An Age-Period-Cohort Analysis of Cardiovascular Disease Mortality in the United States from 1999 to 2018.

BACKGROUND: Although cardiovascular disease mortality rates in the United States declined from the 1970s to 2010s, they have now plateaued. The independent effects of age, period, and birth year (cohort) on cardiovascular disease mortality have not previously been defined. METHODS: We used data from the Centers for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research to examine the effects of age, period, and cohort on cardiovascular disease mortality among individuals aged 20-84 years from 1999 to 2018, prior to the onset of the coronavirus disease 2019 pandemic. Age effects were described as cardiovascular disease-related mortality rates in each 5-year age group adjusted for year of death (period) and year of birth (cohort). Period and cohort effects were quantified as adjusted rate ratios (RRs) comparing cardiovascular disease mortality rates in each period and cohort to the reference periods and reference cohort (ie, 1919 birth cohort), respectively. RESULTS: Between 1999 to 2018, there were 10,404,327 cardiovascular disease deaths among US adults. In each individual birth cohort, the age-specific cardiovascular disease mortality rates were stable between ages 20 through 39 years. Age-specific rates were higher for each year older between ages 40 through 84 years adjusting for period effects. The period cardiovascular disease mortality rates were lower in later periods (2004-2008 period RR 0.87, 95% confidence interval [CI] 0.85 to 0.88; 2009-2013 period RR 0.78, 95% CI 0.76 to 0.80) compared with the reference period (1999 to 2003) and plateaued thereafter. The cohort cardiovascular disease mortality rates were progressively lower in more recent birth cohorts (1924 birth cohort RR 0.85, 95% CI 0.83 to 0.87; 1974 birth cohort RR 0.29, 95% CI 0.27 to 0.32) compared with the reference cohort (1919 cohort) and plateaued thereafter. CONCLUSION: Although cardiovascular disease mortality rates declined rapidly among those born between 1919 and 1974, improvements plateaued in birth cohorts thereafter even adjusted for period effects.

Career outlook and satisfaction in the presence of workload intensification-a survey of early career pharmacists.

BACKGROUND: The demographics of the pharmacy workforce is changing with an increased proportion of pharmacists less than 30 years old (early career pharmacists-ECPs). In parallel, the profession has experienced workload intensification and workforce attrition. It is important to understand ECPs career satisfaction to retain this section of the pharmacy profession. OBJECTIVES: This study aimed to collect data on the current career satisfaction of ECPs, and identify workplace factors that were most important to this group. Further, to use these findings to inform sector recommendations. METHODS: A steering group of ECPs in Aotearoa New Zealand developed a survey based on one used previously. An invitation email was sent to all pharmacists who had been registered for less than 10 years and were members of the Pharmaceutical Society of New Zealand. RESULTS: A total of 1418 ECPs were identified and invited to participate, and responses were received by 416 of these. While 90% believe that they are making a useful contribution to the health of their patients, over half are unhappy and discontented, with over a third dissatisfied with their careers. A large proportion (44%) were considering leaving the profession in the next 5 years. The top three factors for career satisfaction were ability to progress and learn new skills, the people they work with, and the remuneration. CONCLUSIONS: This study provides a starting point for understanding the current environment and level of dissatisfaction of young pharmacists. There are several areas of concern that need to be addressed if a strong vibrant viable pharmacy profession is to be achieved.

Stress, burnout, and the need for support: a survey of early career pharmacists.

BACKGROUND: Burnout of health professionals is of concern internationally and the pharmacy profession is no exception. The period of transition from University to autonomous practitioner is recognized to be challenging and these Early Career Pharmacists (ECPs), may be at increased risk of stress and burnout. OBJECTIVES: This study aimed to collect data on the current extent of self-identified stress and burnout, of ECPs, and to (i) identify contributing factors and (ii) identify strategies used to manage this stress. METHODS: This study was conducted in Aotearoa New Zealand and was based on a survey used previously in Australia. A national database was used to identify all pharmacists who had been registered for <10 years. The survey was emailed to each pharmacist, and was further advertised through social media platforms. RESULTS: A total of 1418 ECPs were identified and invited to participate, and responses were received by 416 of these. The majority of respondents were female (73%) and community pharmacy based (79%). A vast majority (89%) indicated that a normal working day was at least moderately stressful with 79% indicating a level of burnout. These reflect a combination of "external" stressors, i.e. negative patient interactions, staff shortages, and "internal" stressors, i.e. fear of making a mistake, adjustment from University to working life. CONCLUSIONS: Stress and burnout appear to be widespread in the ECPs, this study highlights areas of concern and potential support where efforts can be focussed to create a more sustainable working environment.

