Stroke genetics informs drug discovery and risk prediction across ancestries.

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

The phenotype-genotype reference map: Improving biobank data science through replication.

Population-scale biobanks linked to electronic health record data provide vast opportunities to extend our knowledge of human genetics and discover new phenotype-genotype associations. Given their dense phenotype data, biobanks can also facilitate replication studies on a phenome-wide scale. Here, we introduce the phenotype-genotype reference map (PGRM), a set of 5,879 genetic associations from 523 GWAS publications that can be used for high-throughput replication experiments. PGRM phenotypes are standardized as phecodes, ensuring interoperability between biobanks. We applied the PGRM to five ancestry-specific cohorts from four independent biobanks and found evidence of robust replications across a wide array of phenotypes. We show how the PGRM can be used to detect data corruption and to empirically assess parameters for phenome-wide studies. Finally, we use the PGRM to explore factors associated with replicability of GWAS results.

Large-scale distributed linear algebra with tensor processing units.

We have repurposed Google tensor processing units (TPUs), application-specific chips developed for machine learning, into large-scale dense linear algebra supercomputers. The TPUs' fast intercore interconnects (ICIs), physically two-dimensional network topology, and high-bandwidth memory (HBM) permit distributed matrix multiplication algorithms to rapidly become computationally bound. In this regime, the matrix-multiply units (MXUs) dominate the runtime, yielding impressive scaling, performance, and raw size: Operating in float32 precision, a full 2,048-core pod of third-generation TPUs can multiply two matrices with linear size [Formula: see text] in about 2 min. Via curated algorithms emphasizing large, single-core matrix multiplications, other tasks in dense linear algebra can similarly scale. As examples, we present 1) QR decomposition; 2) resolution of linear systems; and 3) the computation of matrix functions by polynomial iteration, demonstrated by the matrix polar factorization.

Plant phenolics inhibit focal adhesion kinase and suppress host cell invasion by uropathogenic Escherichia coli.

Traditional folk treatments for the prevention and management of urinary tract infections (UTIs) and other infectious diseases often include plants and plant extracts that are rich in phenolic compounds. These have been ascribed a variety of activities, including inhibition of bacterial interactions with host cells. Here, we tested a panel of four well-studied phenolic compounds-caffeic acid phenethyl ester (CAPE), resveratrol, catechin, and epigallocatechin gallate-for the effects on host cell adherence and invasion by uropathogenic Escherichia coli (UPEC). These bacteria, which are the leading cause of UTIs, can bind and subsequently invade bladder epithelial cells via an actin-dependent process. Intracellular UPEC reservoirs within the bladder are often protected from antibiotics and host defenses and likely contribute to the development of chronic and recurrent infections. In cell culture-based assays, only resveratrol had a notable negative effect on UPEC adherence to bladder cells. However, both CAPE and resveratrol significantly inhibited UPEC entry into the host cells, coordinate with attenuated phosphorylation of the host actin regulator Focal Adhesion Kinase (FAK or PTK2) and marked increases in the numbers of focal adhesion structures. We further show that the intravesical delivery of resveratrol inhibits UPEC infiltration of the bladder mucosa in a murine UTI model and that resveratrol and CAPE can disrupt the ability of other invasive pathogens to enter host cells. Together, these results highlight the therapeutic potential of molecules like CAPE and resveratrol, which could be used to augment antibiotic treatments by restricting pathogen access to protective intracellular niches.IMPORTANCEUrinary tract infections (UTIs) are exceptionally common and increasingly difficult to treat due to the ongoing rise and spread of antibiotic-resistant pathogens. Furthermore, the primary cause of UTIs, uropathogenic Escherichia coli (UPEC), can avoid antibiotic exposure and many host defenses by invading the epithelial cells that line the bladder surface. Here, we identified two plant-derived phenolic compounds that disrupt activation of the host machinery needed for UPEC entry into bladder cells. One of these compounds, resveratrol, effectively inhibited UPEC invasion of the bladder mucosa in a mouse UTI model, and both phenolic compounds significantly reduced host cell entry by other invasive pathogens. These findings suggest that select phenolic compounds could be used to supplement existing antibacterial therapeutics by denying uropathogens shelter within host cells and tissues and help explain some of the benefits attributed to traditional plant-based medicines.

Remote vision-based digital patient monitoring of pulse and respiratory rates in acute medical wards.

