the very smallest survey areas. Applanix has brought its experience in manned photogrammetry applications to this challenge, setting out the requirements for increasing the efficiency of mapping operations from small UAVs, using survey-grade GNSS-Inertial technology to accomplish direct georeferencing of the platform and/or the imaging payload. The Direct Mapping Solution for Unmanned Aerial Vehicles (DMS-UAV) is a complete and ready-to-integrate OEM solution for Direct Georeferencing (DG) on unmanned aerial platforms. Designed as a solution for systems integrators to create mapping payloads for UAVs of all types and sizes, the DMS produces directly georeferenced products for any imaging payload (visual, LiDAR, infrared, multispectral imaging, even video). Additionally, DMS addresses the airframe's requirements for high-accuracy position and orientation for such tasks as precision RTK landing and Precision Orientation for Air Data Systems (ADS), Guidance and Control. This paper presents results using a DMS comprised of an Applanix APX-15 UAV with a Sony a7R camera to produce highly accurate orthorectified imagery without Ground Control Points on a Microdrones md4-1000 platform conducted by Applanix and Avyon. APX-15 UAV is a single-board, small-form-factor GNSS-Inertial system designed for use on small, lightweight platforms. The Sony a7R is a prosumer digital RGB camera sensor, with a 36MP, 4.9-micron CCD producing images at 7360 columns by 4912 rows. It was configured with a 50mm AF-S Nikkor f/1.8 lens and subsequently with a 35mm Zeiss Sonnar T* FE F2.8 lens. Both the camera/lens combinations and the APX-15 were mounted to a Microdrones md4-1000 quad-rotor VTOL UAV. The Sony A7R and each lens combination were focused and calibrated terrestrially using the Applanix camera calibration facility, and then integrated with the APX-15 GNSS-Inertial system using a custom mount specifically designed for UAV applications. The mount is constructed in such a way as to maintain the stability of both the interior orientation and IMU boresight calibration over shock and vibration, thus turning the Sony A7R into a metric imaging solution. In July and August 2015, Applanix and Avyon carried out a series of test flights of this system. The goal of these test flights was to assess the performance of DMS APX-15 direct georeferencing system under various scenarios. Furthermore, an examination of how DMS APX-15 can be used to produce accurate map products without the use of ground control points and with reduced sidelap was also carried out. Reducing the side lap for survey missions performed by small UAVs can significantly increase the mapping productivity of these platforms. The area mapped during the first flight campaign was a 250m x 300m block and a 775m long railway corridor in a rural setting in Ontario, Canada. The second area mapped was a 450m long corridor over a dam known as Fryer Dam (over Richelieu River in Quebec, Canada). Several ground control points were distributed within both test areas. The flight over the block area included 8 North-South lines and 1 cross strip flown at 80m AGL, resulting in a ~1cm GSD. The flight over the railway corridor included 2 North-South lines also flown at 80m AGL. Similarly, the flight over the dam corridor included 2 North-South lines flown at 50m AGL. The focus of this paper was to analyse the results obtained from the two corridors. Test results from both areas were processed using Direct Georeferencing techniques, and then compared for accuracy against the known positions of ground control points in each test area. The GNSS-Inertial data collected by the APX-15 was post-processed in Single Base mode, using a base station located in the project area via POSPac UAV. For the block and railway corridor, the base-station's position was precisely determined by processing a 12-hour session using the CSRS-PPP Post Processing service. Similarly, for the flight over Fryer Dam, the base-station's position was also precisely determined by processing a 4-hour session using the CSRS-PPP Post Processing service. POSPac UAV's camera calibration and quality control (CalQC) module was used to refine the camera interior orientation parameters using an Integrated Sensor Orientation (ISO) approach. POSPac UAV was also used to generate the Exterior Orientation parameters for images collected during the test flight. The Inpho photogrammetric software package was used to develop the final map products for both corridors under various scenarios. The imagery was first imported into an Inpho project, with updated focal length, principal point offsets and Exterior Orientation parameters. First, a Digital Terrain/Surface Model (DTM/DSM) was extracted from the stereo imagery, following which the raw images were orthorectified to produce an orthomosaic product. [ABSTRACT FROM AUTHOR]

