A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Reversed Holocene temperature-moisture relationship in the Horn of Africa.

Anthropogenic climate change is predicted to severely impact the global hydrological cycle1, particularly in tropical regions where agriculture-based economies depend on monsoon rainfall2. In the Horn of Africa, more frequent drought conditions in recent decades3,4 contrast with climate models projecting precipitation to increase with rising temperature5. Here we use organic geochemical climate-proxy data from the sediment record of Lake Chala (Kenya and Tanzania) to probe the stability of the link between hydroclimate and temperature over approximately the past 75,000 years, hence encompassing a sufficiently wide range of temperatures to test the 'dry gets drier, wet gets wetter' paradigm6 of anthropogenic climate change in the time domain. We show that the positive relationship between effective moisture and temperature in easternmost Africa during the cooler last glacial period shifted to negative around the onset of the Holocene 11,700 years ago, when the atmospheric carbon dioxide concentration exceeded 250 parts per million and mean annual temperature approached modern-day values. Thus, at that time, the budget between monsoonal precipitation and continental evaporation7 crossed a tipping point such that the positive influence of temperature on evaporation became greater than its positive influence on precipitation. Our results imply that under continued anthropogenic warming, the Horn of Africa will probably experience further drying, and they highlight the need for improved simulation of both dynamic and thermodynamic processes in the tropical hydrological cycle.

Accurately computing the electronic properties of a quantum ring.

A promising approach to study condensed-matter systems is to simulate them on an engineered quantum platform1-4. However, the accuracy needed to outperform classical methods has not been achieved so far. Here, using 18 superconducting qubits, we provide an experimental blueprint for an accurate condensed-matter simulator and demonstrate how to investigate fundamental electronic properties. We benchmark the underlying method by reconstructing the single-particle band structure of a one-dimensional wire. We demonstrate nearly complete mitigation of decoherence and readout errors, and measure the energy eigenvalues of this wire with an error of approximately 0.01 rad, whereas typical energy scales are of the order of 1 rad. Insight into the fidelity of this algorithm is gained by highlighting the robust properties of a Fourier transform, including the ability to resolve eigenenergies with a statistical uncertainty of 10-4 rad. We also synthesize magnetic flux and disordered local potentials, which are two key tenets of a condensed-matter system. When sweeping the magnetic flux we observe avoided level crossings in the spectrum, providing a detailed fingerprint of the spatial distribution of local disorder. By combining these methods we reconstruct electronic properties of the eigenstates, observing persistent currents and a strong suppression of conductance with added disorder. Our work describes an accurate method for quantum simulation5,6 and paves the way to study new quantum materials with superconducting qubits.

A novel electronic health record-based, machine-learning model to predict severe hypoglycemia leading to hospitalizations in older adults with diabetes: A territory-wide cohort and modeling study.

BACKGROUND: Older adults with diabetes are at high risk of severe hypoglycemia (SH). Many machine-learning (ML) models predict short-term hypoglycemia are not specific for older adults and show poor precision-recall. We aimed to develop a multidimensional, electronic health record (EHR)-based ML model to predict one-year risk of SH requiring hospitalization in older adults with diabetes. METHODS AND FINDINGS: We adopted a case-control design for a retrospective territory-wide cohort of 1,456,618 records from 364,863 unique older adults (age ≥65 years) with diabetes and at least 1 Hong Kong Hospital Authority attendance from 2013 to 2018. We used 258 predictors including demographics, admissions, diagnoses, medications, and routine laboratory tests in a one-year period to predict SH events requiring hospitalization in the following 12 months. The cohort was randomly split into training, testing, and internal validation sets in a 7:2:1 ratio. Six ML algorithms were evaluated including logistic-regression, random forest, gradient boost machine, deep neural network (DNN), XGBoost, and Rulefit. We tested our model in a temporal validation cohort in the Hong Kong Diabetes Register with predictors defined in 2018 and outcome events defined in 2019. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) statistics, and positive predictive value (PPV). We identified 11,128 SH events requiring hospitalization during the observation periods. The XGBoost model yielded the best performance (AUROC = 0.978 [95% CI 0.972 to 0.984]; AUPRC = 0.670 [95% CI 0.652 to 0.688]; PPV = 0.721 [95% CI 0.703 to 0.739]). This was superior to an 11-variable conventional logistic-regression model comprised of age, sex, history of SH, hypertension, blood glucose, kidney function measurements, and use of oral glucose-lowering drugs (GLDs) (AUROC = 0.906; AUPRC = 0.085; PPV = 0.468). Top impactful predictors included non-use of lipid-regulating drugs, in-patient admission, urgent emergency triage, insulin use, and history of SH. External validation in the HKDR cohort yielded AUROC of 0.856 [95% CI 0.838 to 0.873]. Main limitations of this study included limited transportability of the model and lack of geographically independent validation. CONCLUSIONS: Our novel-ML model demonstrated good discrimination and high precision in predicting one-year risk of SH requiring hospitalization. This may be integrated into EHR decision support systems for preemptive intervention in older adults at highest risk.