Remote Vision-Based digital Patient Monitoring (VBPM) of pulse (PR) and respiratory rate (RR) was set up in six single rooms in an acute medical and an orthopaedic ward. We compared 102 PR and 154 RR VBPM measurements (from 27 patients) with paired routine nurse measurements. VBPM measurements of RR were validated by reviewing video footage. Nurse measurements of RR were often 16-18 breaths/minute, and did not match VBPM RR (overestimating at low RR and underestimating at high RR). Nurse measurements of pulse were on average 3.9 beats per minute greater than matched VBPM measurements. VBPM was unobtrusive and well accepted.

Next-generation phenotyping: introducing phecodeX for enhanced discovery research in medical phenomics.

MOTIVATION: Phecodes are widely used and easily adapted phenotypes based on International Classification of Diseases codes. The current version of phecodes (v1.2) was designed primarily to study common/complex diseases diagnosed in adults; however, there are numerous limitations in the codes and their structure. RESULTS: Here, we present phecodeX, an expanded version of phecodes with a revised structure and 1,761 new codes. PhecodeX adds granularity to phenotypes in key disease domains that are under-represented in the current phecode structure-including infectious disease, pregnancy, congenital anomalies, and neonatology-and is a more robust representation of the medical phenome for global use in discovery research. AVAILABILITY AND IMPLEMENTATION: phecodeX is available at https://github.com/PheWAS/phecodeX.

A tRNA modifying enzyme as a tunable regulatory nexus for bacterial stress responses and virulence.

Post-transcriptional modifications can impact the stability and functionality of many different classes of RNA molecules and are an especially important aspect of tRNA regulation. It is hypothesized that cells can orchestrate rapid responses to changing environmental conditions by adjusting the specific types and levels of tRNA modifications. We uncovered strong evidence in support of this tRNA global regulation hypothesis by examining effects of the well-conserved tRNA modifying enzyme MiaA in extraintestinal pathogenic Escherichia coli (ExPEC), a major cause of urinary tract and bloodstream infections. MiaA mediates the prenylation of adenosine-37 within tRNAs that decode UNN codons, and we found it to be crucial to the fitness and virulence of ExPEC. MiaA levels shifted in response to stress via a post-transcriptional mechanism, resulting in marked changes in the amounts of fully modified MiaA substrates. Both ablation and forced overproduction of MiaA stimulated translational frameshifting and profoundly altered the ExPEC proteome, with variable effects attributable to UNN content, changes in the catalytic activity of MiaA, or availability of metabolic precursors. Cumulatively, these data indicate that balanced input from MiaA is critical for optimizing cellular responses, with MiaA acting much like a rheostat that can be used to realign global protein expression patterns.

Validating the Breathing Vigilance Questionnaire for use in dysfunctional breathing.

BACKGROUND: Dysfunctional breathing is common among people with and without primary respiratory pathology. While anxiety can contribute to dysfunctional breathing, the underpinning mechanism is unclear. One explanation is that anxiety induces conscious, vigilant monitoring of breathing, disrupting "automatic" breathing mechanics. We validated a new tool that quantifies such breathing-related "vigilance": the Breathing Vigilance Questionnaire (Breathe-VQ). METHODS: 323 healthy adults (mean (range) age 27.3 (18-71) years; 161 males) were analysed. We developed an initial Breathe-VQ (11 items, 1-5 Likert scale) based on the Pain Vigilance and Awareness Scale, using feedback from the target population and clinicians. At baseline, participants completed the Breathe-VQ, Nijmegen Questionnaire (NQ), State-Trait Anxiety Inventory form 2 and Movement-Specific Reinvestment Scale (assessing general conscious processing). 83 people repeated the Breathe-VQ 3 weeks later. RESULTS: Five items were removed based on item-level analysis. The resulting six-item Breathe-VQ questionnaire (score range 6-30) has excellent internal (α=0.892) and test-retest reliability (intraclass correlation 0.810), a minimal detectable change of 6.5 and no floor/ceiling effects. Validity was evidenced by significant positive correlations with trait anxiety and conscious processing scores (r=0.35-0.46). Participants at high risk of having dysfunctional breathing (NQ >23; n=76) had significantly higher Breathe-VQ score (mean±sd 19.1±5.0) than low-risk peers (n=225; mean±sd 13.8±5.4; p<0.001). In this "high risk of dysfunctional breathing" group, Breathe-VQ and NQ scores were significantly associated (p=0.005), even when controlling for risk factors (e.g. trait anxiety). CONCLUSIONS: The Breathe-VQ is a valid and reliable tool to measure breathing vigilance. High breathing vigilance may contribute to dysfunctional breathing and could represent a therapeutic target. Further research is warranted to test Breathe-VQ's prognostic value and assess intervention effects.