Comprehensive sub-mitochondrial protein map of the parasitic protist Trypanosoma brucei defines critical features of organellar biology.

We have generated a high-confidence mitochondrial proteome (MitoTag) of the Trypanosoma brucei procyclic stage containing 1,239 proteins. For 337 of these, a mitochondrial localization had not been described before. We use the TrypTag dataset as a foundation and take advantage of the properties of the fluorescent protein tag that causes aberrant but fortuitous accumulation of tagged matrix and inner membrane proteins near the kinetoplast (mitochondrial DNA). Combined with transmembrane domain predictions, this characteristic allowed categorization of 1,053 proteins into mitochondrial sub-compartments, the detection of unique matrix-localized fucose and methionine synthesis, and the identification of new kinetoplast proteins, which showed kinetoplast-linked pyrimidine synthesis. Moreover, disruption of targeting signals by tagging allowed mapping of the mode of protein targeting to these sub-compartments, identifying a set of C-tail anchored outer mitochondrial membrane proteins and mitochondrial carriers likely employing multiple target peptides. This dataset represents a comprehensive, updated mapping of the mitochondrion.

Cardiac Structure and Function Phenogroups and Risk of Incident Heart Failure (from the Multi-ethnic Study of Atherosclerosis).

Indices of cardiac structure and function, such as left ventricular (LV) mass and ejection fraction, have been associated with risk of incident heart failure (HF), but the clinical relevance of data-driven grouping of a comprehensive set of cardiac parameters is unclear. In Multi-Ethnic Study of Atherosclerosis participants, latent class analysis was applied in the sample stratified by gender to define phenogroups on the basis of cardiovascular magnetic resonance imaging parameters of right ventricular and LV structure and function at baseline. Cox proportional hazard models in gender-stratified analyses were used to assess the association between phenogroup membership and risk of HF subtypes adjusting for potential confounders. In the 4,204 participants (mean age 61 ± 10 years, 53% women), the mean follow-up time was 14 ± 4 years for men and 15 ± 4 years for women. For both genders, 4 distinct phenogroups were identified: (1) ideal cardiac mechanics; (2) higher output/hypertrophied LV; (3) impaired ejection fraction/dilated LV; and (4) higher output/hyperdynamic (LV). Men in phenogroups 4 (hazard ratio [HR] 2.91, 95% confidence interval [CI] 1.60 to 5.31, p = 0.0005), 3 (HR 3.52, 95% CI 1.90 to 6.53, p <0.0001), and 2 (HR 3.49, 95% CI 1.94 to 6.28, p <0.0001) had higher rates of incident HF than did men in phenogroup 1, in fully adjusted models. No significant associations were found between phenogroup membership and incident HF in women. In conclusion, phenogroup membership based on cardiac structure and function in men was significantly associated with incident HF. Integration of cardiac magnetic resonance imaging variables may help identify differential risk for HF in men.

Attendance at Supervised Exercise Sessions and Walking Outcomes in Peripheral Artery Disease: Results From 2 Randomized Clinical Trials.