Improved outcomes of large B-cell lymphoma patients treated with CD19 CAR T in the UK over time.

The success of CD19 Chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off-the-shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the 'standard-of-care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020-2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression-free survival (1-year PFS 50% vs. 32%, p < 0.001) and overall survival (1-year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high-grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up-to-date clinical data when comparing CAR T against new treatment options for r/r LBCL.

Outcome and feasibility of radiotherapy bridging in large B-cell lymphoma patients receiving CD19 CAR T in the UK.

Radiotherapy (RT) has potential synergistic effects with chimeric antigen receptor (CAR) T but is not widely used as bridging therapy due to logistical challenges and lack of standardised protocols. We analysed RT bridging in a multicentre national cohort of large B-cell lymphoma patients approved for 3L axicabtagene ciloleucel or tisagenlecleucel across 12 UK centres. Of 763 approved patients, 722 were leukapheresed, 717 had data available on bridging therapy. 169/717 (24%) received RT bridging, 129 as single modality and 40 as combined modality treatment (CMT). Of 169 patients, 65.7% had advanced stage, 36.9% bulky disease, 86.5% elevated LDH, 41.7% international prognostic index (IPI) ≥3 and 15.2% double/triple hit at the time of approval. Use of RT bridging varied from 11% to 32% between centres and increased over time. Vein-to-vein time and infusion rate did not differ between bridging modalities. RT-bridged patients had favourable outcomes with 1-year progression-free survival (PFS) of 56% for single modality and 47% for CMT (1-year PFS 43% for systemic bridging). This is the largest cohort of LBCL patients receiving RT bridging prior to CAR T reported to date. Our results show that RT bridging can be safely and effectively used even in advanced stage and high-risk disease, with low dropout rates and excellent outcomes.

Global availability and uptake of psychological services for adults, caregivers and children with food allergy.

BACKGROUND: Food allergy (FA) is associated with poor health-related quality of life and high levels of psychological distress. Psychological support is extremely important but not always available. As part of the Global Access to Psychological Services for Food Allergy (GAPS) study, we aimed to assess psychological distress and service use among adults, caregivers and children with FA in a global survey. METHODS: Participants (n = 1329 adults with FA; n = 1907 caregivers of children with FA) from >20 countries were recruited through patient organisations, social media advertisements and online survey panels to complete an online survey. Surveys were available in six languages. RESULTS: A total of 67.7% of adults and 77.2% of caregivers reported direct experience, and 51.6% of caregivers said their child had experienced FA-related psychological distress. The most commonly reported issue was anxiety about having an allergic reaction. Less than 20% had been assessed for FA-related psychological distress. There were significant differences across countries for levels of distress, screening for distress, seeing a mental health professional and being diagnosed with a FA-related mental health disorder (all p < .001). The United Kingdom, Australia and Brazil had the highest number of participants reporting distress. The most commonly reported barrier to seeing a mental health professional was cost. CONCLUSIONS: FA-related distress is common across countries, but with substantial country-to-country variability. Allergy providers are encouraged to routinely assess families for psychological distress and provide access to appropriate mental health resources. Development and implementation of evidence-based, patient-informed accessible, affordable FA interventions in multiple languages is urgently needed.

Using Inundation Extents to Predict Microbial Contamination in Private Wells after Flooding Events.