Lung volume reduction surgery versus endobronchial valves: a randomised controlled trial.

BACKGROUND: Lung volume reduction surgery (LVRS) and bronchoscopic lung volume reduction (BLVR) with endobronchial valves can improve outcomes in appropriately selected patients with emphysema. However, no direct comparison data exist to inform clinical decision making in people who appear suitable for both procedures. Our aim was to investigate whether LVRS produces superior health outcomes when compared with BLVR at 12 months. METHODS: This multicentre, single-blind, parallel-group trial randomised patients from five UK hospitals, who were suitable for a targeted lung volume reduction procedure, to either LVRS or BLVR and compared outcomes at 1 year using the i-BODE score. This composite disease severity measure includes body mass index, airflow obstruction, dyspnoea and exercise capacity (incremental shuttle walk test). The researchers responsible for collecting outcomes were masked to treatment allocation. All outcomes were assessed in the intention-to-treat population. RESULTS: 88 participants (48% female, mean±sd age 64.6±7.7 years, forced expiratory volume in 1 s percent predicted 31.0±7.9%) were recruited at five specialist centres across the UK and randomised to either LVRS (n=41) or BLVR (n=47). At 12 months follow-up, the complete i-BODE was available in 49 participants (21 LVRS/28 BLVR). Neither improvement in the i-BODE score (LVRS -1.10±1.44 versus BLVR -0.82±1.61; p=0.54) nor in its individual components differed between groups. Both treatments produced similar improvements in gas trapping (residual volume percent predicted: LVRS -36.1% (95% CI -54.6- -10%) versus BLVR -30.1% (95% CI -53.7- -9%); p=0.81). There was one death in each treatment arm. CONCLUSION: Our findings do not support the hypothesis that LVRS is a substantially superior treatment to BLVR in individuals who are suitable for both treatments.

Modified Prolonged Exposure Therapy for Posttraumatic Stress Disorder with an 85-Year-Old Native American Cajun Man With Late-Onset Deafness: A Case Report.

OBJECTIVES: Few studies of exposure therapy with adults 85 years and older exist. This case report presents results of prolonged exposure (PE) for posttraumatic stress disorder (PTSD) modified for an 85-year-old Native American Cajun man with late-onset deafness, who used a cochlear implant, and reported high Western/non-Native American acculturation. The following modifications were made primarily in response to the client's individual, disability-related barriers to completing the standard PE protocol: (a) inclusion of the client's spouse in aspects of treatment planning and homework assignments; (b) variable session length and frequency; (c) homework was limited to the daily practice of breathing retraining and in vivo exposure to triggering images; and (d) therapist reliance on nonverbal indicators of distress during imaginal exposures. METHODS: The PTSD Checklist for DSM-5 (PCL-5) and 15-item Geriatric Depression Scale (GSD-15) were primary progress and outcome measures. RESULTS: The modified treatment was associated with clinically significant decreases in baseline PTSD (19 points) and depressive (8 points) symptoms. CONCLUSIONS: PE protocol modifications did not compromise treatment outcomes for this client. CLINICAL IMPLICATIONS: PE protocols should be modified based on the individual needs of diverse older adults underrepresented in efficacy research.

Dietary nitrate supplementation to enhance exercise capacity in hypoxic COPD: EDEN-OX, a double-blind, placebo-controlled, randomised cross-over study.