Background Supervised exercise therapy (SET) is the first-line therapy for walking impairment in peripheral artery disease (PAD). This study evaluated the association between attendance at SET and improved walking performance, compared with a control group, in PAD. Methods and Results Data from 2 randomized clinical trials of SET for PAD were combined. In each trial, participants were randomized to 3 times weekly supervised treadmill exercise or an attention control group for 6 months (maximum, 77 exercise sessions). Participants randomized to SET were categorized into tertiles, according to the proportion of exercise sessions they attended. Results adjusted for age, sex, race, baseline walking performance, comorbidities, and other potential confounders. A total of 272 participants with PAD (mean age, 67.9±9.3 years; 44% women; 61% Black race) were included. For participants randomized to SET, tertiles of attendance rates at exercise sessions were as follows: 11% to 68% (N=45), 69% to <85% (N=46), and ≥85% (N=46). Compared with control, mean improvement in 6-minute walk was significantly greater in each SET tertile: mean (95% CI) for tertile 1, 27.9 m (1.3-54.4 m; P=0.04), tertile 2, 38.2 m (12.2-64.2 m; P=0.001), and tertile 3, 56.9 m (29.9-83.8 m; P<0.0001). Among participants randomized to SET, greater SET attendance was associated with greater improvement in 6-minute walk distance (overall P for trend=0.025). Compared with control, improvement in maximal treadmill walking time was greater in each SET attendance tertile: tertile 1 (3.3 minutes [95% CI, 1.7-4.8 minutes]; P<0.0001), tertile 2 (3.8 minutes [95% CI, 2.3-5.3 minutes]; P<0.0001), and tertile 3 (5.4 minutes [95% CI, 3.9-7.0 minutes]; P:<0.0001). Among participants randomized to SET, greater attendance at SET was not significantly associated with greater improvement in maximal treadmill walking time (overall P for trend=0.064). Conclusions Among people with PAD randomized to SET, better attendance at exercise sessions was associated with significantly greater 6-minute walk improvement. Among all participants with PAD, even relatively low SET attendance was associated with significantly greater improvement in walking performance, compared with a control group who did not exercise. Registration URL: https://clinicaltrials.gov/ct2/show/NCT01408901. URL: https://clinicaltrials.gov/ct2/show/NCT00106327.

Euglena International Network (EIN): Driving euglenoid biotechnology for the benefit of a challenged world.

Euglenoids (Euglenida) are unicellular flagellates possessing exceptionally wide geographical and ecological distribution. Euglenoids combine a biotechnological potential with a unique position in the eukaryotic tree of life. In large part these microbes owe this success to diverse genetics including secondary endosymbiosis and likely additional sources of genes. Multiple euglenoid species have translational applications and show great promise in production of biofuels, nutraceuticals, bioremediation, cancer treatments and more exotically as robotics design simulators. An absence of reference genomes currently limits these applications, including development of efficient tools for identification of critical factors in regulation, growth or optimization of metabolic pathways. The Euglena International Network (EIN) seeks to provide a forum to overcome these challenges. EIN has agreed specific goals, mobilized scientists, established a clear roadmap (Grand Challenges), connected academic and industry stakeholders and is currently formulating policy and partnership principles to propel these efforts in a coordinated and efficient manner.

Effects of Walking Exercise at a Pace With Versus Without Ischemic Leg Symptoms on Functional Performance Measures in People With Lower Extremity Peripheral Artery Disease: The LITE Randomized Clinical Trial.

Background In people with peripheral artery disease, post hoc analyses of the LITE (Low Intensity Exercise Intervention in Peripheral Artery Disease) randomized trial were conducted to evaluate the effects of walking exercise at a pace inducing ischemic leg symptoms on walking velocity and the Short Physical Performance Battery, compared with walking exercise without ischemic leg symptoms and compared with a nonexercising control group. Methods and Results Participants with peripheral artery disease were randomized to: home-based walking exercise that induced ischemic leg symptoms; home-based walking exercise conducted without ischemic leg symptoms; or a nonexercising control group for 12 months. Outcomes were change of walking velocity over 4 m and change of the Short Physical Performance Battery (0-12, with 12=best) at 6- and 12-month follow-up. A total of 264 participants (48% women, 61% Black race) were included. Compared with walking exercise without ischemic symptoms, walking exercise that induced ischemic symptoms improved change in usual-paced walking velocity over 4 m at 6-month (0.056 m/s [95% CI, 0.019-0.094 m/s]; P<0.01) and 12-month follow-up (0.084 m/s [95% CI, 0.049-0.120 m/s]; P<0.01), change in fast-paced of walking velocity over 4 m at 6-month follow-up (P=0.03), and change in the Short Physical Performance Battery at 12-month follow-up (0.821 [95% CI, 0.309-1.334]; P<0.01). Compared with control, walking exercise at a pace inducing ischemic symptoms improved change in usual-paced walking velocity over 4 m at 6-month follow-up (0.066 m/s [95% CI, 0.021-0.111 m/s]; P<0.01). Conclusions In people with peripheral artery disease, those who walked for exercise at a comfortable pace without ischemic leg symptoms slowed their walking speed during daily life and worsened the Short Physical Performance Battery score, a potentially harmful effect, compared with people who walked for exercise at a pace inducing ischemic leg symptoms. Compared with a control group who did not exercise, home-based walking exercise at a pace inducing ischemic leg symptoms significantly improved change of walking velocity over 4 m at 6-month follow-up, but this benefit did not persist at 12-month follow-up. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02538900.

