Acetylcholine esterase of Drosophila melanogaster: a laboratory model to explore insecticide susceptibility gene drives.

BACKGROUND: One of the proposed applications of gene drives has been to revert pesticide resistant mutations back to the ancestral susceptible state. Insecticides that have become ineffective because of the rise of resistance could have reinvigorated utility and be used to suppress pest populations again, perhaps at lower application doses. RESULTS: We have created a laboratory model for susceptibility gene drives that replaces field-selected resistant variants of the acetylcholine esterase (Ace) locus of Drosophila melanogaster with ancestral susceptible variants. We constructed a CRISPR/Cas9 homing drive and found that homing occurred in many genetic backgrounds with varying efficiencies. While the drive itself could not be homozygous, it converted resistant alleles into susceptible ones and produced recessive lethal alleles that could suppress populations. Our studies provided evidence for two distinct classes of gene drive resistance (GDR): rather than being mediated by the conventional non-homologous end-joining (NHEJ) pathway, one seemed to involve short homologous repair and the other was defined by genetic background. Additionally, we used simulations to explore a distinct application of susceptibility drives; the use of chemicals to prevent the spread of synthetic gene drives into protected areas. CONCLUSIONS: Insecticide susceptibility gene drives could be useful tools to control pest insects however problems with particularities of target loci and GDR will need to be overcome for them to be effective. Furthermore, realistic patterns of pest dispersal and high insecticide exposure rates would be required if susceptibility were to be useful as a 'safety-switch' to prevent the unwanted spread of gene drives. © 2024 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Net cost savings arising from patient completion of an active self-management program.

OBJECTIVE: The objective of this study is to investigate changes in willingness for total knee replacement (TKR) surgery following a randomised control trial (RCT) of an osteoarthritis management program, and to extrapolate orthopaedic cost consequences for private health insurers (PHI). METHODS: Willingness for surgery data from the RCT is analysed using a multinomial logistic regression model. A decision analytic model is used to conduct a break-even cost benefit analysis of the intervention from a PHI payer perspective. The analysis estimates the minimum probability of progression to surgery required for the intervention to be cost-neutral when considering savings limited to reduced orthopaedic costs. Cost data and orthopaedic pathway probabilities are sourced from payer data. RESULTS: At baseline, 39% of participants in the treatment and control group were willing for surgery. At 12 months, 16% of participants in the treatment group remained willing for surgery, versus 36% in the control group. Participants in the treatment group are 2.96 (95% CI: 1.01-8.66) times more likely than those in the control group to move from initially willing for surgery, to unsure or unwilling at 12 months. The analysis indicates that the intervention is likely to be cost saving when at least 60% of initially willing participants progress to surgery over a 5-year time horizon. CONCLUSION: Our study estimates that an education, exercise and weight loss intervention can deliver both improved participant outcomes and a return on investment to Australian PHIs through a reduction in TKR surgery incidence.

Contrast sensitivity, visual acuity and the effect of behavioural state on optokinetic gain in fiddler crabs.

Most animals rely on visual information for a variety of everyday tasks. The information available to a visual system depends in part on its spatial resolving power and contrast sensitivity. Because of their competing demands for physical space within an eye, these traits cannot simultaneously be improved without increasing overall eye size. The contrast sensitivity function is an integrated measure of visual performance that measures both resolution and contrast sensitivity. Its measurement helps us identify how different species have made a trade-off between contrast sensitivity and spatial resolution. It further allows us to identify the evolutionary drivers of sensory processing and visually mediated behaviour. Here, we measured the contrast sensitivity function of the fiddler crab Gelasimus dampieri using its optokinetic responses to wide-field moving sinusoidal intensity gratings of different orientations, spatial frequencies, contrasts and speeds. We further tested whether the behavioural state of the crabs (i.e. whether crabs are actively walking or not) affects their optokinetic gain and contrast sensitivity. Our results from a group of five crabs suggest a minimum perceived contrast of 6% and a horizontal and vertical visual acuity of 0.4 cyc deg-1 and 0.28 cyc deg-1, respectively, in the crabs' region of maximum optomotor sensitivity. Optokinetic gain increased in moving crabs compared with restrained crabs, adding another example of the importance of naturalistic approaches when studying the performance of animals.

Quality Improvement to Eliminate Disparities in Developmental Screening for Patients Needing Interpreters.