RATIONALE: Dietary nitrate supplementation improves skeletal muscle oxygen utilisation and vascular endothelial function. We hypothesised that these effects might be sufficient to improve exercise performance in patients with COPD and hypoxia severe enough to require supplemental oxygen. METHODS: We conducted a single-centre, double-blind, placebo-controlled, cross-over study, enrolling adults with COPD who were established users of long-term oxygen therapy. Participants performed an endurance shuttle walk test, using their prescribed oxygen, 3 hours after consuming either 140 mL of nitrate-rich beetroot juice (BRJ) (12.9 mmol nitrate) or placebo (nitrate-depleted BRJ). Treatment order was allocated (1:1) by computer-generated block randomisation. MEASUREMENTS: The primary outcome was endurance shuttle walk test time. The secondary outcomes included area under the curve to isotime for fingertip oxygen saturation and heart rate parameters during the test, blood pressure, and endothelial function assessed using flow-mediated dilatation. Plasma nitrate and nitrite levels as well as FENO were also measured. MAIN RESULTS: 20 participants were recruited and all completed the study. Nitrate-rich BRJ supplementation prolonged exercise endurance time in all participants as compared with placebo: median (IQR) 194.6 (147.5-411.7) s vs 159.1 (121.9-298.5) s, estimated treatment effect 62 (33-106) s (p<0.0001). Supplementation also improved endothelial function: NR-BRJ group +4.1% (-1.1% to 14.8%) vs placebo BRJ group -5.0% (-10.6% to -0.6%) (p=0.0003). CONCLUSION: Acute dietary nitrate supplementation increases exercise endurance in patients with COPD who require supplemental oxygen. Trial registration number ISRCTN14888729.

Limited clinical utility for GWAS or polygenic risk score for postoperative acute kidney injury in non-cardiac surgery in European-ancestry patients.

BACKGROUND: Prior studies support a genetic basis for postoperative acute kidney injury (AKI). We conducted a genome-wide association study (GWAS), assessed the clinical utility of a polygenic risk score (PRS), and estimated the heritable component of AKI in patients who underwent noncardiac surgery. METHODS: We performed a retrospective large-scale genome-wide association study followed by a meta-analysis of patients who underwent noncardiac surgery at the Vanderbilt University Medical Center ("Vanderbilt" cohort) or Michigan Medicine, the academic medical center of the University of Michigan ("Michigan" cohort). In the Vanderbilt cohort, the relationship between polygenic risk score for estimated glomerular filtration rate and postoperative AKI was also tested to explore the predictive power of aggregating multiple common genetic variants associated with AKI risk. Similarly, in the Vanderbilt cohort genome-wide complex trait analysis was used to estimate the heritable component of AKI due to common genetic variants. RESULTS: The study population included 8248 adults in the Vanderbilt cohort (mean [SD] 58.05 [15.23] years, 50.2% men) and 5998 adults in Michigan cohort (56.24 [14.76] years, 49% men). Incident postoperative AKI events occurred in 959 patients (11.6%) and in 277 patients (4.6%), respectively. No loci met genome-wide significance in the GWAS and meta-analysis. PRS for estimated glomerular filtration rate explained a very small percentage of variance in rates of postoperative AKI and was not significantly associated with AKI (odds ratio 1.050 per 1 SD increase in polygenic risk score [95% CI, 0.971-1.134]). The estimated heritability among common variants for AKI was 4.5% (SE = 4.5%) suggesting low heritability. CONCLUSION: The findings of this study indicate that common genetic variation minimally contributes to postoperative AKI after noncardiac surgery, and likely has little clinical utility for identifying high-risk patients.

Marine Biotoxins in Whole and Processed Scallops from the Argentine Sea.

Harmful algal blooms are an increasing worldwide threat to the seafood industry and human health as a consequence of the natural production of biotoxins that can accumulate in shellfish. In the Argentine Sea, this has been identified as an issue for the offshore fisheries of Patagonian scallops (Zygochlamys patagonica), leading to potentially harmful effects on consumers. Here we assess spatial and temporal patterns in marine biotoxin concentrations in Patagonian scallops harvested in Argentinian waters between 2012-2017, based on analyses for paralytic shellfish toxins, lipophilic toxins, and amnesic shellfish toxins. There was no evidence for concentrations of lipophilic or amnesic toxins above regulatory acceptance thresholds, with trace concentrations of pectenotoxin 2, azaspiracid 2 and okadaic acid group toxins confirmed. Conversely, paralytic shellfish toxins were quantified in some scallops. Gonyautoxins 1 and 2 dominated the unusual toxin profiles (91%) in terms of saxitoxin equivalents with maximum concentrations reaching 3985 µg STX eq/kg and with changes in profiles linked in part to seasonal changes. Total toxin concentrations were compared between samples of the adductor muscle and whole tissue, with results showing the absence of toxins in the adductor muscle confirming toxin accumulation in the digestive tracts of the scallops and the absence of a human health threat following the processing of scallop adductor meat. These findings highlight that paralytic shellfish toxins with an unusual toxin profile can occur in relatively high concentrations in whole Patagonian scallops in specific regions and during particular time periods, also showing that the processing of scallops on board factory ships to obtain frozen adductor muscle is an effective management process that minimizes the risk of poisonings from final products destined for human consumption.

