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ABSTRACT: Improving health and welfare outcomes for replacement and surplus dairy calves is important for the sustainability of the dairy industry. Dairy farmers and veterinarians hold expertise in calf management and have valuable perspectives on how to practically motivate improvements. The objective of this study was to determine strategies that could improve the care calves receive on dairy farms from the perspective of dairy farmers and their herd veterinarians. Two veterinary clinics specializing in dairy practice in British Columbia, Canada, and 21 of their client dairy farms participated in the project. Following a meeting in which calf colostrum management was discussed between farmers and their herd veterinarian, participant interviews were conducted. Separate interviews were conducted for the farmers (n = 27 farmers from 21 farms) and their herd veterinarians (n = 7, with 1 to 5 farms that each vet worked with enrolled in the study) using tailored semi-structured question guides. Interviews (n = 42) were transcribed and coded following inductive thematic analysis methodology. The themes identified included strategies for farmers, veterinarians, and calf buyers, as well as contexts that influenced the dairy farmers' internal motivation to provide good calf care. Results indicated that farmers could optimize their calf management through fostering engagement of calf care personnel or by enlisting technology. Veterinarians could provide support to farms by being actively involved in calf monitoring, assisting in developing operating protocols, and setting goals, and especially by using farm-specific data to guide their management recommendations. Calf buyers could communicate with and provide accountability to farmers and improve their purchasing strategies to encourage farms to raise more vigorous surplus calves. Farmers' personal values, social networks, and relationships with different dairy industry stakeholders influenced their concern about the standards of their calf care practices. These findings provide guidance on how dairy farmers could achieve or be prompted to achieve improvements in their calf care practices.

Abstract Background Laboratory data can provide great value to support research aimed at reducing the incidence, prolonging survival and enhancing outcomes of cancer. Data is characterized by the information it carries and the format it holds. Data captured in Alberta’s biomarker laboratory repository is free text, cluttered and rouge. Such data format limits its utility and prohibits broader adoption and research development. Text analysis for information extraction of unstructured data can change this and lead to more complete analyses. Previous work on extracting relevant information from free text, unstructured data employed Natural Language Processing (NLP), Machine Learning (ML), rule-based Information Extraction (IE) methods, or a hybrid combination between them. Methods In our study, text analysis was performed on Alberta Precision Laboratories data which consisted of 95,854 entries from the Southern Alberta Dataset (SAD) and 6944 entries from the Northern Alberta Dataset (NAD). The data covers all of Alberta and is completely population-based. Our proposed framework is built around rule-based IE methods. It incorporates topics such as Syntax and Lexical analyses to achieve deterministic extraction of data from biomarker laboratory data (i.e., Epidermal Growth Factor Receptor (EGFR) test results). Lexical analysis compromises of data cleaning and pre-processing, Rich Text Format text conversion into readable plain text format, and normalization and tokenization of text. The framework then passes the text into the Syntax analysis stage which includes the rule-based method of extracting relevant data. Rule-based patterns of the test result are identified, and a Context Free Grammar then generates the rules of information extraction. Finally, the results are linked with the Alberta Cancer Registry to support real-world cancer research studies. Results Of the original 5512 entries in the SAD dataset and 5017 entries in the NAD dataset which were filtered for EGFR, the framework yielded 5129 and 3388 extracted EGFR test results from the SAD and NAD datasets, respectively. An accuracy of 97.5% was achieved on a random sample of 362 tests. Conclusions We presented a text analysis framework to extract specific information from unstructured clinical data. Our proposed framework has shown that it can successfully extract relevant information from EGFR test results.

AlphaFold2 is an Artificial Intelligence-based program developed to predict the 3D structure of proteins given only their amino acid sequence at atomic resolution. Due to the accuracy and efficiency at which AlphaFold2 can generate 3D structure predictions and its widespread adoption into various aspects of biochemical research, the technique of protein structure prediction should be considered for incorporation into the undergraduate biochemistry curriculum. A module for introducing AlphaFold2 into a senior-level biochemistry laboratory classroom was developed. The module's focus was to have students predict the structures of proteins from the MPOX 22 global outbreak virus isolate genome, which had no structures elucidated at that time. The goal of this study was to both determine the impact the module had on students and to develop a framework for introducing AlphaFold2 into the undergraduate curriculum so that instructors for biochemistry courses, regardless of their background in bioinformatics, could adapt the module into their classrooms.

The prognosis of early non-small-cell lung cancer (eNSCLC) remains poor. An understanding of current therapies and outcomes can provide insights into how novel therapies can be integrated into clinics. We conducted a large, retrospective, population-based cohort study of patients with de novo eNSCLC (stages IB, IIA, IIB, and IIIA) diagnosed in Alberta, Canada, between 2010 and 2019. The primary objectives were to describe treatment patterns and survival outcomes among patients with eNSCLC. A total of 5126 patients with eNSCLC were included. A total of 45.3% of patients were referred to a medical oncologist, ranging from 23.7% in stage IB to 58.3% in IIIA. A total of 23.6% of patients initiated systemic therapy (ST), ranging from 3.5% in stage IB to 38.5% in IIIA. For stage IIB and IIIA individuals who received surgery, adjuvant ST was associated with a decreased likelihood of death (hazard ratios (HR) of 0.77 (95% CI: 0.56–1.07) and 0.69 (95% CI: 0.54–0.89), respectively). In a Canadian real-world setting, stage IIB and IIIA patients who received adjuvant ST tended to have better survival than patients who did not, but future studies that provide adjustment of additional confounders are warranted. Examining referral pathways that account for disparities based on age, sex, and comorbidities in the real world would also provide further insights.

ABSTRACT: This study used realistic evaluation to determine how, and in which circumstances, providing dairy farmers with benchmarked data on their calves can motivate improved colostrum management practices. Dairy farmers from British Columbia, Canada, were recruited through 2 veterinary clinics that offered benchmarking of calf data as part of their services. For approximately 8 wk, blood samples were collected from newborn calves to evaluate serum total protein concentrations as an indicator of the effectiveness of the farmer's colostrum management. These data were analyzed separately for heifer calves (“replacement calves”) and non-replacement calves, including males and beef crossbred females (“surplus calves”). The results of these analyses were benchmarked against other participating herds and presented to dairy farmers (n = 27) by their herd veterinarian (n = 7). Follow-up interviews were conducted separately with the farmers and veterinarians after each meeting to determine their perspectives on the utility of this benchmarking strategy. Therefore, a total of 42 interviews were coded, and realistic evaluation was used to determine common contexts and mechanisms that contributed to the success or failure of the benchmark meeting, with success characterized by farmers' expressed intention to improve their colostrum management practices. Four important contexts were identified that influenced the outcome of the benchmark meetings: (1) farm resources (e.g., facility limitations), (2) the farmer's perception of their calf performance, (3) management strategies, and (4) the farmer's personal values. Depending on these contexts, some farmers intended to improve their calf care practices based on resources the benchmark meeting provided, which included illustrative data and veterinary advice. These resources motivated change through influencing farmer decision-making, which depended on the value they saw in the data as a decision-making tool. The economic or moral interest farmers expressed in their surplus calves also influenced whether farmers intended to implement management changes. Recommendations for future implementation of benchmarking include targeting producers who are motivated to improve and who value the future performance of their calves, those who have engaged calf care personnel, and those who prefer data-driven decision-making. This study supports the important role veterinarians can play in motivating improved calf care practices through providing benchmarking services.