Children from households with a preferred language other than English are less likely to receive timely identification and treatment for developmental delay than children of native English speakers. In dismantling this inequity, the role of primary care pediatrics is to establish equitable systems for screening and referral. This project, conducted in a network of twelve pediatric primary care centers, focused on eliminating a small but systematic disparity in developmental screening rates between families who did and did not require interpreters (86% versus 92%). The specific aim was to increase developmental screen completion among patients needing interpreters from 86% to 92% of age-appropriate well-child visits. Methods: Data were extracted from the electronic health record (EHR) to measure the proportion of 9-, 18-, 24-, and 30-month well-child visits at which developmental screens were completed, stratified by interpreter need (n = 31,461 visits; 7500 needing interpreters). One primary care center tested small changes to standardize processes, eliminate workarounds, and leverage EHR features using the Institute for Healthcare Improvement's Model for Improvement. The QI team plotted screen completion on control charts and spread successful changes to all 12 clinics. Statistical process control evaluated the significance of changes in screening rates. Results: For patients needing interpreters, screen completion rose across all clinics from 86% to 93% when the clinics implemented the new process. Screen completion for patients not needing interpreters remained at 92%. Conclusion: A standardized process supported by the EHR improved developmental screening among patients needing interpreters, eliminating disparities.

Using Quality Improvement to Design Early Childhood Services Navigation in Primary Care.

Enrollment in high-quality early childhood education (ECE) improves educational and health outcomes and can mitigate racial and economic disparities. Pediatricians are encouraged to promote ECE yet lack the time and knowledge to assist families effectively. In 2016, our academic primary care center hired an ECE Navigator to promote ECE and help families enroll. Our SMART aims were to increase the number of children with facilitated referrals to high-quality ECE programs from 0 to 15 per month and to confirm enrollment on a subset to achieve an enrollment rate of 50% by December 31, 2020. Methods: We used the Institute for Healthcare Improvement's Model for Improvement. Interventions included system changes in partnership with ECE agencies (eg, interactive map of subsidized preschool options, streamlined enrollment forms), case management with families, and population-based approaches to understand families' needs and the program's overall impact. We plotted the number of monthly facilitated referrals and the percentage of referrals enrolled on run and control charts. We used standard probability-based rules to identify special causes. Results: Facilitated referrals increased from 0 to 29 per month and remained above 15. The percentage of enrolled referrals increased from 30% to 74% in 2018, then decreased to 27% in 2020 when childcare availability declined during the pandemic. Conclusions: Our innovative ECE partnership improved access to high-quality ECE. Interventions could be adopted in part or whole by other clinical practices or WIC offices to equitably improve early childhood experiences for low-income families and racial minorities.

A diversity of endosymbionts across Australian aphids and their persistence in aphid cultures.

There is increasing interest in the use of endosymbionts in pest control, which will benefit from the identification of endosymbionts from potential donor species for transfer to pest species. Here, we screened for endosymbionts in 123 Australian aphid samples across 32 species using 16S DNA metabarcoding. We then developed a qPCR method to validate the metabarcoding data set and to monitor endosymbiont persistence in aphid cultures. Pea aphids (Acyrthosiphon pisum) were frequently coinfected with Rickettsiella and Serratia, and glasshouse potato aphids (Aulacorthum solani) were coinfected with Regiella and Spiroplasma; other secondary endosymbionts detected in samples occurred by themselves. Hamiltonella, Rickettsia and Wolbachia were restricted to a single aphid species, whereas Regiella was found in multiple species. Rickettsiella, Hamiltonella and Serratia were stably maintained in laboratory cultures, although others were lost rapidly. The overall incidence of secondary endosymbionts in Australian samples tended to be lower than recorded from aphids overseas. These results indicate that aphid endosymbionts probably exhibit different levels of infectivity and vertical transmission efficiency across hosts, which may contribute to natural infection patterns. The rapid loss of some endosymbionts in cultures raises questions about factors that maintain them under field conditions, while endosymbionts that persisted in laboratory culture provide candidates for interspecific transfers.

Engineering BioBricks for Deoxysugar Biosynthesis and Generation of New Tetracenomycins.