Playing the harmonica with chronic obstructive pulmonary disease. A qualitative study.

Objectives: To investigate the experience of playing the harmonica for individuals with COPD.Methods: A qualitative, phenomenological study using semi-structured interviews and reflexive thematic analysis.Results: Eight people living with COPD (six females, two males) were recruited, who had attended at least six weeks of harmonica group sessions, either face-to-face prior to the COVID-19 pandemic or remotely. Five themes were generated. Themes included 'hard in the beginning', 'holding the condition', 'breathing control', 'gives you a high' and 'needing the Zoom class'.Discussion: Playing the harmonica with COPD is difficult at first, particularly drawing a breath through the harmonica. With practice, experience in a fun activity and quality teaching, individuals were able to become more attuned and embodied with their breathing, and playing the harmonica offered a breathing control strategy. Songs, rather than breathing, became the focus, and participants were able to escape living with respiratory disease when playing. Participants reported the harmonica helped mucous expectoration. The group was a priority in the weekly lives of participants, even though the 'buzz' of being part of a group was lost when participating online. Further mechanistic studies and randomised controlled trials are needed to investigate the biopsychosocial benefits of playing the harmonica with COPD.

Creating and implementing a COVID-19 recruitment Data Mart.

The COVID-19 pandemic has resulted in an unprecedented strain on every aspect of the healthcare system, and clinical research is no exception. Researchers are working against the clock to ramp up research studies addressing every angle of COVID-19 - gaining a better understanding of person-to-person transmission, improving methods for diagnosis, and developing therapies to treat infection and vaccines to prevent it. The impact of the virus on research efforts is not limited to investigators and their teams. Potential participants also face unparalleled opportunities and requests to participate in research, which can result in a significant amount of participant fatigue. The Vanderbilt Institute for Clinical and Translational Research recognized early in the pandemic that a solution to assist researchers in the rapid identification of potential participants was critical, and thus developed the COVID-19 Recruitment Data Mart. This solution does not rest solely on technology; the addition of experienced project managers to support researchers and facilitate collaboration was essential. Since the platform and study support tools were launched on July 20, 2020, four studies have been onboarded and a total of 1693 potential participant matches have been shared. Each of these patients had agreed in advance to direct contact for COVID-19 research and had been matched to study-specific inclusion/exclusion criteria. Our innovative Data Mart system is scalable and looks promising as a generalizable solution for simultaneously recommending individuals from a pool of patients against a pool of time-sensitive trial opportunities.

Marine invertebrate interactions with Harmful Algal Blooms - Implications for One Health.

Harmful Algal Blooms (HAB) are natural atypical proliferations of micro or macro algae in either marine or freshwater environments which have significant impacts on human, animal and ecosystem health. The causative HAB organisms are primarily dinoflagellates and diatoms in marine and cyanobacteria within freshwater ecosystems. Several hundred species of HABs, most commonly marine dinoflagellates affect animal and ecosystem health either directly through physical, chemical or biological impacts on surrounding organisms or indirectly through production of algal toxins which transfer through lower-level trophic organisms to higher level predators. Traditionally, a major focus of HABs has concerned their natural production of toxins which bioaccumulate in filter-feeding invertebrates, which with subsequent trophic transfer and biomagnification cause issues throughout the food web, including the human health of seafood consumers. Whilst in many regions of the world, regulations, monitoring and risk management strategies help mitigate against the impacts from HAB/invertebrate toxins upon human health, there is ever-expanding evidence describing enormous impacts upon invertebrate health, as well as the health of higher trophic level organisms and marine ecosystems. This paper provides an overview of HABs and their relationships with aquatic invertebrates, together with a review of their combined impacts on animal, human and ecosystem health. With HAB/invertebrate outbreaks expected in some regions at higher frequency and intensity in the coming decades, we discuss the needs for new science, multi-disciplinary assessment and communication which will be essential for ensuring a continued increasing supply of aquaculture foodstuffs for further generations.

The Common Sunstar Crossaster papposus-A Neurotoxic Starfish.