Introduction: Over the past decade, the treatment of metastatic castration-sensitive prostate cancer (mCSPC) has changed significantly. Current guidelines suggest the use of androgen deprivation therapy (ADT) plus an additional systemic therapy, regardless of disease burden and risk, based on phase 1 evidence showing improved overall survival. We sought to describe treatment patterns of patients with mCSPC in the province of Alberta. Methods: This was a retrospective, population-based, cohort study of male patients aged ≥18 with mCSPC at the time of diagnosis and who initiated ADT between 1 January 2016 and 31 December 2020. Data were obtained from the Alberta Cancer Registry. Patients were assigned to an ADT-alone cohort or a treatment intensification cohort (cohorts 2–5). The primary objectives of this study were to describe baseline characteristics and the treatment of mCSPC patients who initiated ADT with or without treatment intensification. Overall survival between cohorts was a secondary objective. Descriptive statistics were used to describe differences in baseline characteristics of each cohort. Overall survival was calculated using the Kaplan–Meier method. All statistical tests were two-sided and are used to call out likely cohort differences descriptively. Results: Between 1 January 2016 and 31 December 2020, we identified a total of 960 patients with mCSPC (median age 74 years, IQR 66–82). Most patients received ADT alone (67%), followed by ADT plus abiraterone (18%), ADT plus docetaxel (12%), and ADT plus enzalutamide or apalutamide (3%). Over the study period, we observed an increase in the utilization of treatment intensification over time, in particular, the increased use of androgen-receptor-axis-targeted (ARAT) therapies. Patients who received ADT alone were older, were more likely to have more than one comorbid condition, had fewer sites of metastatic disease, and were less likely to be on opioid medications. Conclusions: In this study, we show that patients who received ADT alone as treatment for mCSPC are older, have more comorbidities, and have less extensive disease. While there has been a decline over time in the number of patients treated with ADT alone, over 50% of all patients with mCSPC continue to receive ADT alone. Further work is needed to understand barriers to treatment intensification and for knowledge translation initiatives to improve the treatment of patients with mCSPC.

Minimal Canadian data are available on the RAS testing rates, treatment patterns, and corresponding overall survival (OS) in metastatic colorectal cancer (mCRC) patients. We conducted a population-based cohort study of left-sided RAS wild-type (WT) mCRC patients diagnosed between 1 January 2014 and 31 December 2019, and who were treated with first-line (1L) chemotherapy plus the epidermal growth factor receptor inhibitor panitumumab, chemotherapy plus bevacizumab, or chemotherapy alone, in Alberta, Canada, using electronic medical records and administrative health system data. Of the 2721 patients identified with left-sided mCRC, 320 patients with RAS WT mCRC were treated with 1L systemic therapy: chemotherapy plus panitumumab (n = 64), chemotherapy plus bevacizumab (n = 52), or chemotherapy alone (n = 204). Only 65% and 39% of the 320 1L-treated patients initiated second- and third-line therapy, respectively. A total of 71% of individuals with treated left-sided mCRC underwent RAS testing. The median OS for mCRC patients with RAS WT left-sided tumours was higher for patients treated with 1L panitumumab plus chemotherapy (34.3 months; 95% CI: 23.8–39.6) than for patients who received 1L chemotherapy alone (30.0 months; 95% CI: 24.9–34.1) or 1L bevacizumab plus chemotherapy (25.6 months; 95% CI: 21.2–35.7). These findings highlight an unmet need in left-sided RAS WT mCRC, with relatively few individuals receiving a biologic agent in combination with chemotherapy in the 1L setting, a high rate of attrition between lines, and a need for increased RAS testing before treatment initiation.

Abstract. Introduction:. Lumbosacral radiculopathy (LR), also known as sciatica, is a common type of radiating neurologic pain involving burning, tingling, and numbness in the lower extremities. It has an estimated lifetime prevalence as high as 43%. Objectives:. The objective of this randomized controlled trial was to evaluate the impact of virtually delivered Mindfulness-Oriented Recovery Enhancement (MORE) on patients with LR during the COVID-19 pandemic. Methods:. Potentially eligible patients were identified using electronic health record queries and phone screenings. Participants were then randomized to MORE or treatment-as-usual (TAU) for 8 weeks, with pain intensity assessed daily. At baseline and follow-up visits, participants completed questionnaires assessing the primary outcome, disability, as well as quality of life, depression, mindful reinterpretation of pain, and trait mindfulness. Results:. In our study, patients undergoing virtual delivery of MORE had greater improvements in daily pain intensity (P = 0.002) but not in disability (P = 0.09), depression (P = 0.26), or quality of life (P = 0.99 and P = 0.89, SF-12 physical and mental component scores, respectively), relative to TAU patients. In addition, patients in MORE experienced significantly greater increases in mindful reinterpretation of pain (P = 0.029) and trait mindfulness (P = 0.035). Conclusion:. Among patients with lumbar radiculopathy, MORE significantly reduced daily pain intensity but did not decrease disability or depression symptoms. Given the long duration of symptoms in our sample, we hypothesize the discrepancy between changes in daily pain intensity and disability is due to fear avoidance behaviors common in patients with chronic pain. As the first trial of a mindfulness intervention in patients with LR, these findings should inform future integrative approaches to LR treatment, particularly when considering the increasing use of virtual interventions throughout the COVID-19 pandemic.

BackgroundNaloxone is critical for reversing opioid-related overdoses. However, there is a dearth of research examining how naloxone possession and carriage are impacted by time-varying individual and social determinants, and if this differed during the height of the COVID-related mitigation measures (e.g., shutdowns).MethodsWe utilized weekly ecological momentary assessments (EMA) to measure factors associated with naloxone possession and carriage among 40 people who use illicit opioids in New York City, for 24 months. Descriptive statistics were used to explore the frequency of weeks with consistent naloxone possession and carriage. Mixed effects binary and multivariable logistic regression was used to test for the impact of time-varying EMA- and baseline-level factors on each outcome.ResultsApproximately 70% of weekly EMAs were associated with consistent naloxone possession or carriage. In multivariable models, compared to during the height of the COVID-related shutdowns (March 12, 2020-May 19, 2021), the time before was associated with lower odds of consistent possession (Odds Ratio (OR) = 0.05, 95% Confidence Interval (CI) = 0.01-0.15) and consistent carriage (OR = 0.06, CI = 0.01-0.25). Additionally, being female (OR = 11.15, CI = 2.85-43.42), being White versus being Black or Hispanic/Latinx (OR = 8.05, CI = 1.96-33.06), and lifetime overdose (OR = 1.96, CI = 1.16-19.80) were associated with higher odds of consistent possession. Recent opioid injection (OR = 3.66, CI = 1.34-9.94), being female (OR = 7.91, CI = 3.91-8.23), and being White (OR = 5.77, CI = 1.35-24.55) were associated with higher odds of consistent carriage. Not wanting to be perceived as a drug user was reported in nearly one third (29.0%; 190/656) of EMAs where inconsistent possession was reported.ConclusionsOur findings paint a relatively positive picture of possession and carriage during COVID-related shutdowns, particularly among white and female participants, and highlight the importance of capturing time-varying factors to understand naloxone-related behavior. To curb growing disparities, outreach to equip Black and Hispanic/Latinx people with naloxone is needed as well as interventions to reduce stigma as a barrier to naloxone engagement.

The development of high molecular weight (HMW) genomic DNA (gDNA) extraction protocols for non-model species is essential to fully exploit long-read sequencing technologies in order to generate genome assemblies that can help answer complex questions about these organisms. Obtaining enough high-quality HMW gDNA can be challenging for these species, especially for tissues rich in polysaccharides such as biomass from species within the Botryococcus genus. The existing protocols based on column-based DNA extraction and biochemical lysis kits can be inefficient and may not be useful due to variations in biomass polysaccharide content. We developed an optimized protocol for the efficient extraction of HMW gDNA from Botryococcus biomass for use in long-read sequencing technologies. The protocol utilized an initial wash step with sorbitol to remove polysaccharides and yielded HMW gDNA concentrations up to 220 ng/μL with high purity. We then demonstrated the suitability of the HMW gDNA isolated from this protocol for long-read sequencing on the Oxford Nanopore PromethION platform for three Botryococcus species. Our protocol can be used as a standard for efficient HMW gDNA extraction in microalgae rich in polysaccharides and may be adapted for other challenging species.