Tetracenomycins and elloramycins are polyketide natural products produced by several actinomycetes that exhibit antibacterial and anticancer activities. They inhibit ribosomal translation by binding in the polypeptide exit channel of the large ribosomal subunit. The tetracenomycins and elloramycins are typified by a shared oxidatively modified linear decaketide core, yet they are distinguished by the extent of O-methylation and the presence of a 2',3',4'-tri-O-methyl-α-l-rhamnose appended at the 8-position of elloramycin. The transfer of the TDP-l-rhamnose donor to the 8-demethyl-tetracenomycin C aglycone acceptor is catalyzed by the promiscuous glycosyltransferase ElmGT. ElmGT exhibits remarkable flexibility toward transfer of many TDP-deoxysugar substrates to 8-demethyltetracenomycin C, including TDP-2,6-dideoxysugars, TDP-2,3,6-trideoxysugars, and methyl-branched deoxysugars in both d- and l-configurations. Previously, we developed an improved host, Streptomyces coelicolor M1146::cos16F4iE, which is a stable integrant harboring the required genes for 8-demethyltetracenomycin C biosynthesis and expression of ElmGT. In this work, we developed BioBricks gene cassettes for the metabolic engineering of deoxysugar biosynthesis in Streptomyces spp. As a proof of concept, we used the BioBricks expression platform to engineer biosynthesis for d-configured TDP-deoxysugars, including known compounds 8-O-d-glucosyl-tetracenomycin C, 8-O-d-olivosyl-tetracenomycin C, 8-O-d-mycarosyl-tetracenomycin C, and 8-O-d-digitoxosyl-tetracenomycin C. In addition, we generated four new tetracenomycins including one modified with a ketosugar, 8-O-4'-keto-d-digitoxosyl-tetracenomycin C, and three modified with 6-deoxysugars, including 8-O-d-fucosyl-tetracenomycin C, 8-O-d-allosyl-tetracenomycin C, and 8-O-d-quinovosyl-tetracenomycin C. Our work demonstrates the feasibility of BioBricks cloning, with the ability to recycle intermediate constructs, for the rapid assembly of diverse carbohydrate pathways and glycodiversification of a variety of natural products.

The Influence of Oral Cannabidiol on 24-h Ambulatory Blood Pressure and Arterial Stiffness in Untreated Hypertension: A Double-Blind, Placebo-Controlled, Cross-Over Pilot Study.

INTRODUCTION: Studies reveal that cannabidiol may acutely reduce blood pressure and arterial stiffness in normotensive humans; however, it remains unknown if this holds true in patients with untreated hypertension. We aimed to extend these findings to examine the influence of the administration of cannabidiol on 24-h ambulatory blood pressure and arterial stiffness in hypertensive individuals. METHODS: Sixteen volunteers (eight females) with untreated hypertension (elevated blood pressure, stage 1, stage 2) were given oral cannabidiol (150 mg every 8 h) or placebo for 24 h in a randomised, placebo-controlled, double-blind, cross-over study. Measures of 24-h ambulatory blood pressure and electrocardiogram (ECG) monitoring and estimates of arterial stiffness and heart rate variability were obtained. Physical activity and sleep were also recorded. RESULTS: Although physical activity, sleep patterns and heart rate variability were comparable between groups, arterial stiffness (~ 0.7 m/s), systolic blood pressure (~ 5 mmHg), and mean arterial pressure (~ 3 mmHg) were all significantly (P < 0.05) lower over 24 h on cannabidiol when compared to the placebo. These reductions were generally larger during sleep. Oral cannabidiol was safe and well tolerated with no development of new sustained arrhythmias. CONCLUSIONS: Our findings indicate that acute dosing of cannabidiol over 24 h can lower blood pressure and arterial stiffness in individuals with untreated hypertension. The clinical implications and safety of longer-term cannabidiol usage in treated and untreated hypertension remains to be established.

STEP IN: Supporting Together Exercise and Play and Improving Nutrition; a Feasibility Study of Parent-Led Group Sessions and Fitness Trackers to Improve Family Healthy Lifestyle Behaviors in a Low-Income, Predominantly Black Population.

BACKGROUND: Pediatric obesity is prevalent and challenging to treat. Although family-centered behavioral management is the gold standard, many families face structural inequities to its access and efficacy. Identifying ways to manage pediatric obesity within primary care is needed. METHODS: This feasibility study included three sequential trials of peer-led group sessions occurring biweekly or monthly between 3/2016 and 2/2017. Parent-child dyads were recruited from a large academic primary care clinic via mailed invitations, prioritizing patients living in local zip codes of historical disinvestment. Eligible patients were 6 to 12 years with a body mass index ≥85th percentile, with parent and child interest in making healthy lifestyle changes, and English speaking. RESULTS: 27 dyads participated, 77% were non-Hispanic Black. Retention and attendance rates were highest in the initial four-session biweekly pilot (100%, 0 dropouts), high in the full six-session biweekly cohort (83%, 1 dropout), and moderate in the monthly cohort (62.7%, 4 dropouts). Families reported high satisfaction with the sessions (4.75/5). Qualitative comments suggested social connections had motivated behavior change in some families. CONCLUSION: Parent-led group sessions for pediatric weight management show promise in engaging families. A future large trial is needed to assess behavior change and anthropometric outcomes.