Disaster recovery poses unique challenges for residents reliant on private wells. Flooding events are drivers of microbial contamination in well water, but the relationship observed between flooding and contamination varies substantially. Here, we investigate the performance of different flood boundaries─the FEMA 100 year flood hazard boundary, height above nearest drainage-derived inundation extents, and satellite-derived extents from the Dartmouth Flood Observatory─in their ability to identify well water contamination following Hurricane Florence. Using these flood boundaries, we estimated about 2600 wells to 108,400 private wells may have been inundated─over 2 orders of magnitude difference based on boundary used. Using state-generated routine and post-Florence testing data, we observed that microbial contamination rates were 7.1-10.5 times higher within the three flood boundaries compared to routine conditions. However, the ability of the flood boundaries to identify contaminated samples varied spatially depending on the type of flooding (e.g., riverine, overbank, coastal). While participation in testing increased after Florence, rates were overall still low. With <1% of wells tested, there is a critical need for enhanced well water testing efforts. This work provides an understanding of the strengths and limitations of inundation mapping techniques, which are critical for guiding postdisaster well water response and recovery.

Evaluating Readmission Rates for a Statewide In-Home Ecosystemic Family-Based Treatment Program for Youth with Serious Emotional Disturbance.

Family Based Mental Health Services (FBMHS) with an embedded clinical model, Ecosystemic Structural Family Therapy, is an intervention designed for youth with a serious emotional disturbance (SED) who are at risk of out-of-home placement. The current evaluation examines the association between receipt of FBMHS and rates of out-of-home and community-based care during and after an episode of FBMHS. We identified 25,016 Medicaid-enrolled youth ages 3 to 17 years with receipt of a new FBMHS episode from 1/1/2015 to 6/30/2021. 14% of youth received out-of-home services. Rates of out-of-home service decreased during receipt of FBMHS (14.25-6.98%, p < .0001) and remained lower 6 months following discharge (to 6.95%, p < .0001). Short and longer doses of service were both associated with decreased rates of out-of-home services. FBMHS has been scaled across a large geographic area and is associated with lower rates of out-of-home placement for youth with SED.

Farming and the risk of developing osteoarthritis in Alberta, Canada.

INTRODUCTION: Because farming is a physically demanding occupation, farmers may be susceptible to developing osteoarthritis (OA). The aim of this study was to determine the risk of developing OA in Canadian farm, non-farm rural and urban residents. METHODS: A retrospective cohort study of five Alberta health administrative databases examined the risk of developing OA among three groups: farm (n=143 431), non-farm rural (n=143 431) and urban (n=143 431) residents over the fiscal years 2000-2001 through 2020-2021. The algorithm for OA ascertainment defined cases based on criteria including one hospital admission, two physician visits within a 2-year interval, or two ambulatory care visits within 2 years. Incidence rates, lifetime risk, and mortality rates were calculated. Cox proportional hazard models compared the incidence of OA for the three groups over the 21 years. RESULTS: A total of 26 957 OA cases were identified among 1 706 256 person-years (PYs) in the farm cohort. The crude incidence rate of OA over a period of 21 years ranged from 19.1 (95% confidence interval (CI) 18.6-19.6) per 1000 PYs in 2001 to 10.0 (95% CI 9.6-10.5) per 1000 PYs in 2021. The overall incidence rate was higher in the farm group (15.8 (95%CI 15.6-16.0) per 1000 PYs) as compared to the non-farm rural (14.7 (95%CI 14.5-14.9) per 1000 PYs) and the urban groups (13.3 (95%CI 13.1-13.4) per 1000 PYs). After adjusting for age and sex, the farm (6%; 95%CI 4-8%), and non-farm rural (9%; 95%CI 7-12%) groups had higher incidence rates than the urban group. The unadjusted non-injury mortality rate for the farm group with OA was lower (13.2 (95%CI 12.9-13.5) per 1000 PYs) than both the urban (14.5; 95%CI 14.1-14.8) and rural (18.0; 95%CI 17.6-18.4) groups. After adjusting for mortality, the lifetime risk of developing OA was 27.7% for farm residents, 25.6% for the non-farm rural cohort, and 24.0% for the urban cohort. CONCLUSION: When accounting for age and sex, farm and non-farm rural residents have a higher risk of developing OA as compared to the urban population. The higher mortality-adjusted lifetime risk of developing OA among farm residents highlights the necessity of specific interventions aimed at reducing the impact of this condition in rural communities. Further research is required to identify specific occupational and lifestyle risk factors associated with OA among farmers and to develop effective strategies for prevention and management.