Purpose: To determine roles of patient history, donor tissue characteristics, tissue preparation methods, and surgeon technique for graft detachment requiring rebubbling after Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK) procedures., Methods: Retrospective analysis of all eyes undergoing first-time DSAEK or DMEK at the study institution between 2013 and 2022. Data were collected regarding recipients' history, donors' medical history, tissue preparation methods, intraoperative details, and postoperative clinical outcomes. Multivariate statistical analysis was conducted to identify risk factors for graft detachment necessitating rebubbling., Results: Of 1240 eyes meeting inclusion criteria, 746 (60.2%) underwent DSAEK, and 494 (39.8%) underwent DMEK. DSAEK procedures had 12.5% rebubbling rate, whereas DMEK procedures had 18.4% rebubbling rate (P = 0.005). Sub50-DSAEK (<50 μm) grafts had 16.0% rebubble rate, whereas sub100-DSAEK (51-99 μm) and >100 μm DSAEKs had rebubble rate of 9.9% and 9.5%, respectively (P = 0.006). Significant risk factors for DSAEK graft detachment included history of retinal surgery (OR = 2.59), preloaded tissue (OR = 2.70), forceps insertion (OR = 2.33), use of sub50-DSAEK lenticules versus sub100-DSAEK (OR = 2.44) and >100 μm DSAEK (OR = 2.38) lenticules, and donor history of noninsulin-dependent diabetes mellitus (OR = 4.18). DMEK risk factors included recipient history of cancer (OR = 2.51) and use of higher SF6 gas concentration (OR = 1.09). Although rebubbled DMEK eyes had comparable refractive outcomes to nonrebubbled eyes (P >0.05), rebubbled DSAEK eyes had worse refractive outcomes at all time points (P < 0.05)., Conclusions: Graft detachments in DSAEK and DMEK are influenced by various factors, including donor tissue characteristics, tissue preparation, and surgical technique. Identifying and understanding these factors can potentially improve postoperative outcomes., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: First Nations children in Canada experience health inequities. We aimed to determine whether a self-report health app identified children's needs for support earlier in their illness than would typically occur., Methods: Children (aged 8 to 18 yr) were recruited from a rural First Nation community. Children completed the Aaniish Naa Gegii: the Children's Health and Well-being Measure (ACHWM) and then met with a local mental health worker who determined their risk status. ACHWM Emotional Quadrant Scores (EQS) were compared between 3 groups of children: healthy peers (HP) who were not at risk, those with newly identified needs (NIN) who were at risk and not previously identified, and a typical treatment (TT) group who were at risk and already receiving support., Results: We included 227 children (57.1% girls), and the mean age was 12.9 (standard deviation [SD] 2.9) years. The 134 children in the HP group had a mean EQS of 80.1 (SD 11.25), the 35 children in the NIN group had a mean EQS of 67.2 (SD 13.27) and the 58 children in the TT group had a mean EQS of 66.2 (SD 16.30). The HP group had significantly better EQS than the NIN and TT groups ( p < 0.001). The EQS did not differ between the NIN and TT groups ( p = 0.8)., Interpretation: The ACHWM screening process identified needs for support among 35 children, and the associated triage process connected them to local services; the similarity of EQS in the NIN and TT groups highlights the value of community screening to optimize access to services. Future research will examine the impact of this process over the subsequent year in these groups., Competing Interests: Competing interests: None declared., (© 2023 CMA Impact Inc. or its licensors.)

Purposes: To report our experience in a prospective study of implementing a transperineal ultrasound system to monitor intra-fractional prostate motion for prostate stereotactic body radiotherapy (SBRT)., Material and Methods: This IRB-approved prospective study included 23 prostate SBRT patients treated between 04/2016 and 11/2019 at our institution. The prescription doses were 36.25 Gy to the Low-Dose planning target volume (LD-PTV) and 40 Gy to the High-Dose PTV (HD-PTV) in five fractions with 3 mm planning margins. The transperineal ultrasound system was successfully used in 110 of the 115 fractions. For intra-fraction prostate motion, the real-time prostate displacements measured by ultrasound were exported for analysis. The percentage of time prostate movement exceeded a 2 mm threshold was calculated for each fraction of all patients. T-test was used for all statistical comparisons., Results: Ultrasound image quality was adequate for prostate delineation and prostate motion tracking. The setup time for each fraction under ultrasound-guided prostate SBRT was 15.0 ± 4.9 min and the total treatment time per fraction was 31.8 ± 10.5 min. The presence of an ultrasound probe did not compromise the contouring of targets or critical structures. For intra-fraction motion, prostate movement exceeded 2 mm tolerance in 23 of 110 fractions for 11 of 23 patients. For all fractions, the mean percentage of time when the prostate moved more than 2 mm in any direction during each fraction was 7%, ranging from 0% to 62% of a fraction., Conclusion: Ultrasound-guided prostate SBRT is a good option for intra-fraction motion monitoring with clinically acceptable efficiency., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Background Aneurysm size is an imperfect risk assessment tool for those with thoracic aortic aneurysm (TAA). Assessing arterial age may help TAA risk stratification, as it better reflects aortic health. We sought to evaluate arterial age as a predictor of faster TAA growth, independently of chronological age. Methods and Results We examined 137 patients with TAA. Arterial age was estimated according to validated equations, using patients' blood pressure and carotid-femoral pulse wave velocity. Aneurysm growth was determined prospectively from available imaging studies. Multivariable linear regression assessed the association of chronological age and arterial age with TAA growth, and multivariable logistic regression assessed associations of chronological and arterial age with the presence of accelerated aneurysm growth (defined as growth>median in the sample). Mean±SD chronological and arterial ages were 62.2±11.3 and 54.2±24.5 years, respectively. Mean baseline TAA size and follow-up time were 45.9±4.0 mm and 4.5±1.9 years, respectively. Median (interquartile range) TAA growth was 0.31 (0.14-0.52) mm/year. Older arterial age (ß±SE for 1 year: 0.004±0.001, P <0.0001) was independently associated with faster TAA growth, while chronological age was not ( P =0.083). In logistic regression, each 5-year increase in arterial age was associated with a 23% increase in the odds of accelerated TAA growth (95% CI, 1.085-1.394; P =0.001). Conclusions Arterial age is independently associated with accelerated aneurysm expansion, while chronological age is not. Our results highlight that a noninvasive and inexpensive assessment of arterial age can potentially be useful for TAA risk stratification and disease monitoring as compared with the current clinical standard (chronological age).