The colonial green microalga Botryococcus braunii is well known for producing liquid hydrocarbons that can be utilized as biofuel feedstocks. B. braunii is taxonomically classified as a single species made up of three chemical races, A, B, and L, that are mainly distinguished by the hydrocarbons produced. We previously reported a B race draft nuclear genome, and here we report the draft nuclear genomes for the A and L races. A comparative genomic study of the three B. braunii races and 14 other algal species within Chlorophyta revealed significant differences in the genomes of each race of B. braunii. Phylogenomically, there was a clear divergence of the three races with the A race diverging earlier than both the B and L races, and the B and L races diverging from a later common ancestor not shared by the A race. DNA repeat content analysis suggested the B race had more repeat content than the A or L races. Orthogroup analysis revealed the B. braunii races displayed more gene orthogroup diversity than three closely related Chlamydomonas species, with nearly 24-36% of all genes in each B. braunii race being specific to each race. This analysis suggests the three races are distinct species based on sufficient differences in their respective genomes. We propose reclassification of the three chemical races to the following species names: Botryococcus alkenealis (A race), Botryococcus braunii (B race), and Botryococcus lycopadienor (L race).

Myeloid cells are the predominant cell type in the tumor microenvironment of human and murine glioblastoma (GBM). By generating a mouse model deficient for all monocyte chemoattractant proteins, here the authors show that blocking monocyte recruitment promotes a compensatory neutrophil influx and that concomitant neutrophil inhibition is required to improve survival in GBM preclinical models.

Immunotherapy and targeted therapies have been shown to considerably improve long-term survival outcomes in metastatic melanoma patients. Real-world evidence on the uptake of novel therapies and outcomes for this patient population in Canada are limited. We conducted a population-based retrospective cohort study of all metastatic melanoma patients diagnosed in Alberta, Canada (2015–2018) using electronic medical records and administrative data. Information on BRAF testing for patients diagnosed in 2017 or 2018 was obtained through chart abstraction. In total, 434 metastatic melanoma patients were included, of which 110 (25.3%) were de novo metastatic cases. The median age at diagnosis was 66 years (IQR: 57–76) and 70.0% were men. BRAF testing was completed for the majority of patients (88.7%). Among all patients, 60.4%, 19.1%, and 6.0% initiated first-line, second-line, and third-line systemic therapy. The most common therapies were anti-PD-1 and targeted therapies. The two-year survival probability from first-line therapy, second-line therapy, and third-line therapy was 0.50 (95% CI: 0.44–0.57), 0.26 (95% CI: 0.17–0.40), and 0.14 (95% CI: 0.40–0.46), respectively. In the first-line setting, survival was highest for patients that received ipilimumab or ipilimumab plus nivolumab, while targeted therapy had the highest survival in the second-line setting. This study indicates that novel therapies improve survival in the real world but a considerable proportion of patients do not receive treatment with systemic therapy.

Real-world evidence has been increasingly used to support evaluations of emerging therapies. These investigations are often conducted in settings that may not be representative of the underlying population. The purpose of this investigation was to empirically quantify the magnitude of this selection bias. Individuals diagnosed with solid metastatic cancer in Alberta, Canada, between 2010–2019 were identified using the provincial cancer registry for 13 common metastatic sites. Two outcomes used to support oncology reimbursement decisions were examined: the proportion of individuals who initiated systemic therapy and median overall survival (OS). These outcomes were assessed in the entire population and in a subset of individuals who were referred to a medical oncologist. Among the 23,152 individuals in the entire population, 40.8% (95% CI: 40.2–41.4) initiated systemic therapy, and the median OS from diagnosis was 5.4 months (95% CI: 5.3–5.6). Among those who were referred to a medical oncologist (n = 13,372; 57.8%), 67.4% (95% CI: 66.6–68.2) initiated systemic therapy, and the median OS from diagnosis was 11.2 months (95% CI: 10.9–11.5). The magnitude of bias varied by cancer site where lower referral rates were associated with greater bias. Non-referral is an important source of selection bias in real-world investigations. Studies that rely on limited-catchment real-world data should be interpreted with caution, particularly in metastatic cancer settings.

Endometrial cancer (EC) incidence has increased in recent decades. However, population-based outcomes data are limited. In this retrospective cohort study, we examined characteristics, treatment patterns, and clinical outcomes, including time to next treatment (TNNT) and overall survival (OS), among advanced/recurrent (A/R) EC patients between 2010 and 2018 in Alberta, Canada. Kaplan–Meier statistics evaluated TTNT and OS, stratified by patient (A/R) and treatment. A total of 1053 patients were included: 620 (58.9%) advanced and 433 (41.1%) recurrent. A total of 713 (67.7%) patients received first-line therapy: 466 (75.2%) advanced and 247 (57.0%) recurrent. Platinum-based chemotherapy (PBCT) was the most common first-line regimen (overall: 78.6%; advanced: 96.1%; recurrent: 45.3%). The median TTNT and OS from first-line therapy were 19.9 months (95% confidence interval [CI]: 17.5–23.5) and 35.9 months (95% CI: 31.5–53.5), respectively. Following first-line PBCT, the median OS from second-line chemotherapy (N = 187) was 10.4 months (95% CI: 8.9–13.3) and higher for those rechallenged with PBCT (N = 72; 38.5%) versus no rechallenge (N = 115; 61.5%) (13.3 months [95% CI: 11.2–20.9] vs. 6.4 months [95% CI: 4.6–10.4; p < 0.001]). The findings highlight poor outcomes in A/R EC, particularly following first-line therapy, and that additional tolerable therapeutic options are needed to improve patient outcomes.

ABSTRACT: The primary objective of this study was to compare male and female dairy calf management practices and evaluate risk factors associated with differences in care. Secondary objectives were to understand surplus calf transportation and marketing practices and investigate incentives to motivate calf care improvements. An online survey was distributed to all dairy producers in Ontario (n = 3,367) from November 2020 to March 2021 and Atlantic Canada (n = 557) from April to June 2021. Dairy producers were identified through provincial dairy associations and contacted via e-mail and social media. Descriptive statistics were computed, and a logistic regression model was created to evaluate factors associated with using discrepant feeding practices (i.e., fed less colostrum, fed colostrum later, or fed raw, unsalable milk) for male calves compared with females. The survey had a 7.4% response rate (n = 289/3,924) and was primarily filled out by farm owners (76%). Although colostrum and milk feeding practices were similar between male and female calves, male calves received less milk while still on the dairy farm of origin compared with females. Male calves were also more likely to be fed a higher proportion of raw, unsalable milk. Female producers and those that kept their male calves beyond 10 d of age had lower odds of using poorer feeding practices for male calves. Male calves were mostly sold between 1 and 10 d (64%), primarily through direct sales to a calf-rearing facility (45%), with auctions being the next most common method (35%). A small but notable proportion of producers (18%) agreed that euthanizing male calves is a reasonable alternative when their sale price is very low; however, few producers (13%) reported that financial costs limited their male calf care. The largest proportion (43%) of producers reported that a price premium for more vigorous calves would motivate them to take better care of their male calves. Conversely, only 28% of producers reported that a price discount for calves in poor condition would be motivating. Producers placed importance on the opinion of their calf buyer, their herd veterinarian, and the Canadian Code of Practice for the Care and Handling of Dairy Cattle when considering their calf care practices, and they highly valued practices that promote calf health. Respondents to this survey reported a lower proportion of tiestall barn use and higher milk productivity compared with typical dairy herds in the region, suggesting selection bias for more progressive dairy producers. Nevertheless, our results suggest that dairy producers provide similar care between male and female calves, but some male calves experience challenges due to milk feeding and marketing practices. Feedback from calf buyers along with continued support and guidance from herd veterinarians and the Code of Practice may motivate dairy producers to improve male calf care.

Abstract Background Rural youth often begin developing polysubstance use and other risk behaviors during middle school. However, little polysubstance use research focuses on rural middle school youth. Our research uses Latent Class Analysis to understand existing patterns of rural middle school polysubstance use and risk and protective factors associated with polysubstance use. Methods We used survey data from a rural middle school pregnancy prevention program (N = 2,708). The survey included measures of demographics, lifetime substance use, trauma (adverse childhood experiences and bullying victimization) and aspects of youth development (parent communication on drugs and alcohol, parent connectedness and school connectedness). We used latent class analysis to produce participant polysubstance use profiles and multinomial regression to examine associations between polysubstance use, demographics, trauma and aspects of youth development. Results We categorized our participants into four latent classes. Our analysis classified 2.2% of participants as Regular Polysubstance users, 6.9% as Polysubstance experimenters, 19% as Vape + Alcohol experimenters and 71.9% as Non-Users. More adverse childhood experiences were associated with greater risk of polysubstance use and experimentation. Bullying was positively associated with greater risk of vape and alcohol experimentation. Higher reported parental and school connectedness were associated with lower risk of high frequency polysubstance use. Higher reported school connection was also associated with lower risk of polysubstance experimentation. Conclusion Rural substance use prevention programs should begin during middle school, as polysubstance use development is common among rural middle schoolers. These programs should be trauma informed and focus on connectedness as a modifiable factor to reduce risk of polysubstance use development. Trial registration This article does not report results of a health care intervention on human participants.