CAR T in patients with large B-cell lymphoma not fit for autologous transplant.

Large B-cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa-cel versus axi-cel (52% vs. 48%) compared to 20% versus 80% in ASCT-fit patients; p < 0.0001. The drop-out rate from approval to infusion was significantly higher in the ASCT-unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression-free and overall survival were similar in both cohorts. CAR T was well-tolerated in ASCT-unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real-world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant.

Single fathers' experiences of using egg donation and surrogacy to start a family.

STUDY QUESTION: What are the experiences of single men using egg donation and surrogacy as a route to parenthood? SUMMARY ANSWER: The fathers mainly had a positive relationship with the surrogate and simultaneously exercised agency, and experienced challenges, during the process of surrogacy. WHAT IS KNOWN ALREADY: Little is known about single men's experiences of egg donation and surrogacy arrangements. Studies have focused on single men's decision-making processes about the use of surrogacy and family functioning once these families are formed. Questions remain about how fathers experience and navigate the process of surrogacy as a single man. STUDY DESIGN, SIZE, DURATION: The study is an international, in-depth qualitative study of fathers who chose to begin a family and parent alone. Data were collected between 2018 and 2021 as part of a larger study of solo fathers with different routes to parenthood. The present study reports on 21 fathers who used surrogacy and egg donation to begin their family. The average age of the fathers was 44 years, the fathers had young children aged 6 years or younger, and lived in countries across Australia, Europe, and North America. PARTICIPANTS/MATERIALS, SETTING, METHODS: Purposive sampling was used to recruit participants. In-depth semi-structured interviews were conducted. Interview topics included fathers' experiences of the process of using egg donation and surrogacy, and navigating the relationship with the surrogate. The audio-recorded interviews lasted around 2 hours and were subsequently transcribed verbatim. MAIN RESULTS AND THE ROLE OF CHANCE: Data were analysed using reflexive thematic analysis and qualitative content analysis. Most of the fathers chose an identifiable egg donor. Regarding the relationship with the surrogate, many fathers had remained in contact with her, but to differing degrees, and they generally reported positive relationships. Thematic analysis led to the identification of three themes relating to the fathers' experiences of choosing surrogacy as a single man: the ability to make choices; challenges and constraints; and special relationship. LIMITATIONS, REASONS FOR CAUTION: Due to the variation between different countries regarding laws on surrogacy, contextual factors may have impacted on the experiences of single fathers, and the sample size was small. However, the research provides new insights into an area with little academic literature. WIDER IMPLICATIONS OF THE FINDINGS: Given the growing trend of single men having children through surrogacy, the findings suggest that this new path to parenthood can be both rewarding and challenging. Single men may benefit from tailored support and counselling to help them navigate the surrogacy journey. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Wellcome Trust (grant number 208013/Z/17/Z). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: n/a.

'I know it's not normal but it's normal to me, and that's all that matters': experiences of young adults conceived through egg donation, sperm donation, and surrogacy.