'The fact that I know I can do it is quite a motivator now': a qualitative study exploring experiences maintaining weight loss 6 months after completing a weight loss programme for knee osteoarthritis.

OBJECTIVE: To explore experiences maintaining weight loss 6 months after completing a multicomponent weight loss programme for knee osteoarthritis. DESIGN: Qualitative study based on an interpretivist paradigm and a phenomenological approach that was embedded within a randomised controlled trial. SETTING: Semistructured interviews were conducted with participants 6 months after completing a 6-month weight loss programme (ACTRN12618000930280) involving a ketogenic very low calorie diet (VLCD), exercise and physical activity programme, videoconferencing consultations with a dietitian and physiotherapist, and provision of educational and behaviour change resources and meal replacement products. Interviews were audio recorded, transcribed verbatim and data were analysed based on the principles of reflexive thematic analysis. PARTICIPANTS: 20 people with knee osteoarthritis. RESULTS: Three themes were developed: (1) successfully maintained weight loss; (2) empowering self-management of weight (understand importance of exercise; increased knowledge about food and nutrition; resources from programme still useful; knee pain as a motivator; confidence in ability to self-regulate weight) and (3) challenges keeping on track (loss of accountability to dietitian and study; old habits and social situations; stressful life events or changes in health). CONCLUSION: Participants had overall positive experiences maintaining their weight loss since completing the weight loss programme and were confident in their ability to self-regulate their weight in the future. Findings suggest a programme incorporating dietitian and physiotherapist consultations, a VLCD, and educational and behaviour change resources supports confidence maintaining weight loss in the medium term. Further research is required to explore strategies to overcome barriers like loss of accountability and returning to old eating habits.

How Does Exercise, With and Without Diet, Improve Pain and Function in Knee Osteoarthritis? A Secondary Analysis of a Randomized Controlled Trial Exploring Potential Mediators of Effects.

OBJECTIVE: To explore the mediators of effects of two 6-month telehealth-delivered exercise programs, including exercise with and without weight-loss diet, on pain and function improvements in knee osteoarthritis (OA). METHODS: Secondary analysis of 345 participants from a 3-arm randomized controlled trial of exercise (Exercise program) and exercise plus diet (Diet + Exercise program) versus information (Control program) was conducted. Outcomes were changes in pain (11-point numeric rating scale) and function (Western Ontario and McMaster Universities Osteoarthritis Index [score range 0-68]) at 12 months. Potential mediators were change at 6 months in attitudes toward self-management, fear of movement, arthritis self-efficacy, weight, physical activity, and willingness for knee surgery. For the Diet + Exercise program versus the Exercise program, only change in weight was evaluated. RESULTS: Possible mediators of the Exercise program versus the Control program included reduced fear of movement (accounting for -1.11 units [95% confidence interval (95% CI) -2.15, -0.07] improvement in function) and increased arthritis self-efficacy (-0.40 units [95% CI -0.75, -0.06] reduction in pain, -1.66 units [95% CI -3.04, -0.28] improvement in function). The Diet + Exercise program versus the Control program mediators included reduced fear of movement (-1.13 units [95% CI -2.17, -0.08] improvement in function), increased arthritis self-efficacy (-0.77 units [95% CI -1.26, -0.28] reduction in pain, -5.15 units [95% CI -7.34, -2.96] improvement in function), and weight loss (-1.20 units [95% CI -1.73, -0.68] reduction in pain, -5.79 units [95% CI -7.96, -3.63] improvement in function). Weight loss mediated the Diet + Exercise program versus the Exercise program (-0.89 units [95% CI -1.31, -0.47] reduction in pain, -4.02 units [95% CI -5.77, -2.26] improvement in function). CONCLUSION: Increased arthritis self-efficacy, reduced fear of movement, and weight loss may partially mediate telehealth-delivered exercise program effects, with and without diet, on pain and/or function in knee OA. Weight loss may partially mediate the effect of diet and exercise compared to exercise alone.