Purpose: A utologous stem cell transplant (ASCT) remains a standard of care among older adults (aged ≥65) with multiple myeloma (MM). However, heterogeneity in the eligibility and utilization of ASCT remains. We identified decision-making factors that influence ASCT eligibility and utilization among older adults with MM., Methods: A qualitative study across two academic and two community centres in Ontario was conducted between July 2019-July 2020. Older adults with MM (newly diagnosed MM aged 65-75 in whom a decision had been made about ASCT in <12 months) and treating oncologists completed a baseline survey and a subsequent interview, which was analyzed using thematic analysis., Results: Eighteen patients completed the survey and 9 follow-up interviews were conducted. Patients were happy with their treatment decision with "trust in their oncologist" and "wanting the best treatment" as the most important to proceed with ASCT. "Afraid of side effects" was the most common reason for declining ASCT. Fifteen oncologists completed the survey and 10 follow-up interviews were conducted. Most relied on the 'eye-ball' test for ASCT eligibility over geriatric screening tools. The lack of both high-quality evidence and local guidelines impacted decision-making. Both oncologists and patients felt that chronological age alone should not affect ASCT eligibility., Conclusion: While decision-making factors regarding ASCT can be variable, both oncologists and patients indicated that chronological age alone should not represent a barrier for ASCT among older adults. Future simplification and incorporation of ASCT eligibility geriatric assessment tools in studies as well as the inclusion of these tools in local guidelines may further improve ASCT decision-making., Competing Interests: AM received consultancy/honoraria fees from Celgene, Takeda, Janssen, Amgen, Sanofi. TW received research funding from Janssen and is a consultant for Carevive Systems, Seattle Genetics and Sanofi. HM received consultancy/Honoraria fees from Celgene, Takeda, Janssen, Amgen, Sanofi The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mian, Puts, McCurdy, Wildes, Fiala, Kang, Salib, Alibhai and Mian.)

Background: Thoracic aortic aneurysm (TAA) is a deadly disease whose current method for risk stratification (aneurysm size) is imperfect. We sought to evaluate whether combining aortic size with hemodynamic measures that reflect the aorta's function was superior to aortic size alone in the assessment of TAA expansion., Methods: One hundred thirty-seven nonoperated participants with TAA were followed prospectively. Aortic stiffness and pulsatile hemodynamics were noninvasively assessed at baseline with a combination of arterial tonometry with echocardiography using validated methodology. Aneurysm growth was calculated from standard imaging modalities. Multivariable linear regression models adjusted for potential confounders evaluated the association of aneurysm size and arterial hemodynamics, alone and in combination, with TAA growth., Results: Sixty-nine percent of participants were male. Mean ± SD age, baseline aneurysm size, follow-up, and aneurysm expansion were, respectively, 62.2 ± 11.4 years, 45.9 ± 4.0 mm, 4.5 ± 1.9 years, and 0.41 ± 0.46 mm/year. In the linear regression models, the standardised β (β∗) for the association of aneurysm size with aneurysm expansion was 0.178 (P = 0.044). This was improved by combining aortic size with most measures of aortic function, with β∗ ranging from 0.192 (for aneurysm size combined with central diastolic blood pressure) to 0.484 (for aneurysm size combined with carotid-femoral pulse-wave velocity) (P ≤ 0.05 for each)., Conclusions: Combining aneurysm size with measures of arterial function improves assessment of aneurysm growth over TAA size alone, which is the standard for clinical decisions in TAA. Thus, combining aneurysm size with measures of aortic function provides a clinical advantage in the assessment of TAA disease activity., (Copyright © 2022 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

People exposed to adverse childhood experiences (ACEs) suffer from an increased risk of chronic disease and shorter lifespan. These individuals also tend to exhibit accelerated reproductive development and show signs of advanced cellular aging as early as childhood. These observations suggest that ACEs may accelerate biological processes of aging through direct or indirect mechanisms; however, few population-based studies have data to test this hypothesis. We analysed ACEs and biological aging data from the Canadian Longitudinal Study on Aging (CLSA; n = 23,354 adults aged 45-85) and used the BioAge R package to compute three indices of biological aging from blood-chemistry and organ-function data: Klemera-Doubal method (KDM) biological age, phenotypic age (PA), and homeostatic dysregulation (HD). Adults with ACEs tended to be biologically older than those with no ACEs, although the observed effect-sizes were small (Cohen's d<0.15), with the exception of neglect (d=0.35 for KDM and PA). Associations were similar for men and women and tended to be smaller for older as compared to midlife participants. Subtypes of ACEs perceived as being more severe (e.g., being pushed or kicked, experiencing forced sexual activity, witnessing physical violence) and more frequent and diverse exposures were associated with relatively larger effect-sizes. These findings support the hypothesis that ACEs contribute to accelerated biological aging, although replication is needed in studies with access to prospective records of ACEs and cellular-level measurements of biological aging. Furthermore, future work to better understand the degree to which associations between ACEs and biological aging are moderated by specific life-course pathways, and mediated by lifestyle and socioeconomic factors is warranted., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Tumor dopamine-like DRD2 receptor expression is higher in pheochromocytoma-paraganglioma (PC-PG) compared with other cancers. ONC201 is a bitopic DRD2 antagonist with preclinical ONC201 activity in desmoplastic small round cell tumor (DSRCT)., Patients and Methods: Patients (N = 30) with neuroendocrine tumors were treated on this investigator-initiated trial (NCT03034200). ONC201 dose and schedule were 625 mg orally weekly in cohorts A (PC-PG) + B (other neuroendocrine tumors) and 625 mg orally on 2 consecutive days each week in cohort C, which included 5 responding patients. The primary endpoint was radiographic response measured using RECIST. Secondary endpoints included progression-free survival, overall survival, and safety., Results: In arm A (n = 10; all PC-PG), 50% (5/10) exhibited a partial response (PR) and 2 additional patients had stable disease (SD) >3 months. Median duration of therapy for arm A patients was 9 months (range: 1.5-33 months) with 5 patients treated >1 year. In arm B (n = 12), there were 1 PR (DSRCT) and 2 SD (DSRCT; neuroblastoma) >3 months. Median duration of therapy in arm A was 18 months (range: 1-33 months) and arm B was 3 months (range: 1.5-33 months). Arm C PC-PG (N = 8) showed 1 PR and 7 SD at 3 months, with median duration of therapy >10 months. There was no decline in Karnofsky performance status at week 12 for 28 of 30 patients and no dose modification due to treatment-related adverse events., Conclusions: Oral ONC201 was well tolerated in patients with metastatic neuroendocrine tumors and associated with clinical benefit, including tumor responses, particularly in some patients with DSRCT and the majority of patients with PC-PG. See related commentary by Owen and Trikalinos, p. 1748., (©2022 The Authors; Published by the American Association for Cancer Research.)