New strategies and therapies for the prevention of heart failure in high-risk patients.

Despite declines in total cardiovascular mortality rates in the United States, heart failure (HF) mortality rates as well as hospitalizations and readmissions have increased in the past decade. Increases have been relatively higher among young and middle-aged adults (<65 years). Therefore, identification of individuals HF at-risk (Stage A) or with pre-HF (Stage B) before the onset of overt clinical signs and symptoms (Stage C) is urgently needed. Multivariate risk models (e.g., Pooled Cohort Equations to Prevent Heart Failure [PCP-HF]) have been externally validated in diverse populations and endorsed by the 2022 HF Guidelines to apply a risk-based framework for the prevention of HF. However, traditional risk factors included in the PCP-HF model only account for half of an individual's lifetime risk of HF; novel risk factors (e.g., adverse pregnancy outcomes, impaired lung health, COVID-19) are emerging as important risk-enhancing factors that need to be accounted for in personalized approaches to prevention. In addition to determining the role of novel risk-enhancing factors, integration of social determinants of health (SDoH) in identifying and addressing HF risk is needed to transform the current clinical paradigm for the prevention of HF. Comprehensive strategies to prevent the progression of HF must incorporate pharmacotherapies (e.g., sodium glucose co-transporter-2 inhibitors that have also been termed the "statins" of HF prevention), intensive blood pressure lowering, and heart-healthy behaviors. Future directions include investigation of novel prediction models leveraging machine learning, integration of risk-enhancing factors and SDoH, and equitable approaches to interventions for risk-based prevention of HF.

Using psycho-behavioral phenotyping for overweight and obesity: Confirmation of the 6 factor questionnaire.

Objective: Questionnaires that assess dietary habits, eating behaviors, and relevant psychosocial constructs are routinely used in obesity research and clinical practice. The 6 factor questionnaire (6FQ) was previously developed as an assessment tool for psycho-behavioral phenotyping. The primary purpose of this study was to confirm and validate the original findings in a large diverse adult population. Methods: A total of 5399 self-selected participants (mean age of 48 ± 13 years and body mass index of 32 ± 8 kg/m2) completed the 6FQ online. The association between self-reported demographic data and 6FQ responses was assessed using linear regression models. Results: Mean factor score and odds ratio analyses consistently demonstrated a statistically significant relationship between factors and body weight even after adjusting for age, sex, and race/ethnicity. Conclusions: Although the study was correlational in design, the results demonstrate that the 6FQ, an instrument that represents multidimensional unhealthful lifestyle patterns associated with diet, physical activity, cognition, and self-perception worsen with increasing body weight. Psycho-behavioral phenotyping may be a useful approach when assessing and treating patients with obesity.

Relations Between BMI Trajectories and Habitual Physical Activity Measured by a Smartwatch in the Electronic Cohort of the Framingham Heart Study: Cohort Study.