Substance Use Disorders and Medication-Assisted Therapies: Current Practices and Implications for Nursing.

In the United States, the opioid epidemic and COVID-19-related substance use have exacerbated the overall incidence of substance use disorders (SUDs). Medication-assisted therapy (MAT), or cognitive and behavioral therapy that combines medications that reduce substance use or acute withdrawal symptoms, has dramatically improved outcomes for SUD patients, including preventing mortality. With recent US Congressional funding for MAT, patients presenting for acute care on MAT-related medications will continue to increase. Nurses should be aware of these medications' mechanism of action, typical side effects, and implications on treating acute pain to optimize their care.

A rapidly spreading deleterious aphid endosymbiont that uses horizontal as well as vertical transmission.

Endosymbiotic bacteria that live inside the cells of insects are typically only transmitted maternally and can spread by increasing host fitness and/or modifying reproduction in sexual hosts. Transinfections of Wolbachia endosymbionts are now being used to introduce useful phenotypes into sexual host populations, but there has been limited progress on applications using other endosymbionts and in asexual populations. Here, we develop a unique pathway to application in aphids by transferring the endosymbiont Rickettsiella viridis to the major crop pest Myzus persicae. Rickettsiella infection greatly reduced aphid fecundity, decreased heat tolerance, and modified aphid body color, from light to dark green. Despite inducing host fitness costs, Rickettsiella spread rapidly through caged aphid populations via plant-mediated horizontal transmission. The phenotypic effects of Rickettsiella were sensitive to temperature, with spread only occurring at 19 °C and not 25 °C. Body color modification was also lost at high temperatures despite Rickettsiella maintaining a high density. Rickettsiella shows the potential to spread through natural M. persicae populations by horizontal transmission and subsequent vertical transmission. Establishment of Rickettsiella in natural populations could reduce crop damage by modifying population age structure, reducing population growth and providing context-dependent effects on host fitness. Our results highlight the importance of plant-mediated horizontal transmission and interactions with temperature as drivers of endosymbiont spread in asexual insect populations.

The Impact of the COVID-19 Pandemic on Black and Hispanic Americans' Work Outcomes: a Scoping Review.

In early 2020, it was hypothesized that COVID-19 would lead to disproportionately negative health and work outcomes for Black and Hispanic adults, but sufficient data had yet been collected to fully support this claim. Now, we have empirical evidence, but little has been done to aggregate this information to fully understand its impact on these communities. Utilizing 44 articles from a scoping review of three databases (PubMed, Web of Science, and Business Source Complete), this study seeks to identify the primary work-related risks that help explain Black and Hispanic adults' disparate COVID-19-related work outcomes (e.g., loss of hours, job disruption, stress). Findings illuminate four primary risks faced by Black and Hispanic workers: (1) being an essential worker, (2) type of work performed, (3) workplace factors; and (4) community and geographic factors. We conclude with policy recommendations that will help inform policy and practice for economic recovery from the pandemic for other marginalized populations.

Examining the Relationship Between Existing Community Resources and Community Leaders' Perceptions of Resilience and Rural Health During COVID-19.

This study explored the relationship between existing community resources and community leaders' perceptions of resilience and rural health during COVID-19. Observational data of material capitals (e.g., grocery stores and physical activity resources) present in five rural communities involved in a health promotion project were collected and compared with key informant interviews of perceived community health and resilience during the COVID-19 pandemic. The analysis compares the differences in community leaders' perceptions of resilience during the pandemic to the actual material capitals of the community. While these rural counties were average in terms of available physical activity and nutritional resources, the onset of the pandemic led to varying degrees of disruption in access due to structural closures of mainstay resources, as well as residents perceiving that they cannot or should not access available resources. In addition, county coalition progress was stalled as individuals and groups could not gather together to complete projects, such as building playground equipment. This study demonstrates that existing quantitative instruments, such as NEMS and PARA, fail to take into account perceived access and utility of resources. Therefore, practitioners should consider multiple ways to evaluate resources, capacity, and progress on a health intervention or program and consider community voice to ensure feasibility, relevance, and sustainability-especially when faced with a public health emergency like COVID-19.

Community Gardens: A Catalyst for Community Change.