STUDY QUESTION: What are thoughts and feelings of young adults born following egg donation, sperm donation, and surrogacy? SUMMARY ANSWER: Young adults felt either unconcerned or positive about the method of their conception. WHAT IS KNOWN ALREADY: Much of what we know about adults born to heterosexual couples following anonymous donation has come from samples of donor conceived people who had found out about their origins during adulthood. There have been no studies of how young adults born through surrogacy feel about their conception and towards their surrogate. STUDY DESIGN, SIZE, DURATION: Thirty-five young adults were interviewed as part of the seventh phase of a larger multi-method, multi-informant longitudinal study of assisted conception families in the UK. Adults were conceived using either egg donation, sperm donation, gestational surrogacy, or genetic surrogacy and were raised in households headed by heterosexual couples. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants had a mean age of 20 years and were born following traditional surrogacy (n = 10), gestational surrogacy (n = 5), egg donation (n = 11), or sperm donation (n = 9). All young adults born following sperm donation and most (n = 10) born from egg donation had an anonymous donor. In all surrogacy arrangements, the parents had met the surrogate prior to treatment. The majority of young adults were told about their conception by the age of 4 years. Participants were interviewed over the internet using a semi-structured interview. Interviews were transcribed verbatim and analysed using qualitative content analysis to understand young adults' thoughts and experiences related to their conception and whether they were interested in meeting their donor or surrogate. MAIN RESULTS AND THE ROLE OF CHANCE: Fourteen (40%) young adults felt their conception made them feel special or unique, with the remainder feeling either neutral or unconcerned (n = 21, 60%). A higher proportion of young adults conceived using egg donation (n = 8, 73%) felt unique/special compared to young adults born following sperm donation and surrogacy. For 10 of the young adults, their feelings about their conception had changed over time, with most becoming more positive (n = 9, 26%). For most young adults (n = 22, 63%), conception was rarely or infrequently discussed with others. However, when it was, these conversations were largely conducted with ease. Most (n = 25, 71%) did not know other individuals born through the same method of conception as themselves, and the vast majority (n = 34, 97%) were not members of any support groups. For the 25 young adults not in contact with their donor or surrogate, 11 wished to meet them, 8 did not want to have contact, and 6 were unsure. Young adults in contact with their donor or surrogate had varying levels of closeness to them. Only one young adult had searched for the identity of their donor. LIMITATIONS, REASONS FOR CAUTION: Of the 47 young adults invited to participate in the present study, 35 agreed to take part resulting in a response rate of 74%. It is therefore not known how those who did not take part felt about their conception. Given that the families reported here had been taking part in this longitudinal study from when the target child was aged 1 year, they may have been more likely to discuss the child's conception than other families. The study also utilized self-report measures, which may have been prone to social desirability, with donor conceived young adults wanting to present their experiences in a positive light. WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that young adults born through surrogacy and donor conception do not feel negatively about their birth and this may be a consequence of the young age at which they found out about their conception. Although some young adults said they wished to meet their donor, this did not necessarily mean they were actively searching for them. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Wellcome Trust [grant number 208013/Z/17/Z]. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Prior differences in previous trauma exposure primarily drive the observed racial/ethnic differences in posttrauma depression and anxiety following a recent trauma.

BACKGROUND: Racial and ethnic groups in the USA differ in the prevalence of posttraumatic stress disorder (PTSD). Recent research however has not observed consistent racial/ethnic differences in posttraumatic stress in the early aftermath of trauma, suggesting that such differences in chronic PTSD rates may be related to differences in recovery over time. METHODS: As part of the multisite, longitudinal AURORA study, we investigated racial/ethnic differences in PTSD and related outcomes within 3 months after trauma. Participants (n = 930) were recruited from emergency departments across the USA and provided periodic (2 weeks, 8 weeks, and 3 months after trauma) self-report assessments of PTSD, depression, dissociation, anxiety, and resilience. Linear models were completed to investigate racial/ethnic differences in posttraumatic dysfunction with subsequent follow-up models assessing potential effects of prior life stressors. RESULTS: Racial/ethnic groups did not differ in symptoms over time; however, Black participants showed reduced posttraumatic depression and anxiety symptoms overall compared to Hispanic participants and White participants. Racial/ethnic differences were not attenuated after accounting for differences in sociodemographic factors. However, racial/ethnic differences in depression and anxiety were no longer significant after accounting for greater prior trauma exposure and childhood emotional abuse in White participants. CONCLUSIONS: The present findings suggest prior differences in previous trauma exposure partially mediate the observed racial/ethnic differences in posttraumatic depression and anxiety symptoms following a recent trauma. Our findings further demonstrate that racial/ethnic groups show similar rates of symptom recovery over time. Future work utilizing longer time-scale data is needed to elucidate potential racial/ethnic differences in long-term symptom trajectories.

Intravenous Dabigatran Provides Adequate Anticoagulation for Cardiopulmonary Bypass Using a Rabbit Model.