BACKGROUND: The prevalence of obesity is rising. Most previous studies that examined the relations between BMI and physical activity (PA) measured BMI at a single timepoint. The association between BMI trajectories and habitual PA remains unclear. OBJECTIVE: This study assesses the relations between BMI trajectories and habitual step-based PA among participants enrolled in the electronic cohort of the Framingham Heart Study (eFHS). METHODS: We used a semiparametric group-based modeling to identify BMI trajectories from eFHS participants who attended research examinations at the Framingham Research Center over 14 years. Daily steps were recorded from the smartwatch provided at examination 3. We excluded participants with <30 days or <5 hours of smartwatch wear data. We used generalized linear models to examine the association between BMI trajectories and daily step counts. RESULTS: We identified 3 trajectory groups for the 837 eFHS participants (mean age 53 years; 57.8% [484/837] female). Group 1 included 292 participants whose BMI was stable (slope 0.005; P=.75), group 2 included 468 participants whose BMI increased slightly (slope 0.123; P<.001), and group 3 included 77 participants whose BMI increased greatly (slope 0.318; P<.001). The median follow-up period for step count was 516 days. Adjusting for age, sex, wear time, and cohort, participants in groups 2 and 3 took 422 (95% CI -823 to -21) and 1437 (95% CI -2084 to -790) fewer average daily steps, compared with participants in group 1. After adjusting for metabolic and social risk factors, group 2 took 382 (95% CI -773 to 10) and group 3 took 1120 (95% CI -1766 to -475) fewer steps, compared with group 1. CONCLUSIONS: In this community-based eFHS, participants whose BMI trajectory increased greatly over time took significantly fewer steps, compared with participants with stable BMI trajectories. Our findings suggest that greater weight gain may correlate with lower levels of step-based physical activity.

Diplonemids - A Review on "New" Flagellates on the Oceanic Block.

Diplonemids are a group of flagellate protists, that belong to the phylum Euglenozoa alongside euglenids, symbiontids and kinetoplastids. They primarily inhabit marine environments, though are also found in freshwater lakes. Diplonemids have been considered as rare and unimportant eukaryotes for over a century, with only a handful of species described until recently. However, thanks to their unprecedented diversity and abundance in the world oceans, diplonemids now attract increased attention. Recent improvements in isolation and cultivation have enabled characterization of several new genera, warranting a re-examination of all available knowledge gathered so far. Here we summarize available data on diplonemids, focusing on the recent advances in the fields of diversity, ecology, genomics, metabolism, and endosymbionts. We illustrate the life stages of cultivated genera, and summarise all reported interspecies associations, which in turn suggest lifestyles of predation and parasitism. This review also includes the latest classification of diplonemids, with a taxonomic revision of the genus Diplonema. Ongoing efforts to sequence various diplonemids suggest the presence of large and complex genomes, which correlate with the metabolic versatility observed in the model species Paradiplonema papillatum. Finally, we highlight its successful transformation into one of few genetically tractable marine protists.

Eukaryotic cellular intricacies shape mitochondrial proteomic complexity.

Mitochondria have been fundamental to the eco-physiological success of eukaryotes since the last eukaryotic common ancestor (LECA). They contribute essential functions to eukaryotic cells, above and beyond classical respiration. Mitochondria interact with, and complement, metabolic pathways occurring in other organelles, notably diversifying the chloroplast metabolism of photosynthetic organisms. Here, we integrate existing literature to investigate how mitochondrial metabolism varies across the landscape of eukaryotic evolution. We illustrate the mitochondrial remodelling and proteomic changes undergone in conjunction with major evolutionary transitions. We explore how the mitochondrial complexity of the LECA has been remodelled in specific groups to support subsequent evolutionary transitions, such as the acquisition of chloroplasts in photosynthetic species and the emergence of multicellularity. We highlight the versatile and crucial roles played by mitochondria during eukaryotic evolution, extending from its huge contribution to the development of the LECA itself to the dynamic evolution of individual eukaryote groups, reflecting both their current ecologies and evolutionary histories.

Comparison of Daily Routines Between Middle-aged and Older Participants With and Those Without Diabetes in the Electronic Framingham Heart Study: Cohort Study.