Community gardens are increasing in popularity and are associated with extensive physical and mental health benefits, increased access to fresh produce, and increased social connections. However, evidence is primarily from research in urban and school settings, and little is known about the role of community gardens in rural settings as part of policy, systems, and environmental (PSE) changes to promote health. This study explores the implementation of community gardens as part of an obesity prevention project, titled Healthier Together (HT), in five rural Georgia counties with limited food access and high obesity prevalence (>40%) using a mixed-methods research design that included data from project records, a community survey, interviews, and focus groups with county coalition members. Nineteen community gardens were implemented across five counties, 89% distributed produce direct to consumers, and 50% were integrated into the food system. Few (8.3%) of the survey respondents (n = 265) identified gardens as a food source, but 21.9% reported using an HT garden in the past year. Themes emerging from interviews (n = 39) and five focus groups suggested community gardens were a catalyst for broader community health change by increasing awareness of the value and absence of healthy food and generating excitement for future PSE initiatives to more comprehensively address food and physical activity access. Practitioners should consider placement of rural community gardens to optimize access to and distribution of produce as well as communication and marketing strategies to increase engagement and leverage gardens as gateways for PSE approaches to improve rural health.

Affordable Care Act state Medicaid expansion and human papillomavirus vaccination among adolescent and young adult US women: A national study.

OBJECTIVE: To ascertain the impact of Affordable Care Act (ACA) state Medicaid expansion on human papillomavirus (HPV) vaccination among both adolescent and young adult US women. DATA SOURCES: We used state-level data on ACA Medicaid expansion and individual-level data on US women aged 15-25 years living at or below 138% of the Federal Poverty Level (FPL) from the 2011-2017 waves of the National Survey of Family Growth (N = 2408). STUDY DESIGN: We conducted a quasi-experimental study examining the association between ACA state Medicaid expansion and HPV vaccination initiation among eligible adolescent and young adult US women. METHODS: We used linear probability modeling within a difference-in-differences approach, adjusting for individual- and state-level covariates. PRINCIPAL FINDINGS: Adjusting for individual- and state-level covariates, we found a negative association between Medicaid expansion and HPV vaccination among US women aged 15-25 years living in low-income households in the first year post-expansion (coefficient: -15.9 percentage points; 95% confidence interval [CI]: -30.1, -1.6 points). In contrast, we observed a positive association in the third year post-expansion (coefficient: 20.5 percentage points; 95% confidence interval [CI]: -1.8, 42.9 points). CONCLUSIONS: Medicaid expansion may have increased HPV vaccination among adolescent and young adult US women over time. Additional research is needed to identify the mechanisms and differential effects of Medicaid expansion on HPV vaccination among diverse subgroups of US women.

Cost-Effectiveness of Telehealth-Delivered Exercise and Dietary Weight Loss Programs for Knee Osteoarthritis Within a Twelve-Month Randomized Trial.

OBJECTIVE: To evaluate the cost-effectiveness of telehealth-delivered exercise and diet-plus-exercise programs within 12 months. METHODS: An economic evaluation within a 12-month, 3-arm, parallel randomized trial of two 6-month telehealth-delivered exercise programs, with and without a dietary component. A total of 415 people with knee osteoarthritis ages 45-80 years and body mass index of 28-40 kg/m2 were assigned to 1 of 2 telehealth-delivered exercise programs, 1 without (n = 172) and 1 with (n = 175) a dietary component (ketogenic very low calorie diet), or to an education control (n = 67), for 6 months, with 6 months follow-up. The primary economic outcomes were quality-adjusted life years (QALYs) and health system costs. Measured costs were the direct intervention (consultations, equipment/resources, and meal replacements) and health care use in 2020 Australian dollars ($AU1.5 = $US1). Secondary analysis included weight loss and work productivity gains. RESULTS: The clinical trial demonstrated greater improvements in pain and function compared to information only for individuals with knee osteoarthritis and overweight/obesity. We can be 88% confident that diet plus exercise is cost effective ($45,500 per QALY), 53% confident that exercise is cost-effective ($67,600 per QALY) compared to the control, and 86% confident that augmenting exercise with the diet program is cost effective ($21,100 per QALY). CONCLUSION: Telehealth-delivered programs targeting exercise with dietary intervention for people with knee osteoarthritis who have overweight/obesity are likely to be cost-effective, particularly if potential long-term gains from weight loss and work productivity are realized.

Brachial artery responses to acute hypercapnia: The roles of shear stress and adrenergic tone.

