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Abstract Background Appropriate use of medication is a key indicator of the quality of care provided in long-term care (LTC). The objective of this study was to determine whether resident-facility language concordance/discordance is associated with the odds of potentially inappropriate prescribing of antipsychotics (PIP-AP) in LTC. Methods We conducted a population-based, retrospective cohort study of LTC residents in Ontario, Canada from 2010 to 2019. We obtained resident language from standardized resident assessments, and derived facility language by determining the proportion of residents belonging to each linguistic group within individual LTC homes. Using linked administrative databases, we identified all instances of PIP-AP during a 1-year follow-up period. PIP-AP was defined using the STOPP-START criteria, which have previously been shown to predict adverse clinical events such as emergency department (ED) visits and hospitalizations. The association between linguistic factors and PIP-AP was assessed using adjusted multivariable logistic regression analysis. Results We identified 198,729 LTC residents consisting of 162,814 Anglophones (81.9%), 6,230 Francophones (3.1%), and 29,685 Allophones (14.9%). The odds of PIP-AP of were higher for both Francophones (aOR 1.15, 95% CI 1.08–1.23) and Allophones (aOR 1.11, 95% CI 1.08–1.15) when compared to Anglophones. When compared to English LTC homes, French LTC homes had greater odds of PIP-AP (aOR 1.12, 95% CI 1.05–1.20), while Allophone homes had lower odds of PIP-AP (aOR 0.82, 95% CI 0.77–0.86). Residents living in language-discordant LTC homes had higher odds of PIP-AP when compared to LTC residents living in language-concordant LTC homes (aOR 1.07, 95% CI 1.04–1.10). Conclusion This study identified linguistic factors related to the odds of PIP-AP in LTC, suggesting that the linguistic environment may have an impact on the quality of care provided to residents.

Abstract Introduction Hindfoot varus deformity is common in people with unilateral upper motor neuron syndrome (UMNS) and can be dynamic or persistent. The aims of this study were (1) to gain insight into plantar pressure characteristics of people with chronic UMNS in relation to hindfoot varus and (2) to propose a quantitative outcome measure, based on plantar pressure, for the scientific evaluation of surgical interventions. Methods In this retrospective study, a cohort comprising plantar pressure data of 49 people with UMNS (22 “no hindfoot varus”, 18 “dynamic hindfoot varus”, and 9 “persistent hindfoot varus”), and 586 healthy controls was analyzed. As an indication of plantigrade foot contact, the ratio between the plantar contact area of the affected and the non‐affected foot was calculated. To investigate spatial and temporal aspects of plantar pressure, normalized plantar pressure patterns and center of pressure trajectories were computed. Results People with UMNS had lower plantar pressure area ratios compared to healthy controls. Additionally, increased plantar pressure underneath the lateral foot was found in people with a persistent hindfoot varus. Center of pressure trajectories were more lateral during the first 26% of the stance phase in people with a dynamic hindfoot varus and during the first 82% of the stance phase in people with a persistent hindfoot varus compared to healthy controls. Conclusion Spatial and temporal differences in plantar pressure were found in people with dynamic or persistent hindfoot varus deformity. We propose to primarily use the medio‐lateral center of pressure trajectory as outcome measure for the scientific evaluation of surgical interventions targeting hindfoot varus.

Background: Research comparing artificial intelligence and machine learning (AI/ML) methods with classical statistical methods applied to large population health databases is limited. Objectives: This retrospective cohort study aimed to compare the predictive performance of AI/ML algorithms against conventional multivariate logistic regression models using linked health administrative data. Methods: Using Ontario's population health databases, we created a cohort of residents of the city of Ottawa, Ontario, who underwent a PCR test for COVID-19 between March 10, 2020, and May 13, 2021. Using demographic, socio-economic and health data (including COVID-19 PCR test results and available, symptom data), we developed predictive models for the purpose of COVID-19 case identification using the following approaches: classical multivariate logistic regression (LR); deep neural network (DNN); random forest (RF); and gradient boosting trees (GBT). Model performance comparisons were made using the area under the curve (AUC) swarm plot for 10-fold cross-validation. Results: The cohort consisted of n = 351,248 Ottawa residents tested for COVID-19 during the study period. Among whom, a total of n = 883,879 unique COVID-19 tests were performed (2.6 % positive test results). Inclusion of COVID-19 symptoms data in the analysis improved model performance and variable predictive value across all tested models (p