Lipid nanoparticles (LNPs) have been established as an essential platform for nucleic acid delivery. Efforts have led to the development of vaccines that protect against SARS-CoV-2 infection using LNPs to deliver messenger RNA (mRNA) coding for the viral spike protein. Out of the four essential components that comprise LNPs, phospholipids represent an underappreciated opportunity for fundamental and translational study. We investigated this avenue by systematically modulating the identity of the phospholipid in LNPs with the goal of identifying specific moieties that directly enhance or hinder delivery efficacy. Results indicate that phospholipid chemistry can enhance mRNA delivery by increasing membrane fusion and enhancing endosomal escape. Phospholipids containing phosphoethanolamine (PE) head groups likely increase endosomal escape due to their fusogenic properties. Additionally, it was found that zwitterionic phospholipids mainly aided liver delivery, whereas negatively charged phospholipids changed the tropism of the LNPs from liver to spleen. These results demonstrate that the choice of phospholipid plays a role intracellularly by enhancing endosomal escape, while also driving organ tropism in vivo . These findings were then applied to Selective Organ Targeting (SORT) LNPs to manipulate and control spleen-specific delivery. Overall, selection of the phospholipid in LNPs provides an important handle to design and optimize LNPs for improved mRNA delivery and more effective therapeutics.

Introduction: Frailty in older adults, characterized by a decline in multiple physiological systems and increasing vulnerability to loss of independence, disability, and death, is a public health priority in developed countries. Etiology of frailty extends across the lifespan and may begin in early life, but empirical evidence for this association is scarce. In this study, we examined whether adverse childhood experiences (ACEs) are associated with frailty in later life., Methods: We conducted a cross-sectional analysis of data for a population-based sample of 27,748 adults aged 45-85 years from the Canadian Longitudinal Study on Aging. The frailty index (FI) was computed with 76 health-related characteristics of physical and cognitive performance, self-rated health, chronic conditions, visual and hearing ability, activities of daily living, and well-being. Self-reported exposure to ACEs included physical, emotional, and sexual abuse, neglect, and witnessing intimate partner violence prior age of 16 and parental death, divorce, and living with a family member with mental illness prior age of 18. Generalized linear regression models with gamma error distribution and identity link function, adjusted for age and sex, were used to examine associations of each ACE type and the number of ACE types (0, 1, 2, or 3+) reported by an individual with FI. All models were adjusted for income, education, smoking, and alcohol consumption in sensitivity analysis., Results: Individuals exposed to ACEs had elevated levels of FI (mean = 0.13, SD = 0.09) than those unexposed, with the largest difference observed for neglect (B [95% CI]: 0.05 [0.04, 0.06]) and the smallest for parental death and divorce (0.015 [0.01,0.02]). The ACE count was associated with frailty in a graded manner, with the FI difference reaching 0.04 [0.037, 0.044] for participants exposed to 3+ ACE types. The association between ACEs and frailty tended to be stronger for women than men and for men aged 45-64 years than older men., Conclusions: Our study supports previous studies showing that exposure to ACEs is associated with frailty in adults. Our findings suggest that screening for ACEs involving childhood maltreatment may be useful for identifying individuals at risk of frailty and prevention of ACEs may have long-term benefits for healthy aging., (© 2021 S. Karger AG, Basel.)

Background: Recent studies have demonstrated that even in the absence of lung impairment as determined by spirometry, smoking and respiratory symptoms are associated with poor overall health and well-being. However, this relationship is not well defined; and it remains unclear the degree to which symptoms are related to poor health, independent of smoking. This is of particular importance to older adults, as they are more likely to exhibit respiratory symptoms and are, therefore, at risk of not receiving appropriate treatment if they have never smoked and have normal spirometry., Methods: We performed a cross-sectional analysis of data from the Canadian Longitudinal Study on Aging to delineate the associations of respiratory symptoms and smoking on the health of participants age 45-86 who exhibited normal spirometry. Participant health was estimated using a frailty index, a multidimensional measure of vulnerability to adverse outcomes that has been validated in numerous health settings., Results: Of the 21,293 participants included in our analysis, 87% exhibited a normal FEV 1 , FVC, and FEV 1 /FVC; of those, 45% reported at least one respiratory symptom, and 50% were former or current smokers. Both respiratory symptoms and smoking were independently associated with frailty (median interquartile range [IQR] = 0.11 [0.07-0.15]), the most substantial associations observed for those having at least one respiratory symptom (adjusted β 0.023, 95% CI 0.022-0.025) and current smokers with > 10 pack-year exposure (adjusted β 0.014, 95% CI [0.010-0.019). Not only was the association between symptoms and frailty evident in never smokers, a significant proportion of the total effect of smoking on frailty was observed to be mediated by symptoms., Conclusions: Our data show that respiratory symptoms, regardless of smoking history, were a significant correlate of frailty in older adults with normal spirometry. Hence, they should not be simply regarded as a benign by-product of aging., Competing Interests: The authors have disclosed no conflicts of interest., (Copyright © 2021 by Daedalus Enterprises.)