BACKGROUND: Daily routines (eg, physical activity and sleep patterns) are important for diabetes self-management. Traditional research methods are not optimal for documenting long-term daily routine patterns in participants with glycemic conditions. Mobile health offers an effective approach for collecting users' long-term daily activities and analyzing their daily routine patterns in relation to diabetes status. OBJECTIVE: This study aims to understand how routines function in diabetes self-management. We evaluate the associations of daily routine variables derived from a smartwatch with diabetes status in the electronic Framingham Heart Study (eFHS). METHODS: The eFHS enrolled the Framingham Heart Study participants at health examination 3 between 2016 and 2019. At baseline, diabetes was defined as fasting blood glucose level ≥126 mg/dL or as a self-report of taking a glucose-lowering medication; prediabetes was defined as fasting blood glucose level of 100-125 mg/dL. Using smartwatch data, we calculated the average daily step counts and estimated the wake-up times and bedtimes for the eFHS participants on a given day. We compared the average daily step counts and the intraindividual variability of the wake-up times and bedtimes of the participants with diabetes and prediabetes with those of the referents who were neither diabetic nor prediabetic, adjusting for age, sex, and race or ethnicity. RESULTS: We included 796 participants (494/796, 62.1% women; mean age 52.8, SD 8.7 years) who wore a smartwatch for at least 10 hours/day and remained in the study for at least 30 days after enrollment. On average, participants with diabetes (41/796, 5.2%) took 1611 fewer daily steps (95% CI 863-2360; P<.001) and had 12 more minutes (95% CI 6-18; P<.001) in the variation of their estimated wake-up times, 6 more minutes (95% CI 2-9; P=.005) in the variation of their estimated bedtimes compared with the referents (546/796, 68.6%) without diabetes or prediabetes. Participants with prediabetes (209/796, 26.2%) also walked fewer daily steps (P=.04) and had a larger variation in their estimated wake-up times (P=.04) compared with the referents. CONCLUSIONS: On average, participants with diabetes at baseline walked significantly fewer daily steps and had larger variations in their wake-up times and bedtimes than the referent group. These findings suggest that modifying the routines of participants with poor glycemic health may be an important approach to the self-management of diabetes. Future studies should be designed to improve the remote monitoring and self-management of diabetes.

One-Year Change in Walking Performance and Subsequent Mobility Loss and Mortality Rates in Peripheral Artery Disease: Longitudinal Data From the WALCS.

Background Associations of 1-year change in functional performance measures with subsequent mobility loss and mortality in people with lower extremity peripheral artery disease are unknown. Methods and Results Six-minute walk and 4-meter walking velocity (usual and fastest pace) were measured at baseline and 1 year later in 612 people with peripheral artery disease (mean age 71±9 years, 37% women). Participants were categorized into tertiles, based on 1-year changes in walking measures. Cox proportional hazards models were used to examine associations between 1-year change in each walking measure and subsequent mobility loss and mortality, respectively, adjusting for potential confounders. Compared with the best tertile, the worst tertile (ie, greatest decline) in 1-year change in each performance measure was associated with higher rates of mobility loss: 6-minute walk (Tertile 1 [T1] cumulative incidence rate [IR], 72/160; Tertile 3 [T3] IR, 47/160; hazard ratio [HR], 2.35; 95% CI, 1.47-3.74), usual-paced 4-meter walking velocity (T1 IR, 54/162; T3 IR, 57/162; HR, 2.21; 95% CI, 1.41-3.47), and fast-paced 4-meter walking velocity (T1 IR, 61/162; T3 IR, 58/162; HR, 1.81; 95% CI, 1.16-2.84). Compared with the best tertile, the worst tertiles in 1-year change in 6-minute walk (T1 IR, 66/163; T3 IR, 54/163; HR, 1.61; 95% CI, 1.07-2.43) and fast-paced 4-meter walking velocity (T1 IR, 63/166; T3 IR, 44/166; HR, 1.75; 95% CI, 1.16, 2.64) were associated with higher mortality. Conclusions In people with peripheral artery disease, greater 1-year decline in 6-minute walk or 4-meter walking velocity may help identify people with peripheral artery disease at highest risk for mobility loss and mortality.

The distinctive flagellar proteome of Euglena gracilis illuminates the complexities of protistan flagella adaptation.

The eukaryotic flagellum/cilium is a prominent organelle with conserved structure and diverse functions. Euglena gracilis, a photosynthetic and highly adaptable protist, employs its flagella for both locomotion and environmental sensing. Using proteomics of isolated E. gracilis flagella we identify nearly 1700 protein groups, which challenges previous estimates of the protein complexity of motile eukaryotic flagella. We not only identified several unexpected similarities shared with mammalian flagella, including an entire glycolytic pathway and proteasome, but also document a vast array of flagella-based signal transduction components that coordinate gravitaxis and phototactic motility. By contrast, the pellicle was found to consist of > 900 protein groups, containing additional structural and signalling components. Our data identify significant adaptations within the E. gracilis flagellum, many of which are clearly linked to the highly flexible lifestyle.