BackgroundLanguage-concordant health care, or health care in a patient’s language of choice, is an important element of health accessibility that improves patient safety and comfort and facilitates an increased quality of care. However, prior research has found that linguistic minorities often face higher travel burdens to access language-concordant care compared to the general population. ObjectiveThis study intended to assess patient experiences and satisfaction with an online interactive physician map that allows patients to find family physicians who speak their preferred language in and around Ottawa, Ontario, Canada, as a means of identifying areas of improvement. MethodsThis study used an online survey with questions related to user satisfaction. Responses to Likert-scale questions were compiled as summary statistics and short-answer responses underwent thematic analysis. The study setting was Ottawa and Renfrew County, Ontario, and the surrounding region, including the province of Quebec. ResultsA total of 93 respondents completed the survey and self-identified as living in Ontario or Quebec. Overall, 57 (61%) respondents were “very satisfied” or “somewhat satisfied” with the map, 16 (17%) were “neither satisfied nor dissatisfied,” and 20 (22%) were “very dissatisfied” or “somewhat dissatisfied.” We found no significant differences in satisfaction by preferred language, age group, physician attachment, or intended beneficiary. A total of 56 respondents provided short-answer responses to an open-ended question about map improvements. The most common specific suggestion was to show which physicians are accepting new patients (n=20). Other suggestions included data refreshes (n=6), user interface adjustments (n=23), and additional languages (n=2). Some participants also provided positive feedback (n=5) or expressed concern with their inability to find a family physician (n=5). Several comments included multiple suggestions. ConclusionsWhile most patients were satisfied with the online map, a significant minority expressed dissatisfaction that the map did not show which family physicians were accepting new patients. This suggests that there may be public interest in an accessible database of which family physicians in Ontario are currently accepting new patients.

Abstract Improved therapies are needed against snakebite envenoming, which kills and permanently disables thousands of people each year. Recently developed neutralizing monoclonal antibodies against several snake toxins have shown promise in preclinical rodent models. Here, we use phage display technology to discover a human monoclonal antibody and show that this antibody causes antibody-dependent enhancement of toxicity (ADET) of myotoxin II from the venomous pit viper, Bothrops asper, in a mouse model of envenoming that mimics a snakebite. While clinical ADET related to snake venom has not yet been reported in humans, this report of ADET of a toxin from the animal kingdom highlights the necessity of assessing even well-known antibody formats in representative preclinical models to evaluate their therapeutic utility against toxins or venoms. This is essential to avoid potential deleterious effects as exemplified in the present study.

Maternal characteristics, social dynamics, and environmental factors can all influence reproduction and survival and shape trade-offs that might arise between these components of fitness. Short-lived mammals like the golden-mantled ground squirrel (GMGS; Callospermophilus lateralis) tend to maximize effort toward current reproduction at the expense of survival but may be complicated by other aspects of the species' life history and environment. Here, we use 25 years of data (1995-2020) collected from a population of GMGS at the Rocky Mountain Biological Research Laboratory in Gothic, Colorado, to test the effect of several maternal characteristics (e.g., age, experience, and timing of litter emergence), social context (e.g., litter sex ratio and kin density), and environmental context (e.g., date of bare ground and length of vegetative growing season) on survival of reproductive female GMGS using Cox proportional hazard models. Our results indicated that social dynamics (i.e., density) and environmental conditions (i.e., standardized first day of permanent snow cover and length of growing season) explained significant variation in annual maternal survival, while maternal characteristics did not. A higher density of related breeding females and the total number of females (both related and unrelated to the focal mother) were associated with an increase in the mortality hazard. A later standardized date of the first day of permanent snow cover and a shorter growing season both reduced the maternal mortality hazard. Together, our results suggest that factors extrinsic to the squirrels affect maternal survival and thus may also influence local population growth and dynamics in GMGS and other short-lived, territorial mammal species.