Saxitoxins (STXs) are a family of potent neurotoxins produced naturally by certain species of phytoplankton and cyanobacteria which are extremely toxic to mammalian nervous systems. The accumulation of STXs in bivalve molluscs can significantly impact animal and human health. Recent work conducted in the North Sea highlighted the widespread presence of various saxitoxins in a range of benthic organisms, with the common sunstar (Crossaster papposus) demonstrating high concentrations of saxitoxins. In this study, an extensive sampling program was undertaken across multiple seas surrounding the UK, with 146 starfish and 5 brittlestars of multiple species analysed for STXs. All the common sunstars analysed (n > 70) contained quantifiable levels of STXs, with the total concentrations ranging from 99 to 11,245 µg STX eq/kg. The common sunstars were statistically different in terms of toxin loading to all the other starfish species tested. Two distinct toxic profiles were observed in sunstars, a decarbomylsaxitoxin (dcSTX)-dominant profile which encompassed samples from most of the UK coast and an STX and gonyautoxin2 (GTX2) profile from the North Yorkshire coast of England. Compartmentalisation studies demonstrated that the female gonads exhibited the highest toxin concentrations of all the individual organs tested, with concentrations >40,000 µg STX eq/kg in one sample. All the sunstars, male or female, exhibited the presence of STXs in the skin, digestive glands and gonads. This study highlights that the common sunstar ubiquitously contains STXs, independent of the geographical location around the UK and often at concentrations many times higher than the current regulatory limits for STXs in molluscs; therefore, the common sunstar should be considered toxic hereafter.

Patient identified factors influencing decisions to seek fertility care: adaptation of a wellness model.

Objective: To adapt a fertility care wellness model.Background: Despite availability of a range of diagnostic and therapeutic services for infertility, many do not seek care or discontinue care prior to achieving a live birth. Wellness models can inform research on patient decisions to seek and continue fertility care, as many barriers and drivers are represented within the dimensions of wellness.Methods: A mixed-methods online survey was completed by 135 people of reproductive age who experienced infertility in the USA. Outcomes included drivers and barriers to seeking or continuing fertility care. Identified factors were compared by treatment history using chi-square and Fisher's exact tests. Themes and patterns were identified within 174 responses to 6 open-response items through conventional content analysis.Results: Thematic analysis revealed practical (environmental, financial, and physical) and affective (emotional, social and spiritual) dimensions of wellness in decisions to seek care (67%), with affective rationales more prominent in decisions to return for care (78%).Conclusion: Decisions to seek fertility care and return after failed treatment integrate practical and affective rationales from financial, physical, environmental, emotional, social and spiritual wellness dimensions. Drivers and barriers within these dimensions should be considered to encourage care seeking and improve patient retention.

Oral nitrate supplementation to enhance pulmonary rehabilitation in COPD: ON-EPIC a multicentre, double-blind, placebo-controlled, randomised parallel group study.

RATIONALE: Dietary nitrate supplementation has been proposed as a strategy to improve exercise performance, both in healthy individuals and in people with COPD. We aimed to assess whether it could enhance the effect of pulmonary rehabilitation (PR) in COPD. METHODS: This double-blind, placebo-controlled, parallel group, randomised controlled study performed at four UK centres, enrolled adults with Global Initiative for Chronic Obstructive Lung Disease grade II-IV COPD and Medical Research Council dyspnoea score 3-5 or functional limitation to undertake a twice weekly 8-week PR programme. They were randomly assigned (1:1) to either 140 mL of nitrate-rich beetroot juice (BRJ) (12.9 mmol nitrate), or placebo nitrate-deplete BRJ, consumed 3 hours prior to undertaking each PR session. Allocation used computer-generated block randomisation. MEASUREMENTS: The primary outcome was change in incremental shuttle walk test (ISWT) distance. Secondary outcomes included quality of life, physical activity level, endothelial function via flow-mediated dilatation, fat-free mass index and blood pressure parameters. RESULTS: 165 participants were recruited, 78 randomised to nitrate-rich BRJ and 87 randomised to placebo. Exercise capacity increased more with active treatment (n=57) than placebo (n=65); median (IQR) change in ISWT distance +60 m (10, 85) vs +30 m (0, 70), estimated treatment effect 30 m (95% CI 10 to 40); p=0.027. Active treatment also impacted on systolic blood pressure: treatment group -5.0 mm Hg (-5.0, -3.0) versus control +6.0 mm Hg (-1.0, 15.5), estimated treatment effect -7 mm Hg (95% CI 7 to -20) (p<0.0005). No significant serious adverse events or side effects were reported. CONCLUSIONS: Dietary nitrate supplementation appears to be a well-tolerated and effective strategy to augment the benefits of PR in COPD. TRIAL REGISTRATION NUMBER: ISRCTN27860457.