Background: Thoracic aortic aneurysm (TAA) is a highly morbid disease. We have previously shown that baseline hemodynamic measures reflecting aortic function are associated with future TAA expansion. However, whether serial arterial hemodynamic assessment further improves TAA growth assessment remains unknown. Therefore, we aimed to compare single vs serial arterial hemodynamic assessments in the evaluation of future TAA growth., Methods: Eighty-six unoperated participants with TAA underwent noninvasive arterial hemodynamic assessment using arterial tonometry and echocardiography at baseline and after 1 year. Aortic diameter was measured serially with the use of standard imaging modalities. Stepwise multivariable linear regression was used to assess associations of baseline and 1-year change (Δ) in arterial hemodynamic measures with TAA growth., Results: Mean age was 62.7 ± 11.0 years; 79% were male. Mean aneurysm growth was 0.48 ± 0.54 mm/year after a follow-up of 2.96 ± 1.03 years. Yearly changes in arterial hemodynamic measures ranged from -3.2% to +4.2%. Linear regression results showed that while baseline arterial hemodynamic measures were independently associated with aneurysm growth (carotid-femoral pulse wave velocity: β ± SE = 0.038 ± 0.013; aortic characteristic impedance: β ± SE = 0.002 ± 0.001; proximal aortic compliance: β ± SE = -0.011 ± 0.006; forward pressure wave amplitude: β ± SE 0.009 ± 0.002; reflected pressure wave amplitude: β ± SE = 0.017 ± 0.006; P < 0.05 for each), the 1-year Δ in these measures did not incrementally add to aneurysm growth assessment (P > 0.05 for each Δ)., Conclusions: Although baseline measures of aortic function independently predict TAA expansion, 1-year changes in these measures do not improve this prediction. Thus, for TAA risk assessment purposes, a baseline assessment of aortic function may suffice, which simplifies its use for potential predictive algorithms., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: The trajectory of frailty in older adults is important to public health; therefore, markers that may help predict this and other important outcomes could be beneficial. Epigenetic clocks have been developed and are associated with various health-related outcomes and sociodemographic factors, but associations with frailty are poorly described. Further, it is uncertain whether newer generations of epigenetic clocks, trained on variables other than chronological age, would be more strongly associated with frailty than earlier developed clocks. Using data from the Canadian Longitudinal Study on Aging (CLSA), we tested the hypothesis that clocks trained on phenotypic markers of health or mortality (i.e., Dunedin PoAm, GrimAge, PhenoAge and Zhang in Nat Commun 8:14617, 2017) would best predict changes in a 76-item frailty index (FI) over a 3-year interval, as compared to clocks trained on chronological age (i.e., Hannum in Mol Cell 49:359-367, 2013, Horvath in Genome Biol 14:R115, 2013, Lin in Aging 8:394-401, 2016, and Yang Genome Biol 17:205, 2016)., Results: We show that in 1446 participants, phenotype/mortality-trained clocks outperformed age-trained clocks with regard to the association with baseline frailty (mean = 0.141, SD = 0.075), the greatest of which is GrimAge, where a 1-SD increase in ΔGrimAge (i.e., the difference from chronological age) was associated with a 0.020 increase in frailty (95% CI 0.016, 0.024), or ~ 27% relative to the SD in frailty. Only GrimAge and Hannum (Mol Cell 49:359-367, 2013) were significantly associated with change in frailty over time, where a 1-SD increase in ΔGrimAge and ΔHannum 2013 was associated with a 0.0030 (95% CI 0.0007, 0.0050) and 0.0028 (95% CI 0.0007, 0.0050) increase over 3 years, respectively, or ~ 7% relative to the SD in frailty change., Conclusion: Both prevalence and change in frailty are associated with increased epigenetic age. However, not all clocks are equally sensitive to these outcomes and depend on their underlying relationship with chronological age, healthspan and lifespan. Certain clocks were significantly associated with relatively short-term changes in frailty, thereby supporting their utility in initiatives and interventions to promote healthy aging., (© 2021. The Author(s).)

Background: Myeloid-derived suppressor cells (MDSC) have immunosuppressive activity and enhance tumor progression. We hypothesized that lower blood MDSC would correlate with pathologic complete response and better outcomes in nonmetastatic urothelial carcinoma (UC)., Patients and Methods: Before cystectomy, blood MDSC were measured in whole blood (WB) and peripheral blood mononuclear cells using flow cytometry. MDSC were defined as CD33 + /HLA-DR - . MDSC subtypes were polymorphonuclear MDSC (CD15 + /CD14 - ), monocytic (M)-MDSC (CD15 - /CD14 + ), and uncommitted (UnC) MDSC (CD15 - /CD14 - ). The Wilcoxon rank sum test was used to compare MDSC between pathologic complete response groups. The optimal cutoff points for MDSC were identified using recursive partitioning analysis with cross-validation. The Cox proportional hazard model was used to associate MDSC and other clinical factors with recurrence-free survival and overall survival (OS)., Results: Overall, 109 patients were included: 86% men with median (range) age of 67 (30-88) years, 76% with pure UC, 29% intravesical therapy, and 41% neoadjuvant chemotherapy. Twenty-one patients (19%) had pT0N0 and 23 (24%) < pT2N0. Median (range) follow-up time was 17.4 (0.4-42.4) months. Total MDSC and polymorphonuclear MDSC percentage in peripheral blood mononuclear cells was significantly lower in patients with pT0N0 disease (P = .03). One- and 2-year OS rates were 94% (95% confidence interval [CI], 90-99) and 83% (95% CI, 75-93), respectively. In the multivariate Cox model after adjusting for age and gender, patients with higher WB M-MDSC and UnC-MDSC had shorter OS (optimal cutoff points by recursive partitioning analysis, hazard ratio = 7.5 [95% CI, 2.5-22.8], P = .0004; hazard ratio = 3.4 [95% CI, 1.0-11.0], P = .046, respectively)., Conclusion: In patients with nonmetastatic UC of bladder, higher WB M-MDSC and UnC-MDSC before cystectomy had negative prognostic value. Prospective validation is warranted., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Despite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on the molecular mechanisms of resistance, understanding of how resistance evolves remains limited. Using an experimental model of ALK positive NSCLC, we explored the evolution of resistance to different clinical ALK inhibitors. We found that resistance can originate from heterogeneous, weakly resistant subpopulations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence for a hybrid scenario involving the gradual, multifactorial adaptation to the inhibitors through acquisition of multiple cooperating genetic and epigenetic adaptive changes. Additionally, we found that during this adaptation tumor cells might present unique, temporally restricted collateral sensitivities, absent in therapy naïve or fully resistant cells, suggesting the potential for new therapeutic interventions, directed against evolving resistance.