Abstract Background Prior studies have demonstrated the negative impact of language barriers on access, quality, and safety of healthcare, which can lead to health disparities in linguistic minorities. As the population ages, those with multiple chronic diseases will require increasing levels of home care and long-term services. This study described the levels of multimorbidity among recipients of home care in Ontario, Canada by linguistic group. Methods Population-based retrospective cohort of 510,685 adults receiving home care between April 1, 2010, to March 31, 2018, in Ontario, Canada. We estimated and compared prevalence and characteristics of multimorbidity (2 or more chronic diseases) across linguistic groups (Francophones, Anglophones, Allophones). The most common combinations and clustering of chronic diseases were examined. Logistic regression models were used to explore the main predictors of ‘severe’ multimorbidity (defined as the presence of five or more chronic diseases). Results The proportion of home care recipients with multimorbidity and severe multimorbidity was 92% and 44%, respectively. The prevalence of multimorbidity was slightly higher among Allophones (93.6%) than among Anglophones (91.8%) and Francophones (92.4%). However, Francophones had higher rates of cardiovascular and respiratory disease (64.9%) when compared to Anglophones (60.2%) and Allophones (61.5%), while Anglophones had higher rates of cancer (34.2%) when compared to Francophones (25.2%) and Allophones (24.3%). Relative to Anglophones, Allophones were more likely to have severe multimorbidity (adjusted OR = 1.04, [95% CI: 1.02–1.06]). Conclusions The prevalence of multimorbidity among Ontarians receiving home care services is high; especially for whose primary language is a language other than English or French (i.e., Allophones). Understanding differences in the prevalence and characteristics of multimorbidity across linguistic groups will help tailor healthcare services to the unique needs of patients living in minority linguistic situations.

Reports suggest possible risks of adverse cardiovascular reactions, including heart failure, associated with non-ergot dopamine agonist (DA) use in Parkinson’s disease (PD). The objectives of our review were to evaluate the risk of heart failure and other adverse cardiovascular reactions in PD patients who received a non-ergot DA compared with other anti-PD pharmacological interventions, placebo, or no intervention. Studies were identified via searches of six bibliographic databases. Randomized controlled trials (RCTs) and non-randomized studies (NRS) were eligible for study inclusion. Random-effect meta-analyses were performed to estimate adverse cardiovascular reaction risks. Quality of evidence was assessed using GRADE. In total, forty-four studies (thirty-six RCTs and eight NRS) satisfied our inclusion criteria. A single RCT found no significant difference in the risk of heart failure with ropinirole compared with bromocriptine (odds ratio (OR) 0.39, 95% confidence interval (CI) 0.07 to 2.04; low certainty). Conversely, three case–control studies reported a risk of heart failure with non-ergot DA treatment. The quality of evidence for the risk of heart failure was judged as low or very low. Findings suggest that non-ergot DA use may be associated with adverse cardiovascular outcomes, including heart failure. Studies are needed to better understand cardiovascular risks associated with PD treatment.

Objective: To evaluate if access to team-based primary care is related to medication management outcomes for older adults. Methods: We completed two retrospective cohort studies using administrative health data for older adults (66+) in Ontario (n = 428,852) and Québec (n = 310,198) who were rostered with a family physician (FP) between the 2001/02 and 2017/18 fiscal years. We generated matched comparison groups of older adults rostered to an FP practicing in a team-based model, and older adults rostered to an FP in a non-team model. We compared the following outcomes between these groups: any adverse drug reactions (ADRs), any potentially inappropriate prescription (PIP), and polypharmacy. Average treatment effects of access to team-based care were estimated using a difference-in-differences estimator. Results: The risk of an ADR was 22 % higher (RR = 1.22, 95 % CI = 1.18, 1.26) for older adults rostered to a team-based FP in Québec and 6 % lower (RR = 0.943, 95 % CI = 0.907, 0.978) in Ontario. However, absolute risk differences were less than 0.5 %. Differences in the risk of polypharmacy were small in Québec (RR = 1.005, 95 % CI = 1.001, 1.009) and Ontario (RR = 1.004, 95 % CI = 1.001, 1.007) and had absolute risk differences of less than 1 % in both provinces. Effects on PIP were not statistically or clinically significant in adjusted models. Interpretation: We did not find evidence that access to team-based primary care in Ontario or Québec meaningfully improved medication management outcomes for older adults.