Background. Organ donors supported by extracorporeal membrane oxygenation (ECMO) have historically been considered high-risk and are judiciously utilized. This study examines transplant outcomes using renal allografts from donors supported on ECMO for nondonation purposes. Methods. Retrospective review of the Gift of Life (Pennsylvania, New Jersey, Delaware) organ procurement organization database, cross-referenced to the Organ Procurement and Transplantation Network database, assessed kidney transplants using donors supported on venoarterial (VA) and venovenous (VV) ECMO for nondonation purposes. Transplants using VA- and VV-ECMO donors were compared with Kidney Donor Profile Index (KDPI)-stratified non-ECMO donors. Regression modeling of the entire ECMO and non-ECMO populations assessed ECMO as predictive of graft survival. Additional regression of the ECMO population alone assessed for donor features associated with graft survival. Results. Seventy-eight ECMO donors yielded 128 kidney transplants (VA: 80, VV: 48). Comparing outcomes using these donors to kidney transplants using organs from KDPI-stratified non-ECMO donors, VA- and VV-ECMO donor grafts conferred similar rates of delayed graft function and posttransplant renal function to KDPI-matched non-ECMO counterparts. VA-ECMO kidneys demonstrated superior graft survival compared with the lowest-quality (KDPI 86%–100%) non-ECMO kidneys and similar graft survival to KDPI

Abstract Amyloid light chain (AL) amyloidosis is a rare and chronic bone marrow disorder. Existing claims data can be used to help understand the real‐world treatment patterns and outcomes of this patient population. Various population‐based administrative databases in Alberta, Canada were queried from 2010 to mid‐2019 to identify cases of AL amyloidosis. Baseline patient and disease characteristics, sequencing of pharmacologic therapies, overall survival, and healthcare resource utilization were evaluated. A total of 215 individuals with AL amyloidosis were included. Among patients diagnosed between 2012 and 2019, 149 (85.1%) initiated first‐line, 67 (38.3%) initiated second‐line, 22 (12.6%) initiated third‐line, and 11 (6.3%) initiated fourth‐line systemic therapy. In the first‐line setting, 99/149 (66.4%) received bortezomib, cyclophosphamide, and dexamethasone (CyBorD) and 21/149 (14.1%) received another bortezomib‐based regimen. Survival from time of diagnosis improved over time, with a median overall survival of 25.8 months (95% CI: 9.8, 57.1) for individuals diagnosed in 2010–2011 versus 52.1 months (95% CI: 25.6, NA) for those diagnosed in 2012–2019. Despite this improvement, the proportion of individuals diagnosed in 2012–2019 who survived beyond five‐years remained low (5‐year survival: 48.4%; 95% CI: 40.9, 57.2) which highlights an unmet need for more efficacious therapies.

Despite a high disease burden, real-world data on treatment patterns in patients with unresectable locally advanced or metastatic urothelial carcinoma (la/mUC) in Canada are limited. This retrospective, longitudinal cohort study describes treatment patterns and survival in a population of patients with de novo unresectable la/mUC from Alberta, Canada, diagnosed between 1 January 2015 and 31 December 2019, followed until mid-2020. The outcomes of interest were systemic therapy treatment patterns and overall survival (OS). Of 206 patients, most (65.0%, n = 134) did not receive any systemic therapies. Of 72 patients (35.0%) who received first-line systemic therapy, the median duration of treatment was 2.8 months (IQR 3.3). Thirty-five patients (48.6% of those who received first-line therapy) received subsequent second-line therapy, for a median of 3.0 months (IQR 3.3). In all patients (n = 206), the median OS from diagnosis was 5.3 months (95% CI, 4.5–7.0). In patients who received treatment, the median OS from the initiation of first-line and second-line systemic therapy was 9.1 (6.4–11.6) and 4.6 months (3.9–19.2), respectively. The majority of patients did not receive first-line systemic therapy, and, in those who did, survival outcomes were poor. This study highlights the significant unmet need for safe and efficacious therapies for patients with la/mUC in Canada.

Real-world evidence surrounding EGFR positive NSCLC patients in Canada is limited. Administrative databases in Alberta, Canada were used to evaluate EGFR testing and mutation prevalence in de novo metastatic NSCLC, as well as the characteristics, treatment patterns, and outcomes of individuals with Exon 19, L858R and Exon20ins mutations. Between 2013–2019, 2974 individuals underwent EGFR testing, of which 451 (15.2%) were EGFR positive. Among EGFR positive individuals, 221 (49.0%) had an Exon 19 mutation, 159 (35.3%) had an L858R mutation, and 18 (4%) had an Exon20ins mutation. The proportion of individuals who initiated 1L systemic therapy was 89.1% for Exon19, 85.5% for L858R, and 72.2% for Exon20ins carriers. The primary front-line systemic therapy was gefitinib or afatinib monotherapy for individuals with Exon 19 (93.4%) and L858R (94.1%) mutations versus platinum combination therapy for individuals with Exon20ins mutations (61.5%). The Exon20ins cohort had worse median overall survival from initiation of 1L systemic therapy (10.5 months [95% CI: 8.0-not estimable]) than the Exon19 (20.6 months [95% CI: 18.4–24.9]), and L858R cohorts (19.1 months [95% CI: 14.5–23.1]). These findings highlight that Exon20ins mutations represent a rare subset of NSCLC in which treatment options are limited and survival outcomes are worse relative to individuals with more common types of EGFR mutations.

Aim: The purpose of this retrospective, population-based, observational cohort analysis was to assess whether routine patient-reported outcomes (PRO) monitoring alone has an impact on real-world overall survival (OS) and hospitalizations among individuals diagnosed with lung, breast or colorectal cancer. The importance of follow-up care in post-PRO data collection was also discussed. Patients & methods: Administrative databases covering 17 cancer centers from Alberta, Canada were queried and individuals ≥18 years old and diagnosed with lung, breast or colorectal cancer from 1 January 2016 to 31 December 2019 were included and followed until 31 December 2020. Patients were stratified by whether they received routine PRO monitoring initiated within 120 days of diagnosis and matched 1:1 with use of propensity scores based on baseline characteristics. OS was assessed from the index date to death, and the respective Kaplan–Meier curves were estimated along with hazard ratios from Cox Proportional Hazard Models. Linear and logistic regression models were used to estimate mean differences and odds ratios (OR) respectively for healthcare resource utilization events including cancer physician visits, emergency department visits and outpatient ambulatory care encounters. Results: 4800 patients were included in each matched cohort. There was no statistically significant difference between PRO monitoring and non-monitoring cohorts in OS (HR = 1.01; 95% CI: 0.93–1.09; p = 0.836) and treatment discontinuation (OR = 0.98; 95% CI: 0.85–1.12; p = 0.75). Median OS was 51.5 months for unmonitored cohort (95% CI: 47.5–NA) versus 50.6 months for monitored cohort (95% CI: 47.6–55.7). Compared with PRO-monitored patients, unmonitored patients were associated with lower hospitalization risks (OR = 1.12; 95% CI: 1.03–1.22; p = 0.01). However, PRO-monitored patients experienced significantly fewer physician visits in comparison to unmonitored patients (MD = -1.036; 95% CI: -1.288 to -0.784, p < 0.001). Conclusion: Our results show that capturing patient-reported symptoms alone reduced the number of physician visits but neither reduced hospitalizations nor improved OS in this real-world cancer population. To drive more meaningful clinical impact, PRO monitoring programs must be met with rigorous follow-up response to the identified symptoms.