Background: Myeloid-derived suppressor cells (MDSCs) were linked to pathologic stage in bladder urothelial carcinoma (UC). Neutrophil lymphocyte ratio (NLR) is an inflammatory biomarker with a prognostic role in metastatic (m)UC., Objective: We hypothesized that MDSC levels correlate with NLR and overall survival (OS) in mUC., Patients and Methods: MDSCs were measured in blood samples from patients with mUC in fresh unfractionated whole blood (WB) and peripheral blood mononuclear cells (PBMC) by flow cytometry and defined as LinloCD33+/HLADR- (Total MDSC). MDSC subsets were defined as polymorphonuclear (PMN-MDSC: CD15+/CD14-), monocytic (M-MDSC: CD15-/CD14+), and uncommitted (UNC-MDSC: CD15-/CD14-). MDSC populations were presented as a percentage of live nucleated blood cells. Spearman's rank correlation assessed correlations between MDSC and NLR. Kaplan-Meier curves and log-rank test estimated OS from the time of MDSC collection to last follow-up or date of death., Results: Of the 76 patients, 78% were men and 43% were never smokers with a median age of 69 years (range 31-83); 72% had pure UC and 76% had lower tract UC. Prior therapies included intravesical therapy (22%), neoadjuvant chemotherapy (30%), cystectomy or nephroureterectomy (55%). Median follow-up for all patients was 12 months (0.6-36.5). PMN-MDSC was the predominant subset in WB and PBMC. There was significant correlation between individual MDSC subsets in WB and PBMC (p ≤ 0.001). Both WB UNC-MDSC/PMN-MDSC ratios (rho = - 0.27, p = 0.03) and PBMC UNC-MDSC/PMN-MDSC (rho = - 0.28, p = 0.02) were negatively correlated with NLR. Median OS was 17.7 months (95% CI: 11.0-NE). Overall 1-year and 3-year survival rates were 0.60 (95% CI 0.49-0.73) and 0.15 (95% CI 0.03-0.67), respectively. Higher WB UNC-MDSC levels (HR 3.78, p = 0.0022) and higher NLR (HR 2.6, p = 0.0179) were associated with shorter OS., Conclusions: Specific MDSC subsets correlate with NLR. Higher WB UNC-MDSC levels and higher NLR were negative prognostic factors. Given the feasibility of serial blood draws, dynamic assessment of MDSC over time and further validation with longer follow-up are warranted.

Rivaroxaban after total knee arthroplasty (TKA) is used to prevent postoperative venous thromboembolism (VTE); however, despite thromboprophylaxis, some patients still develop postoperative VTE. To determine whether tourniquet time, time to initiate rivaroxaban (TTI RIV ), or Body Mass Index (BMI) was associated with postoperative VTE. A retrospective case-control study was conducted. Those patients that developed VTE despite prophylaxis (cases) were compared to controls (no VTE). A univariate analysis was conducted (p < 0.05 statistically significant). Seven VTE cases were identified from 234 TKA-patients. Patients with and without VTE had BMI of 40.1 ± 9.1 and 32.8 ± 7.5, respectively (p = 0.064). TTI RIV in VTE and control group was 28.2 ± 4.7 hours and 26.4 ± 4.2 hours, respectively (p = 0.39). Mean tourniquet time in VTE and control group was 65.0 ± 8.7 minutes and 49 ± 8.8 minutes, respectively (p = 0.0007). Statistically significant differences in tourniquet times were noted between VTE and non-VTE group but not for TTI RIV and BMI. Prolonged tourniquet use could pose a potential risk factor for postoperative VTE. Thromboprophylaxis management may need to be adjusted, based on patient-specific factors that could include increasing doses of oral anticoagulants and/or mechanical prophylaxis. However, further large-scale studies are required to establish pathophysiology.

Purpose: To describe the admissions process and outcomes for Indigenous applicants to the Northern Ontario School of Medicine (NOSM), a Canadian medical school with the mandate to recruit students whose demographics reflect the service region's population., Method: The authors examined 10-year trends (2006-2015) for self-identified Indigenous applicants through major admission stages. Demographics (age, sex, northern and rural backgrounds) and admission scores (grade point average [GPA], preinterview, multiple mini-interview [MMI], final), along with score-based ranks, of Indigenous and non-Indigenous applicants were compared using Pearson chi-square and Mann-Whitney tests. Binary logistic regression was used to assess the relationship between Indigenous status and likelihood of admission outcomes (interviewed, received offer, admitted)., Results: Indigenous qualified applicants (338/17,060; 2.0%) were more likely to be female, mature (25 or older), or of northern or rural background than non-Indigenous applicants. They had lower GPA-based ranks than non-Indigenous applicants (P < .001) but had comparable preinterview-, MMI-, and final-score-based ranks across all admission stages. Indigenous applicants were 2.4 times more likely to be interviewed and 2.5 times more likely to receive an admission offer, but 3 times less likely to accept an offer than non-Indigenous applicants. Overall, 41/338 (12.1%) Indigenous qualified applicants were admitted compared with 569/16,722 (3.4%) non-Indigenous qualified applicants., Conclusions: Increased representation of Indigenous peoples among applicants admitted to medical school can be achieved through the use of socially accountable admissions. Further tracking of Indigenous students through medical education and practice may help assess the effectiveness of NOSM's social accountability admissions process.