BACKGROUND: Heparin anticoagulation has been used successfully for cardiopulmonary bypass (CPB). However, an alternative anticoagulant approach is desirable due to the cases of heparin-induced thrombocytopenia. Dabigatran provides anticoagulation for an in vitro model of simulated CPB. The current analysis tests the hypothesis that dabigatran provides sufficient anticoagulation for CPB in intact rabbits. METHODS: Nonlinear mixed effects models were used to estimate dabigatran parameters for a two-compartment pharmacokinetic model in 10 New Zealand White rabbits. A dabigatran infusion designed to maintain a plasma concentration of 90 µg/ml was run throughout CPB based on the pharmacokinetics. Animals were subjected to sternotomy and anticoagulated with IV dabigatran (six animals) or heparin (four animals). Rabbits were cannulated centrally using the right atrium and ascending aorta and CPB was maintained for 120 min. Measurement of activated clotting time, thromboelastometric reaction time, and blood gases were performed during CPB. Then, the animals were euthanized, and the brain and one kidney were removed for histology. Sections of the arterial filters were inspected using electron microscopy. RESULTS: The observed dabigatran concentrations during CPB were greater than the target concentration, ranging from 137 ± 40 µg/ml at 5 min of CPB to 428 ± 150 µg/ml at 60 min, and 295 ± 35 µg/ml at 120 min. All rabbits completed 2 h of CPB without visible thrombosis. In the two groups, reaction time values were elevated, reaching 10,262 ± 4,198 s (dabigatran group) and 354 ± 141 s (heparin group) at 120 min of CPB. Brains and kidneys showed no evidence of thrombosis or ultrastructural damage. Sections of the arterial line filter showed minimal or no fibrin. There was no significant difference in outcomes between dabigatran- and heparin-treated animals. CONCLUSIONS: In this first-use, proof-of-concept study, the authors have shown that dabigatran provides acceptable anticoagulation similar to heparin to prevent thrombosis using a rabbit CPB model.

The efficiency of the EmERGE pathway of care for people living with HIV in England.

This study estimated the efficiency of implementing the EmERGE Pathway of Care for people living with medically stable HIV in Brighton, UK; an App enables individuals to communicate with caregivers via their smart-phone. Individual data on the use of HIV outpatient services were collected one-year pre- and post-implementation of EmERGE. Unit costs of HIV outpatient services were calculated and linked with mean use of services per patient year. Primary outcomes were CD4 count and viral load; patient activation and quality-of-life measures were secondary outcomes. 565 participants were followed up April 2017 - October 2018: 93% men, mean age at recruitment 47.0 years (95%CI:46.2-47.8). Outpatient visits decreased by 9% from 5.6 (95%CI:5.4-5.8) to 5.1 (95%CI:4.9-5.3). Face-to-face visits decreased and virtual visits increased. Annual costs decreased by 9% from £751 (95%CI: £722-£780) to £678 (95%CI: £653-£705). Including anti-retroviral drugs, total annual cost decreased from £7,343 (95%CI: £7,314-7,372) to £7,270 (95%CI: £7,245-7,297): ARVs costs comprised 90%. EmERGE was a cost-saving intervention, patients remained engaged and clinically stable. Annual costs were reduced, but ARVs continue to dominate costs. Extension of EmERGE to other people with chronic conditions, could produce greater efficiencies but these needs to be evaluated and monitored over time.

CT pulmonary angiography: optimising acute thoracic imaging by fixed-timing contrast medium delivery with a modified breathing instruction.

AIM: To compare the thoracic vascular opacification achieved using the standard bolus-tracking protocol (BTP) with a fixed-timing protocol (FTP) with a modified breathing instruction during computed tomography pulmonary angiography (CTPA) examinations. MATERIALS AND METHODS: A single-centre review of CTPA examinations performed between July 2018 and January 2019 using the BTP or FTP and weight-based contrast dosing of 20 mg iodine/kg body weight/s for 20 seconds at 100 kV tube potential. Radiodensity (in Hounsfield units) was analysed in the right ventricle, main pulmonary artery (MPA), left atrium, left ventricle, and ascending and descending thoracic aorta (DTA). A p-value of <0.05 was considered significant. RESULTS: Of 782 examinations, 88 BTP and 90 FTP examinations were included. Mean attenuation of the MPA was similar in the FTP (396 ± 106 HU) and BTP (362 ± 119 HU; p=0.06); however, good-quality (≥250 HU) MPA opacification was achieved in more FTP examinations (87/90, 96.7%) compared to the BTP (73/88, 82.9%; p=0.002). Mean attenuation of the DTA was better in the FTP (325 ± 72 HU) than the BTP (228 ± 75 HU; p <0.0001), with good-quality opacification (≥250 HU) in 76/90 (84.4%) FTP examinations compared with 36/88 (40.9%) BTP examinations (p <0.001). CONCLUSION: The FTP achieves better opacification of the MPA and DTA compared to the BTP.

On the equivalence of the X-ray scattering retrieval with beam tracking and analyser-based imaging using a synchrotron source.