ABSTRACT Industrial livestock operations (ILOs), particularly processing facilities, emerged as centers of coronavirus disease 2019 (COVID-19) outbreaks in spring 2020. Confirmed cases of COVID-19 underestimate true prevalence. To investigate the prevalence of antibodies against SARS-CoV-2, we enrolled 279 participants in North Carolina from February 2021 to July 2022: 90 from households with at least one ILO worker (ILO), 97 from high-ILO intensity areas (ILO neighbors [ILON]), and 92 from metropolitan areas (metro). More metro (55.4%) compared to ILO (51.6%) and ILON participants (48.4%) completed the COVID-19 primary vaccination series; the median completion date was more than 4 months later for ILO compared to ILON and metro participants, although neither difference was statistically significant. Participants provided a saliva swab we analyzed for SARS-CoV-2 IgG using a multiplex immunoassay. The prevalence of infection-induced IgG (positive for nucleocapsid and receptor binding domain) was higher among ILO (63%) than ILON (42.9%) and metro (48.7%) participants (prevalence ratio [PR], 1.38; 95% confidence interval [CI], 1.06 to 1.80; reference category ILON and metro combined). The prevalence of infection-induced IgG was also higher among ILO participants than among an Atlanta health care worker cohort (PR, 2.45; 95% CI, 1.80 to 3.33) and a general population cohort in North Carolina (PRs, 6.37 to 10.67). The infection-induced IgG prevalence increased over the study period. Participants reporting not masking in public in the past 2 weeks had higher infection-induced IgG prevalence (78.6%) than participants reporting masking (49.3%) (PR, 1.59; 95% CI, 1.19 to 2.13). Lower education, more people per bedroom, Hispanic/Latino ethnicity, and more contact with people outside the home were also associated with higher infection-induced IgG prevalence. IMPORTANCE Few studies have measured COVID-19 seroprevalence in North Carolina, especially among rural, Black, and Hispanic/Latino communities that have been heavily affected. Antibody results show high rates of COVID-19 among industrial livestock operation workers and their household members. Antibody results add to evidence of health disparities related to COVID-19 by socioeconomic status and ethnicity. Associations between masking and physical distancing with antibody results also add to evidence of the effectiveness of these prevention strategies. Delays in the timing of receipt of COVID-19 vaccination reinforce the importance of dismantling vaccination barriers, especially for industrial livestock operation workers and their household members.

Summary: Deciphering the function of neural circuits can help with the understanding of brain function and treating neurological disorders. Progress toward this goal relies on the development of chronically stable neural interfaces capable of recording and modulating neural circuits with high spatial and temporal precision across large areas of the brain. Advanced innovations in designing high-density neural interfaces for small animal models have enabled breakthrough discoveries in neuroscience research. Developing similar neurotechnology for larger animal models such as nonhuman primates (NHPs) is critical to gain significant insights for translation to humans, yet still it remains elusive due to the challenges in design, fabrication, and system-level integration of such devices. This review focuses on implantable surface neural interfaces with electrical and optical functionalities with emphasis on the required technological features to realize scalable multimodal and chronically stable implants to address the unique challenges associated with nonhuman primate studies.

In this paper, we evaluate the feasibility of using ecological momentary assessment (EMA) to understand urinary (UI) and fecal (FI) incontinence in adults with spina bifida (SB). As part of a larger 30-day prospective study to understand the incontinence in adults with SB (N = 89), participants completed end-of-day EMA diaries assessing the frequency and context of UI and FI. We used these data to assess the method feasibility across six dimensions: (a) compliance, or data entry which is consistent with study protocol and substantially complete; (b) reactivity, or behavior change attributed to study participation; (c) participant acceptability, or convenience and ease of method beneficial to compliance; (d) data capture, or the volume of incontinence behaviors collected; (e) the accuracy of incontinence reports; and f) participant-provided feedback for future studies. Participants were highly compliant with diary entry protocol and schedule: submitting 95.7% (2576/2700) of the expected total daily entries. The average completion time was two minutes. Neither the total number of submissions nor the completion time varied by demographic characteristics or health history. A sufficient volume of incontinence and affective outcomes were captured, with small downtrends in reporting of UI and affect over time. Exit survey recall was highly correlated with diary reports. Participants found the methodology to be acceptable, reported their experiences honestly, enjoyed and felt comfortable participating in the study and would engage in similar study in the future. Accurate information about the daily context of UI and FI is a key factor in the success of intervention or education programs relying on this information. Our findings demonstrate that EMA is a feasible way to describe UI and FI in adults with SB.

Human trabecular meshwork is a sieve-like tissue with large pores, which plays a vital role in aqueous humor outflow. Dysfunction of this tissue can occur, which leads to glaucoma and permanent vision loss. Replacement of trabecular meshwork with a tissue-engineered device is the ultimate objective. This study aimed to create a biomimetic structure of trabecular meshwork using electrospinning. Conventional electrospinning was compared to cryogenic electrospinning, the latter being an adaptation of conventional electrospinning whereby dry ice is incorporated in the fiber collector system. The dry ice causes ice crystals to form in-between the fibers, increasing the inter-fiber spacing, which is retained following sublimation. Structural characterization demonstrated cryo-scaffolds to have closer recapitulation of the trabecular meshwork, in terms of pore size, porosity, and thickness. The attachment of a healthy, human trabecular meshwork cell line (NTM5) to the scaffold was not influenced by the fabrication method. The main objective was to assess cell infiltration. Cryo-scaffolds supported cell penetration deep within their structure after seven days, whereas cells remained on the outer surface for conventional scaffolds. This study demonstrates the suitability of cryogenic electrospinning for the close recapitulation of trabecular meshwork and its potential as a 3D in vitro model and, in time, a tissue-engineered device.

Male dairy calves are often sold from the farm of birth within the first few days of life. Research describing the care of male calves is limited, with an emphasis on parsing differences between the care of male and female calves. The aims of this study were to describe dairy producers’ self-reported care practices for male relative to female calves, as well as their perceptions toward male calf care and welfare. Overall, 24 dairy producers in Ohio and Indiana participated in 1 in-person focus group (n = 10) or were individually interviewed (n = 14) using a semi-structured questionnaire with closed and open-ended questions about neonatal calf care and welfare. Discussions were audio recorded and transcribed verbatim. Data from closed-ended questions are described quantitatively, and thematic analysis was used to identify common themes discussed by producers for open-ended questions. A majority of producers described using different care protocols for male and female dairy calves (64%; 9/14 interview participants). Low input care practices were more commonly consistent between male and female calves, such as colostrum protocols (71%; 10/14 interview participants) and navel care (100%; 14/14 interview participants) than more costly treatments. Of the producers that provided disease prevention products to female calves (79%; 11/14 interview participants), only a few also administered them to male calves (27%; 3/11 interview participants). Three major themes were constructed from the open-ended questions, including factors affecting male dairy calf care, attitude toward male calf welfare, and opportunities to improve male dairy calf welfare. Producers described multiple factors that influenced male calf care on the dairy, such as time and money required to care for them. There was divergence in concern among producers about male calf welfare, with some producers expressing concern, particularly for calves slaughtered soon after birth; yet others described feelings of indifference about the topic. Potential ways to improve male calf welfare, including greater sale prices and the involvement in specialized marketing schemes, were suggested by some producers. These findings highlight potential concerns for male calf welfare and ways to improve future care on dairy farms.

The prognosis for extensive-stage small cell lung cancer (ES-SCLC) is poor. Real-world evidence can highlight the unmet clinical need within this population. We conducted a population-based cohort study of ES-SCLC patients diagnosed in a large Canadian province (2010–2018) using electronic medical records and administrative claims data. In all, 1941 ES-SCLC patients were included, of which 476 (25%) were recurrent cases. Median age at diagnosis was 70 years (range: 39–94) and 50.2% were men. Of the 1941 ES-SCLC patients, 29.5% received chemotherapy and radiotherapy, 17.0% chemotherapy alone, 8.7% radiotherapy alone, and 44.8% received best supportive care. Chemotherapy was initiated by 46.5%, 8.5%, and 1.4% of first-, second-, and third-line patients, with lower uptake for recurrent cases. Median survival from first-, second-, and third-line chemotherapy was 7.82 months (95% CI: 7.50–8.22), 5.72 months (95% CI: 4.90–6.87), and 3.83 months (95% CI: 2.99–4.60). Among patients who received first-line therapy, the 2-year and 5-year survival was 7.3% (95% CI: 5.7–9.2) and 2.9% (95% CI: 1.8–4.5). In conclusion, initiation of first-line treatment in ES-SCLC was low with significant attrition in subsequent lines. These results underscore the need for effective front-line treatments and highlight the potential for novel therapies to improve patient outcomes.