Purpose: Long-term outcomes with hypofractionated radiation therapy for prostate cancer are limited. We report 10-year outcomes for patients treated with intensity modulated radiation therapy (IMRT) for localized prostate cancer with 70 Gy in 28 fractions at 2.5 Gy per fraction., Methods and Materials: The study included 854 consecutive patients with localized prostate cancer treated with moderately hypofractionated IMRT and daily image guidance at a single institution between 1998 and 2012. Patients with a single intermediate risk factor were considered to have favorable intermediate-risk (FIR) disease, and those with multiple intermediate risk factors were considered unfavorable (UIR). Biochemical relapse-free survival, clinical relapse-free survival, and overall survival were analyzed using Kaplan-Meier analysis. Prostate cancer-specific mortality (PCSM) was analyzed using competing risk regression. All grade ≥3 genitourinary (GU) and gastrointestinal (GI) toxicities were recorded using Common Terminology Criteria for Adverse Event version 4.03, and cumulative incidence rates of GU and GI toxicity were calculated., Results: The median follow-up was 11.3 years (maximum, 19 years). For patients with low-risk (LR), FIR, UIR, and high-risk (HR) disease, the 10-year biochemical relapse free survival rates were 88%, 78%, 71%, and 42%, respectively, (P < .0001). The 10-year clinical relapse free survival were 95%, 91%, 85%, and 72% for patients with LR, FIR, UIR, and HR, respectively, (P < .0001). For all patients, the 10-year actuarial overall survival rate was 69% (95% confidence interval, 66%-73%), and the 10-year PCSM was 6.8% (95% confidence interval, 5.1%-8.6%) overall. For patients with LR, FIR, UIR and HR disease, the 10-year PCSM rates were 2%, 5%, 5%, and 15%. Long-term grade ≥3 GU or GI toxicity remained low with 10-year cumulative incidences of 2% and 1%, respectively., Conclusions: High-dose moderately hypofractionated IMRT with daily image guidance for localized prostate cancer demonstrates favorable 10-year oncologic outcomes with a low incidence of toxicity. This fractionation schedule appears to be acceptable for patients across all risk groups., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Prostate hypertrophy, median lobe hypertrophy, and pubic arch interference (PAI) are relative contraindications to brachytherapy because of potential morbidity and technical considerations. GnRH analogs or non-steroidal anti-androgens are currently utilized to achieve prostatic downsizing prior to brachytherapy. However, such agents have been associated with effects on body habitus, metabolism, and quality of life. In contrast, 5-alpha reductase inhibitors (5-ARI) are far less frequently associated with these morbidities., Methods and Materials: Patients with large gland size, median lobe hypertrophy, or PAI were offered 5-ARI therapy. Repeat transrectal ultrasound was performed at 3 or 4 months, followed by brachytherapy if resolution was achieved. If downsizing was inadequate, patients were offered continuation of 5-ARI for additional 3 months, gonadotropin-releasing hormone analog (GnRH) agonist or antiandrogen therapy, or other curative treatment., Results: Of 59 patients with follow-up available, 42 (71%) were deemed to have adequate downsizing; 37 (63%) after 3 to 4 months of 5-ARI and 5 (8%) after 7 to 8 months. Seventeen patients (29%) received other treatments because of inadequate effect. Median volume reduction was 20%. Of 41 patients undergoing brachytherapy, 4 (9.7%) required temporary catheterization because of obstruction. Median follow-up after implantation was 25 months (range, 1-64). Median time for return to International Prostate Symptom Score ≤5 of baseline score was 7 months (interquartile ratio, 6-13). All but 1 patient who received brachytherapy remain biochemically controlled., Conclusion: 5-ARI monotherapy is an alternative for downsizing in patients with hypertrophy or PAI, with more than 70% achieving adequate downsizing without use of GnRH analogs or antiandrogens. Patients who received brachytherapy experienced typical rates of postimplant urinary morbidity., (Copyright © 2017 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Interest in prostate dose reduction or focal treatment exists due to expected reductions in treatment morbidity. Prior analyses have not generally corroborated relationships between prostate or urethral dose and urinary toxicity after brachytherapy, but such analyses have been performed on cohorts all receiving the same prescribed dose. We analyzed patients treated to differing prescription doses to assess acute urinary morbidity with dose reduction., Methods and Materials: Patients treated with Pd-103 to either 125 Gy or 90-100 Gy were compared using the International Prostate Symptom Score (IPSS) at 1-month postimplant. Patients in the 90-100 Gy cohort began external beam radiation therapy after their 1-month assessment; thus, toxicities were measured before contribution from external beam radiation therapy. Patient/treatment characteristics were compared to verify subgroup homogeneity. Dose and change in IPSS 1 month after treatment were assessed using a multivariate linear regression model., Results: One hundred ninety-one and 41 patients were treated with 125 Gy versus 90-100 Gy, respectively. Preimplant and postimplant prostate volumes and initial IPSS were similar between groups. Higher prescription dose and increased pretreatment IPSS were independent predictors of increased 1-month IPSS. In addition, every 10 percentage point additional prostate volume receiving a given dose was associated with increase in IPSS after treatment for the same level of pretreatment IPSS., Conclusion: Lower prescription dose and decreased volume of high-dose regions to the prostate correlated with reduced acute urinary morbidity after brachytherapy. Our findings suggest that focal treatment approaches with modest dose reductions to subregions of the prostate may reduce acute morbidity and potentially expand the number of patients eligible for brachytherapy., (Copyright © 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Introduction: The Northern Ontario School of Medicine (NOSM) opened in 2005 with a social accountability mandate to address a long history of physician shortages in northern Ontario. The objective of this qualitative study was to understand the school's effect on recruitment of family physicians into medically underserviced rural communities of northern Ontario., Methods: We conducted a multiple case study of 8 small rural communities in northern Ontario that were considered medically underserviced by the provincial ministry of health and had successfully recruited NOSM-trained physicians. We interviewed 10 people responsible for physician recruitment in these communities. Interview transcripts were analyzed by means of an inductive and iterative thematic method., Results: All 8 communities were NOSM medical education sites with populations of 1600-16 000. Positive changes, linked to collaboration with NOSM, included achieving a full complement of physicians in 5 communities with previous chronic shortages of 30%-50% of the physician supply, substantial reduction in recruitment expenditures, decreased reliance on locums and a shift from crisis management to long-term planning in recruitment activities. The magnitude of positive changes varied across communities, with individual leadership and communities' active engagement being key factors in successful physician recruitment., Conclusion: Locating medical education sites in underserviced rural communities in northern Ontario and engaging these communities in training rural physicians showed great potential to improve the ability of small rural communities to recruit family physicians and alleviate physician shortages in the region.