X-ray phase contrast imaging (XPCI) methods give access to contrast mechanisms that are based on the refractive properties of matter on top of the absorption coefficient in conventional x-ray imaging. Ultra small angle x-ray scattering (USAXS) is a phase contrast mechanism that arises due to multiple refraction events caused by physical features of a scale below the physical resolution of the used imaging system. USAXS contrast can therefore give insight into subresolution structural information, which is an ongoing research topic in the vast field of different XPCI techniques. In this study, we quantitatively compare the USAXS signal retrieved by the beam tracking XPCI technique with the gold standard of the analyzer based imaging XPCI technique using a synchrotron x-ray source. We find that, provided certain conditions are met, the two methods measure the same quantity.

Social participation of older people in urban and rural areas: Canadian Longitudinal Study on Aging.

BACKGROUND AND OBJECTIVES: Although the positive influence of social activity on health is now well-established, a complex relationship exists among social participation, personal, social and the environment. Social participation of older adults was examined in rural and urban settings to identify features of the built-environment and perception of neighborhood specific to the locale. RESEARCH DESIGN AND METHODS: Using cross-sectional data from the Canadian Longitudinal Study on Aging (CLSA), we examined social participation and health of older people (65 + yrs) in relation to the built environment and sociocultural contexts for urban and rural areas. A social participation index was derived from responses on the frequency of participating in 8 social activities over the past 12 months. Personal, household and neighborhood indicators were examined to develop multivariable regression models for social participation in urban and rural cohorts. RESULTS: No meaningful differences were seen with the frequency of social participation between rural and urban settings; however, the type of community-related activities differed in that a greater proportion of urban participants reported sports and educational/cultural events than rural participants. Service club activities were greater for rural than urban participants. Different neighborhood features were statistically significant factors in explaining social participation in rural than in urban locales, although transportation was a significant factor regardless of locale. Trustworthiness, belonging and safety were perceived factors of the neighborhood associated with higher social participation for rural participants. DISCUSSION AND IMPLICATIONS: The relationship between home and health becomes stronger as one ages. Social and physical features of built environment specific to urban and rural settings need to be considered when implementing appropriate social activities for older people.

A park-based group mobility program for older adults with difficulty walking outdoors: a quantitative process evaluation of the Getting Older Adults Outdoors (GO-OUT) randomized controlled trial.

BACKGROUND: Process evaluations of randomized controlled trials (RCTs) of community exercise programs are important to help explain the results of a trial and provide evidence of the feasibility for community implementation. The objectives of this process evaluation for a multi-centre RCT of outdoor walking interventions for older adults with difficulty walking outdoors, were to determine: 1) implementation fidelity (the extent to which elements of the intervention were delivered as specified in the original protocol) and 2) participant engagement (the receipt of intervention components by the participants) in the Getting Older Adults Outdoors (GO-OUT) trial. METHODS: GO-OUT participants attended an active 1-day workshop designed to foster safe, outdoor walking skills. After the workshop, 190 people at 4 sites were randomized to an outdoor walk group (OWG) (n = 98) which met 2x/week for 10 weeks, or the weekly reminders (WR) group (n = 92) which received a phone reminder 1x/week for 10 weeks. The OWG had 5 components - warm-up, continuous distance walk, task-oriented walking activities, 2nd continuous distance walk, and cool-down. Data on implementation fidelity and participant engagement were gathered during the study through site communications, use of standardized forms, reflective notes of the OWG leaders, and accelerometry and GPS assessment of participants during 2 weeks of the OWG. RESULTS: All sites implemented the workshop according to the protocol. Participants were engaged in all 8 activity stations of the workshop. WR were provided to 96% of the participants in the WR intervention group. The 5 components of the OWG sessions were implemented in over 95% of the sessions, as outlined in the protocol. Average attendance in the OWG was not high - 15% of participants did not attend any sessions and 64% of participants in the OWG attended > 50% of the sessions. Evaluations with accelerometry and GPS during week 3 and 9 OWG sessions suggest that participants who attended were engaged and active during the OWG. CONCLUSIONS: This process evaluation helps explain the main study findings and demonstrates the flexibility required in the protocol for safe and feasible community implementation. Future research could explore the use of additional behaviour change strategies to optimize attendance for community implementation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03292510 Date of registration: September 25, 2017.