Introduction: Lumbosacral radiculopathy/radiculitis (LR) or “sciatica” is a commonly intractable sequelae of chronic low back pain (LBP), and challenges in the treatment of LR indicate that persistent pain may have both mechanical and neuropathic origins. Mindfulness-based interventions have been demonstrated to be effective tools in mitigating self-reported pain in LBP patients. This paper describes the protocol for a randomized controlled trial (RCT) evaluating the effects of the specific mindfulness-based intervention Mindfulness-Oriented Recovery Enhancement (MORE) on LR symptoms and sequelae, including mental health and physical function. Methods: Participants recruited from the Portland, OR area are screened before completing a baseline visit that includes a series of self-report questionnaires and surface electromyography (sEMG) of the lower extremity. Upon enrollment, participants are randomly assigned to the MORE (experimental) group or treatment as usual (control) group for 8 weeks. Self-reported assessments and sEMG studies are repeated after the intervention is complete for pre/post-intervention comparisons. The outcome measures evaluate self-reported pain, physical function, quality of life, depression symptoms, trait mindfulness, and reinterpretation of pain, with surface electromyography (sEMG) findings evaluating objective physical function in patients with LR. To our knowledge, this is the first trial to date using an objective measure, sEMG, to evaluate the effects of a mindfulness-based intervention on LR symptoms. Hypotheses: We hypothesize that MORE will be effective in improving self-reported pain, physical function, quality of life, depression symptoms, mindfulness, and reinterpretation of pain scores after 8 weeks of mindfulness training as compared to treatment as usual. Additionally, we hypothesize that individuals in the MORE group with abnormal sEMG findings at baseline will have improved sEMG findings at their 8-week follow-up visit.

Summary: SARS-CoV-2-infected subjects are generally asymptomatic during initial viral replication but may suffer severe immunopathology after the virus has receded and monocytes have infiltrated the airways. In bronchoalveolar lavage fluid from severe COVID-19 patients, monocytes express mRNA encoding inflammatory mediators and contain SARS-CoV-2 transcripts. We leverage a human small airway model of infection and inflammation, whereby primary blood monocytes transmigrate across SARS-CoV-2-infected lung epithelium to characterize viral burden, gene expression, and inflammatory mediator secretion by epithelial cells and monocytes. In this model, lung-infiltrating monocytes acquire SARS-CoV-2 from the epithelium and upregulate expression and secretion of inflammatory mediators, mirroring in vivo data. Combined use of baricitinib (Janus kinase inhibitor) and remdesivir (nucleoside analog) enhances antiviral signaling and viral clearance by SARS-CoV-2-positive monocytes while decreasing secretion of proneutrophilic mediators associated with acute respiratory distress syndrome. These findings highlight the role of lung-infiltrating monocytes in COVID-19 pathogenesis and their importance as a therapeutic target.

Abstract Background Factors that are prognostic of early discontinuation of adjuvant chemotherapy among stage III colon cancer patients have yet to be described. To address this gap, a survey of medical oncologists and a systematic review and meta‐analysis were conducted. Methods A survey was distributed in March 2019 to medical oncologists who treat colon cancer within Alberta, Canada. Clinicians were asked to rank the prognostic importance of a set of variables using a Likert scale and agreement was quantified using a weighted Cohen's kappa. In addition, we systematically searched four databases up to July 2019. Meta‐analyses were conducted using a random‐effects model. Results Of the 25 clinicians who were sent the survey, 14 responded. Overall, there was no agreement regarding which variables were prognostic of early discontinuation (weighted Cohen's kappa = 0.12; 95% CI = 0.05‐0.18). From an initial 3927 articles, 18 investigations were identified for inclusion in our review. Based upon evidence from both the survey and the systematic review, the following four variables were identified as being prognostic of early discontinuation: (a) comorbidity (OR2+ vs 0 = 1.53; 95% CI = 1.30‐1.79); (b) performance status (ORECOG 2+ vs 0‐1 = 1.33; 95%CI = 1.07‐1.65); (c) T stage (ORT4 vs T1‐2 = 1.57; 95% CI = 0.99‐2.50); and (d) chemotherapy regimen (estimates not pooled due to heterogeneity). In addition to these factors, there was some suggestion that age, marital status/social support, muscle mass, N stage, and tumor grade had prognostic value. Conclusions Current evidence is heterogeneous and limited. Additional research is needed to confirm our findings and to explore additional prognostic factors.

The study purpose was to assess, in a U.S. probability sample of women, the specific ways women have discovered to experience pleasure from anal touch. Through qualitative pilot research with women that informed the development of the survey instrument used in this study, we identified three previously unnamed, but distinct, anal touch techniques that many women find pleasurable and that expand the anal sexual repertoire beyond the more commonly studied anal intercourse behaviors: Anal Surfacing, Anal Shallowing, and Anal Pairing. This study defines each technique and describes its prevalence among U.S. adult women. Weighted frequencies were drawn from the Second OMGYES Pleasure Report-a cross-sectional, online, national probability survey of 3017 American women's (age 18-93) sexual experiences and discoveries. Participants were recruited via the Ipsos KnowledgePanel®. Data suggest that 40% of women find 'Anal Surfacing' pleasurable: sexual touch by a finger, penis, or sex toy on and around the anus. Approximately 35% of women have experienced pleasure using 'Anal Shallowing': penetrative touch by a finger, penis, or sex toy just inside the anal opening, no deeper than a fingertip/knuckle. Finally, 40% of women make other forms of sexual touch more pleasurable using 'Anal Pairing': touch on or inside the anus that happens at the same time as other kinds of sexual touch such as vaginal penetration or clitoral touching. These data provide techniques that women can and do use to explore the anus as a pleasurable region for touch-which can enable women to better identify their own preferences, communicate about them and advocate for their sexual pleasure.

Background: The incidence of early-onset (

Abstract Background Several reviews have noted shortcomings regarding the quality and reporting of network meta-analyses (NMAs). We suspect that this issue may be partially attributable to limitations in current NMA software which do not readily produce all of the output needed to satisfy current guidelines. Results To better facilitate the conduct and reporting of NMAs, we have created an R package called “BUGSnet” (Bayesian inference Using Gibbs Sampling to conduct a Network meta-analysis). This R package relies upon Just Another Gibbs Sampler (JAGS) to conduct Bayesian NMA using a generalized linear model. BUGSnet contains a suite of functions that can be used to describe the evidence network, estimate a model and assess the model fit and convergence, assess the presence of heterogeneity and inconsistency, and output the results in a variety of formats including league tables and surface under the cumulative rank curve (SUCRA) plots. We provide a demonstration of the functions contained within BUGSnet by recreating a Bayesian NMA found in the second technical support document composed by the National Institute for Health and Care Excellence Decision Support Unit (NICE-DSU). We have also mapped these functions to checklist items within current reporting and best practice guidelines. Conclusion BUGSnet is a new R package that can be used to conduct a Bayesian NMA and produce all of the necessary output needed to satisfy current scientific and regulatory standards. We hope that this software will help to improve the conduct and reporting of NMAs.