NEW FINDINGS: What is the central question of this study? What are the contributions of shear stress and adrenergic tone to brachial artery vasodilatation during hypercapnia? What is the main finding and its importance? In healthy young adults, shear-mediated vasodilatation does not occur in the brachial artery during hypercapnia, as elevated α1-adrenergic activity typically maintains vascular tone and offsets distal vasodilatation controlling flow. ABSTRACT: We aimed to assess the shear stress dependency of brachial artery (BA) responses to hypercapnia, and the α1-adrenergic restraint of these responses. We hypothesized that elevated shear stress during hypercapnia would cause BA vasodilatation, but where shear stress was prohibited (via arterial compression), the BA would not vasodilate (study 1); and, in the absence of α1-adrenergic activity, blood flow, shear stress and BA vasodilatation would increase (study 2). In study 1, 14 healthy adults (7/7 male/female, 27 ± 4 years) underwent bilateral BA duplex ultrasound during hypercapnia (partial pressure of end-tidal carbon dioxide, +10.2 ± 0.3 mmHg above baseline, 12 min) via dynamic end-tidal forcing, and shear stress was reduced in one BA using manual compression (compression vs. control arm). Neither diameter nor blood flow was different between baseline and the last minute of hypercapnia (P = 0.423, P = 0.363, respectively) in either arm. The change values from baseline to the last minute, in diameter (%; P = 0.201), flow (ml/min; P = 0.234) and conductance (ml/min/mmHg; P = 0.503) were not different between arms. In study 2, 12 healthy adults (9/3 male/female, 26 ± 4 years) underwent the same design with and without α1-adrenergic receptor blockade (prazosin; 0.05 mg/kg) in a placebo-controlled, double-blind and randomized design. BA flow, conductance and shear rate increased during hypercapnia in the prazosin control arm (interaction, P < 0.001), but in neither arm during placebo. Even in the absence of α1-adrenergic restraint, downstream vasodilatation in the microvasculature during hypercapnia is insufficient to cause shear-mediated vasodilatation in the BA.

Blunted hypoxic pulmonary vasoconstriction in apnoea divers.

NEW FINDINGS: What is the central question of this study? Does the hyperbaric, hypercapnic, acidotic, hypoxic stress of apnoea diving lead to greater pulmonary vasoreactivity and increased right heart work in apnoea divers? What is the main finding and its importance? Compared with sex- and age-matched control subjects, divers experienced significantly less change in total pulmonary resistance in response to short-duration isocapnic hypoxia. With oral sildenafil (50 mg), there were no differences in total pulmonary resistance between groups, suggesting that divers can maintain normal pulmonary artery tone in hypoxic conditions. Blunted hypoxic pulmonary vasoconstriction might be beneficial during apnoea diving. ABSTRACT: Competitive apnoea divers dive repetitively to depths >50 m. During the final portions of ascent, divers experience significant hypoxaemia. Additionally, hyperbaria during diving increases thoracic blood volume while simultaneously reducing lung volume and increasing pulmonary artery pressure. We hypothesized that divers would have exaggerated hypoxic pulmonary vasoconstriction, leading to increased right heart work owing to their repetitive hypoxaemia and hyperbaria, and that the administration of sildenafil would have a greater effect in reducing pulmonary resistance in divers. We recruited 16 divers (Divers) and 16 age- and sex-matched non-diving control subjects (Controls). Using a double-blinded, placebo-controlled, cross-over design, participants were evaluated for normal cardiac and lung function, then their cardiopulmonary responses to 20-30 min of isocapnic hypoxia (end-tidal partial pressure of O2  = 50 mmHg) were measured 1 h after ingestion of 50 mg sildenafil or placebo. Cardiac structure and cardiopulmonary function were similar at baseline. With placebo, Divers had a significantly smaller increase in total pulmonary resistance than Controls after 20-30 min isocapnic hypoxia (change -3.85 ± 72.85 vs. 73.74 ± 91.06 dyns cm-5 , P = 0.0222). With sildenafil, Divers and Controls had similar blunted increases in total pulmonary resistance after 20-30 min of hypoxia. Divers also had a significantly lower systemic vascular resistance after sildenafil in normoxia. These data indicate that repetitive apnoea diving leads to a blunted hypoxic pulmonary vasoconstriction. We suggest that this is a beneficial adaption allowing for increased cardiac output with reduced right heart work and thus reducing cardiac oxygen utilization in hypoxaemic conditions.