Background: Despite current therapies, glioblastoma is a devastating cancer, and validation of effective biomarkers for it will enable better diagnosis and therapeutic intervention for this disease. We recently discovered a new biomarker for high-grade gliomas, ELTD1 (epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1) via bioinformatics, and validated that ELTD1 protein levels are significantly higher in human and rodent gliomas. The focus of this study was to assess the effect on tumor growth of an antibody against ELTD1 in orthotopic, GL261, and G55 xenograft glioma models., Methods: The effect of anti-ELTD1 antibody therapy was assessed by animal survival, MRI measured tumor volumes, MR angiography, MR perfusion imaging, and immunohistochemistry (IHC) characterization of microvessel density in mouse glioma models. Comparative treatments included anti-vascular endothelial growth factor (VEGF) and anti-c-Met antibody therapies, compared with untreated controls., Results: Tumor volume and survival data in this study show that antibodies against ELTD1 inhibit glioma growth just as effectively or even more so compared with other therapeutic targets studied, including anti-VEGF antibody therapy. Untreated GL261 or G55 tumors were found to have significantly higher ELTD1 levels (IHC) compared with contralateral normal brain. The anti-angiogenic effect of ELTD1 antibody therapy was observed in assessment of microvessel density, as well as from MR angiography and perfusion measurements, which indicated that anti-ELTD1 antibody therapy significantly decreased vascularization compared with untreated controls., Conclusions: Either as a single therapy or in conjunction with other therapeutic approaches, anti-ELTD1 antibodies could be a valuable new clinical anti-angiogenic therapeutic for high-grade gliomas., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The current standard of care for patients with locally advanced prostate cancer is a combination of androgen deprivation and radiation therapy. Radiation is typically given with androgen suppression when testosterone levels are at their nadir. Recent reports have shown that androgen stimulation of androgen-deprived prostate cancer cells leads to formation of double-strand breaks (DSB). Here, we exploit this finding and investigate the extent and timing of androgen-induced DSBs and their effect on tumor growth following androgen stimulation in combination with ionizing radiation (IR)., Experimental Design: Androgen-induced DNA damage was assessed by comet assays and γH2A.X foci formation. Effects of androgen stimulation and radiation were determined in vitro and in vivo with xenograft models., Results: We document that androgen treatment of androgen-deprived prostate cancer cell lines resulted in a dose- and time-dependent induction of widespread DSBs. Generation of these breaks was dependent on androgen receptor and topoisomerase II beta but not on cell-cycle progression. In vitro models demonstrated a synergistic interaction between IR and androgen stimulation when IR is given at a time point corresponding with high levels of androgen-induced DSB formation. Furthermore, in vivo studies showed a significant improvement in tumor growth delay when radiation was given shortly after androgen repletion in castrated mice., Conclusions: These results suggest a potential cooperative effect and improved tumor growth delay with androgen-induced DSBs and radiation with implications for improving the therapeutic index of prostate cancer radiation therapy. Clin Cancer Res; 22(13); 3310-9. ©2016 AACRSee related commentary by Chua and Bristow, p. 3124., (©2016 American Association for Cancer Research.)

Background: The purpose of the study was to examine factors related to the retention of registered nurses in northeastern Ontario, Canada., Objective/method: A cross-sectional survey of registered nurses working in northeastern Ontario, Canada was conducted. Logistic regression analyses were used to consider intent to stay in current employment in relation to the following: 1) demographic factors, and 2) occupation and career satisfaction factors., Results: A total of 459 (29.8% response rate) questionnaires were completed. The adjusted odds logistic regression analysis of RNs who intended to remain in their current position for the next five years, demonstrated that respondents in the 46 to 56 age group (OR: 2.65; 95% CI: 1.50 to 4.69), the importance of staff development in the organization (OR: 3.04; 95% CI: 1.13 to 8.13) northeastern Ontario lifestyle (OR: 2.61; 95% CI: 1.55 to 4.40), working in nursing for 14 to 22.5 years (OR: 2.55; 95% CI: 1.10 to 5.93), and working between 0 to 1 hour of overtime per week (OR: 1.20; 95% CI: 1.20 to 4.64) were significant factors in staying in their current position for the next five years., Conclusions: This study shows that a further understanding of the work environment could assist with developing retention for rural nurses. Furthermore, employers may use such information to ameliorate the working conditions of nurses, while researchers may use such evidence to develop interventions that are applicable to improving the working conditions of nurses.