Glaucoma is the second leading cause of irreversible blindness worldwide. Glaucoma is a progressive optic neuropathy in which permanent loss of peripheral vision results from neurodegeneration in the optic nerve head. The trabecular meshwork is responsible for regulating intraocular pressure, which to date, is the only modifiable risk factor associated with the development of glaucoma. Lowering intraocular pressure reduces glaucoma progression and current surgical approaches for glaucoma attempt to reduce outflow resistance through the trabecular meshwork. Many surgical approaches use minimally invasive glaucoma surgeries (MIGS) to control glaucoma. In this progress report, biomaterials currently employed to treat glaucoma, such as MIGS, and the issues associated with them are described. The report also discusses innovative biofabrication approaches that aim to revolutionise glaucoma treatment through tissue engineering and regenerative medicine (TERM). At present, there are very few applications targeted towards TM engineering in vivo, with a great proportion of these biomaterial structures being developed for in vitro model use. This is a consequence of the many anatomical and physiological attributes that must be considered when designing a TERM device for microscopic tissues, such as the trabecular meshwork. Ongoing advancements in TERM research from multi-disciplinary teams should lead to the development of a state-of-the-art device to restore trabecular meshwork function and provide a bio-engineering solution to improve patient outcomes.

Non-human primates (NHPs) are precious resources for cutting-edge neuroscientific research, including large-scale viral vector-based experimentation such as optogenetics. We propose to improve surgical outcomes by enhancing the surgical preparation practices of convection-enhanced delivery (CED), which is an efficient viral vector infusion technique for large brains such as NHPs’. Here, we present both real-time and next-day MRI data of CED in the brains of ten NHPs, and we present a quantitative, inexpensive, and practical bench-side model of the in vivo CED data. Our bench-side model is composed of food coloring infused into a transparent agar phantom, and the spread of infusion is optically monitored over time. Our proposed method approximates CED infusions into the cortex, thalamus, medial temporal lobe, and caudate nucleus of NHPs, confirmed by MRI data acquired with either gadolinium-based or manganese-based contrast agents co-infused with optogenetic viral vectors. These methods and data serve to guide researchers and surgical team members in key surgical preparations for intracranial viral delivery using CED in NHPs, and thus improve expression targeting and efficacy and, as a result, reduce surgical risks.

The study purpose was to assess, in a U.S. probability sample of women, the specific ways women have discovered to make vaginal penetration more pleasurable. Through qualitative pilot research with women that informed the development of the survey instrument used in this study, we identified four previously unnamed, but distinct, techniques women use to make vaginal penetration more pleasurable: Angling, Rocking, Shallowing and Pairing. This study defines each technique and describes its prevalence among U.S. adult women. Weighted frequencies were drawn from the Second OMGYES Pleasure Report-a cross-sectional, online, national probability survey of 3017 American women's (age 18-93) sexual experiences and discoveries. Participants were recruited via the Ipsos KnowledgePanel®. Data suggest that 87.5% of women make vaginal penetration more pleasurable using 'Angling': rotating, raising, or lowering the pelvis/hips during penetration to adjust where inside the vagina the toy or penis rubs and what it feels like. Approximately 76% of women make vaginal penetration more pleasurable using 'Rocking': the base of a penis or sex toy rubbing against the clitoris constantly during penetration, by staying all the way inside the vagina rather than thrusting in and out. About 84% of women make vaginal penetration more pleasurable using 'Shallowing': penetrative touch just inside of the entrance of the vagina-not on the outside, but also not deep inside-with a fingertip, sex toy, penis tip, tongue, or lips. Finally, 69.7% of women orgasm more often or make vaginal penetration more pleasurable using 'Pairing': when a woman herself (Solo Pairing) or her partner (Partner Pairing) reaches down to stimulate her clitoris with a finger or sex toy at the same time as her vagina is being penetrated. These data provide techniques that are at women's disposal to make penetration more pleasurable-which can enable women to better identify their own preferences, communicate about them and advocate for their sexual pleasure.

The popularity of mindset theory has resulted in a surge of mindset interventions in schools. However, with increased popularity, there is the potential for misunderstandings and hesitations about what a growth mindset fully entails. Therefore, we sought to disentangle which components of growth mindset messages pre-service teachers find hard to accept alongside their level of agreement with growth mindset questionnaire items. We used a descriptive design with both quantitative and qualitative data to explore 182 pre-service teachers’ responses to growth mindset messages. The results of this study suggest that pre-service teachers hold a growth mindset. However, despite strong quantitative endorsements, in the qualitative analyses we determined three ways in which participants found a growth mindset hard to accept: (1) the notion of mindset theory itself, (2) the level of growth, (3) and the necessary actions behind having a growth mindset. The findings of this study suggest we need to pay close attention to false growth mindsets in theory and practice.

Background: Due to their history of renal disease and exposure to immunosuppression, kidney transplant recipients with a failing graft may be at higher risk of adverse outcomes compared to nontransplant controls. Understanding the burden of disease in transplant recipients may inform treatment decisions of people whose native kidneys are failing and may be eligible for a transplant. Objective: To compare mortality and morbidity in kidney transplant recipients with a failing graft to matched nontransplant controls. Design: Retrospective cohort study. Setting: Alberta, Canada. Patients: Kidney transplant recipients with a failing graft were identified as having at least 2 estimated glomerular filtration rate (eGFR) measurements between 15-30 mL/min/1.73 m 2 (90-365 days apart). We also identified nontransplant controls with a similar degree of kidney dysfunction. Measurements: Mortality and hospitalization. Methods: We propensity-score matched 520 kidney transplant recipients with a failing graft to 520 nontransplant controls. Results: The median age of the matched cohort was 57 years and 40% were women. Compared to matched nontransplant controls, recipients with a failing graft had a higher hazard of death (hazard ratio, 1.54; 95% confidence interval [CI], 1.28-1.85; p < .001) and a higher rate of all-cause hospitalization (rate ratio, 1.67; 95% CI, 1.42-1.97; p < .001). Kidney transplant recipients also had a higher rate of several cause-specific hospitalizations including genitourinary, cardiovascular, and infectious causes. Limitations: Observational design with the risk of residual confounding. Conclusions: A failing kidney transplant is associated with an increased burden of mortality and morbidity beyond chronic kidney disease. This information may assist the discussion of prognosis in kidney transplant recipients with a failing graft and the design of strategies to minimize risks.

Glaucoma is linked to raised intraocular pressure (IOP). The trabecular meshwork (TM) plays a major role in regulating IOP by enabling outflow of aqueous humor from the eye through its complex 3D structure. A lack of therapies targeting the dysfunctional TM highlights the need to develop biomimetic scaffolds that provide 3D in vitro models for glaucoma research or as implantable devices to regenerate TM tissue. To artificially mimic the TM’s structure, we assessed methods for its decellularization and outline an optimized protocol for cell removal and structural retention. Using bovine TM, we trialed 2 lysing agents—Trypsin (0.05% v/v) and Ammonium Hydroxide (NH4OH; 2% v/v). Twenty-four hours in Trypsin caused significant structural changes. Shorter exposure (2 h) reduced this disruption whilst decellularizing the tissue (dsDNA 26 ± 14 ng/mL (control 1970 ± 146 ng/mL)). In contrast, NH4OH lysed all cells (dsDNA 25 ± 21 ng/mL), and the TM structure remained intact. For human TM, 2% v/v NH4OH similarly removed cells (dsDNA 52 ± 4 ng/mL (control 1965 ± 233 ng/mL)), and light microscopy and SEM presented no structural damage. X-ray computed tomography enabled a novel 3D reconstruction of decellularized human TM and observation of the tissue’s intricate architecture. This study provides a new, validated method using NH4OH to decellularize delicate human TM without compromising tissue structure.

Abstract Cardiovascular disease has been identified as one of the late complications of cancer therapy. The purpose of this study was to quantify the long‐term risk of cardiovascular mortality among lymphoma survivors relative to that of the general population. A systematic review and meta‐analysis were conducted. Articles were identified in November 2016 by searching EMBASE, MEDLINE, and CINAHL databases. Observational studies were included if they assessed cardiovascular mortality in patients with lymphoma who survived for at least 5 years from time of diagnosis or if they had a median follow‐up of 10 years. A pooled standardized mortality ratio (SMR) was estimated using a DerSimonian and Laird random‐effects model. The Q and I2 statistics were used to assess heterogeneity. Funnel plots and Begg's and Egger's tests were used to evaluate publication bias. Of the 7450 articles screened, 27 studies were included in the systematic review representing 46 829 Hodgkin and 14 764 non‐Hodgkin lymphoma survivors. The pooled number of deaths attributable to cardiovascular disease among Hodgkin and non‐Hodgkin disease was estimated to be 7.31 (95% CI: 5.29‐10.10; I2 = 95.4%) and 5.35 (95% CI: 2.55‐11.24; I2 = 94.0%) times that of the general population, respectively. This association was greater among Hodgkin lymphoma survivors treated before the age of 21 (pooled SMR = 13.43; 95% CI: 9.22‐19.57; I2 = 78.9%). There was a high degree of heterogeneity and a high risk of bias due to confounding in this body of literature. Lymphoma survivors have an increased risk of fatal cardiovascular events compared to the general population and should be targeted for cardiovascular screening and prevention campaigns.

Abstract Background and aims Lymphoma patients are frequently treated with cancer therapies that may increase the risk of adverse health outcomes later in life, including cardiovascular disease (CVD) mortality. We sought to investigate the long‐term risk of CVD incidence in this survivor population relative to the general population to quantify this health burden. Methods A systematic review and meta‐analysis was conducted using EMBASE, MEDLINE, and CINAHL databases, from date of inception to November 2016, with additional searches completed through June 2018. Included reports were observational studies assessing CVD incidence in patients of either Hodgkin or non‐Hodgkin lymphoma (HL, NHL) who survived for at least 5 years from the time of diagnosis or if the study had a median follow‐up of 10 years. Meta‐analyses were performed using random effects models, and subgroup analyses were conducted to determine the incidence of specific CVD subtypes (coronary heart disease, pericardial disease, valvular heart disease, myocardial disease, cardiac dysrhythmia, and cerebrovascular disease). Heterogeneity was assessed using I2 statistics and prediction intervals. Results Of the 7734 studies identified, 22 studies were included in this review, representing 32 438 HL and NHL survivors. Relative to the general population, lymphoma survivors had statistically significant two to threefold increases in the risk for nearly all subtypes of CVD examined. Lymphoma survivors appeared to be particularly susceptible to pericardial diseases (HL: 10.67, 95% confidence interval (CI), 7.75‐14.69; NHL: 4.70, 95% CI, 2.08‐10.61) and valvular diseases (HL: 13.10, 95% CI, 7.41‐23.16; NHL: 3.76, 95% CI, 2.12‐6.66). Although the 95% CIs were suggestive of increased risks, the 95% prediction intervals often included the null, reflecting the high heterogeneity of the estimates. Conclusion Given the suggested increased risks of cardiovascular outcomes in lymphoma survivor populations relative to the general population, tailored screening and prevention programmes may be warranted to offset the future burden of disease.

Physical activity is associated with a lower risk of breast, colon, and endometrial cancer. Epigenetic mechanisms such as changes in DNA methylation may help to explain these protective effects. We assessed the impact of a one year aerobic exercise intervention on DNA methylation biomarkers believed to play a role in carcinogenesis. The Alberta Physical Activity and Breast Cancer Prevention (ALPHA) Trial was a two-armed randomized controlled trial in 320 healthy, inactive, postmenopausal women with no history of cancer. In an ancillary analysis, frozen blood samples (n = 256) were reassessed for levels of DNA methylation within LINE-1 and Alu repeats as well as within the promoter regions of APC, BRCA1, RASSF1, and hTERT genes. Differences between the exercise and control arm at 12-months, after adjusting for baseline values, were estimated within an intent-to-treat and per-protocol analysis using linear regression. No significant differences in DNA methylation between the exercise and control arms were observed. In an exploratory analysis, we found that the prospective change in estimated VO2max was negatively associated with RASSF1 methylation in a dose-response manner (p-trend = 0.04). A year-long aerobic exercise intervention does not affect LINE-1, Alu, APC, BRCA1, RASSF1, or hTERT methylation in healthy, inactive, postmenopausal women. Changes in DNA methylation within these genomic regions may not mediate the association between physical activity and cancer in healthy postmenopausal women. Additional research is needed to validate our findings with RASSF1 methylation. TRIAL REGISTRATION:ClinicalTrials.gov NCT00522262.

DNA vaccine-induced immunity can be enhanced by the co-delivery of synthetic gene-encoding molecular adjuvants. Many of these adjuvants have included cytokines, chemokines or co-stimulatory molecules that have been demonstrated to enhance vaccine-induced immunity by increasing the magnitude or type of immune responses and/or protective efficacy. In this way, through the use of adjuvants, immune responses can be highly customizable and functionally tailored for optimal efficacy against pathogen specific (i.e., infectious agent) or non-pathogen (i.e., cancer) antigens. In the novel study presented here, we examined the use of cellular transcription factors as molecular adjuvants. Specifically the co-delivery of (a) RelA, a subunit of the NF-κB transcription complex or (b) T-bet, a Th1-specific T box transcription factor, along with a prototypical DNA vaccine expressing HIV-1 proteins was evaluated. As well, all of the vaccines and adjuvants were administered to mice using in vivo electroporation (EP), a technology demonstrated to dramatically increase plasmid DNA transfection and subsequent transgene expression with concomitant enhancement of vaccine induced immune responses. As such, this study demonstrated that co-delivery of either adjuvant resulted in enhanced T and B cell responses, specifically characterized by increased T cell numbers, IFN-γ production, as well as enhanced antibody responses. This study demonstrates the use of cellular transcription factors as adjuvants for enhancing DNA vaccine-induced immunity.

Numerous studies have suggested that an effective Hepatitis C Virus (HCV) vaccine must induce strong cytotoxic and IFN-γ+ T cell responses targeting the non-structural region of the virus. Most importantly, these responses must be able to migrate into and remain functional within the liver, an organ known to cause T cell tolerance. Using three novel HCV DNA vaccines encoding non-structural proteins NS4B, NS5A and NS5B, we assessed the ability of peripheral immunization to induce functional intrahepatic immunity both in the presence and absence of cognate HCV antigen expression within the liver. We have shown that these constructs induced potent HCV-specific CD4+ and CD8+ T cell responses in the spleen of C57BL/6 mice and that these responses were detected within the liver following peripheral immunization. Additionally, using a transfection method to express HCV antigen within the liver, we showed that intrahepatic HCV-specific T cells remained highly functional within the liver and retained the ability to become highly activated as evidenced by upregulation of IFN-γ and clearance of HCV protein expressing hepatocytes. Taken together, these findings suggest that peripheral immunization can induce potent HCV-specific T cell responses able to traffic to and function within the tolerant environment of the liver.

While HIV-1-specific cellular immunity is thought to be critical for the suppression of viral replication, the correlates of protection have not yet been determined. Rhesus macaques (RM) are an important animal model for the study and development of vaccines against HIV/AIDS. Our laboratory has helped to develop and study DNA-based vaccines in which recent technological advances, including genetic optimization and in vivo electroporation (EP), have helped to dramatically boost their immunogenicity. In this study, RMs were immunized with a DNA vaccine including individual plasmids encoding SIV gag, env, and pol alone, or in combination with a molecular adjuvant, plasmid DNA expressing the chemokine ligand 5 (RANTES), followed by EP. Along with standard immunological assays, flow-based activation analysis without ex vivo restimulation and high-throughput gene expression analysis was performed. Strong cellular immunity was induced by vaccination which was supported by all assays including PBMC microarray analysis that identified the up-regulation of 563 gene sequences including those involved in interferon signaling. Furthermore, 699 gene sequences were differentially regulated in these groups at peak viremia following SIVmac251 challenge. We observed that the RANTES-adjuvanted animals were significantly better at suppressing viral replication during chronic infection and exhibited a distinct pattern of gene expression which included immune cell-trafficking and cell cycle genes. Furthermore, a greater percentage of vaccine-induced central memory CD8+ T-cells capable of an activated phenotype were detected in these animals as measured by activation analysis. Thus, co-immunization with the RANTES molecular adjuvant followed by EP led to the generation of cellular immunity that was transcriptionally distinct and had a greater protective efficacy than its DNA alone counterpart. Furthermore, activation analysis and high-throughput gene expression data may provide better insight into mechanisms of viral control than may be observed using standard immunological assays.