Abstract Background Hereditary motor and sensory neuropathies (HMSN), also known as Charcot-Marie-Tooth disease, are characterized by affected peripheral nerves. This often results in foot deformities that can be classified into four categories: (1) plantar flexed first metatarsal, neutral hindfoot, (2) plantar flexed first metatarsal, correctable hindfoot varus, (3) plantar flexed first metatarsal, uncorrectable hindfoot varus, and (4) hindfoot valgus. To improve management and for the evaluation of surgical interventions, a quantitative evaluation of foot function is required. The first aim of this study was to provide insight into plantar pressure of people with HMSN in relation to foot deformities. The second aim was to propose a quantitative outcome measure for the evaluation of surgical interventions based on plantar pressure. Methods In this historic cohort study, plantar pressure measurements of 52 people with HMSN and 586 healthy controls were evaluated. In addition to the evaluation of complete plantar pressure patterns, root mean square deviations (RMSD) of plantar pressure patterns from the mean plantar pressure pattern of healthy controls were calculated as a measure of abnormality. Furthermore, center of pressure trajectories were calculated to investigate temporal characteristics. Additionally, plantar pressure ratios of the lateral foot, toes, first metatarsal head, second/third metatarsal heads, fifth metatarsal head, and midfoot were calculated to measure overloading of foot areas. Results Larger RMSD values were found for all foot deformity categories compared to healthy controls (p

Circulating cell-free nucleic acids (ccfNAs) of plasma are a remarkable source of genetic, epigenetic and transcriptomic materials originating from different cells, tissues and organs of an individual. They have been increasingly studied over the past decade as they can carry several important pieces of information about the health status of an individual, which makes them biomarkers of choice for non-invasive diagnosis of numerous diseases and health conditions. However, few studies have investigated variations of plasma ccfNAs in healthy subjects, particularly in relation to aging, healthy aging and longevity, despite the great variability of these biological processes among individuals. Here, we reviewed several studies that focused on the analysis of circulating cell-free DNA (ccfDNA) and microRNAs (ccfmiRNAs) during aging and in the elderly, including some on exceptionally long-lived individuals, i.e., centenarians. After a brief overview of the types, origins and functions of plasma ccfNAs, we described the variations of both ccfDNA and ccfmiRNAs during aging as well as the identification of several potential ccfDNA-based and ccfmiRNA-based biomarkers of aging, healthy aging and/or longevity. We finally highlighted some prospects offered by ccfNAs for the understanding and improvement of healthy aging and longevity.

BackgroundImplementation of eHealth is progressing slowly. In-depth insight into patients’ preferences and needs regarding eHealth might improve its use. ObjectiveThis study aimed to describe when patients want to use eHealth, how patients want to communicate and receive information digitally, and what factors influence the use of eHealth in clinical practice. MethodsA multimethod study was conducted. Two meetings of ~5.5 hours with plenary information sessions and focus groups were held with 22 patients from the rheumatology, orthopedics, and rehabilitation departments of a Dutch hospital specialized in musculoskeletal disorders. Assignments were performed during the focus groups in which qualitative (eg, semistructured interview questions) and quantitative (ie, voting and ranking factors) data were collected. ResultsThe way patients want to use eHealth varies between patients and moments of a patient’s care pathway. Patients’ digital channel preferences depended on the need for interaction with a health care provider (HCP). The interaction need is in turn influenced by the degree to which information or communication is specific to an individual patient and leads to consequences for the patient. The 5 most important factors influencing the use of eHealth were access to medical information (eg, electronic health records), perceived control over disease management, correctness and completeness of information, data security, and access to information or an HCP at any time. The 5 least important factors influencing eHealth use were help with using digital devices, having internet or equipment, digital skills, attitude or emotions toward eHealth, and societal benefits. ConclusionsPatients identified opportunities for using eHealth during all moments of their care pathway. However, preferences for eHealth varied between patients and phases in the care pathway. As a consequence, eHealth should be tailored to fit individual patients’ preferences but also the need for interaction regarding different topics by offering a variety of digital channels with a gradient of interaction possibilities. Furthermore, digital skills and access to the internet might become less important to focus on in the future. Improving eHealth use by patients may be achieved by providing patients access to correct and safe (medical) information and more control over their care.

In mammalian cells, >25% of synthesized proteins are exported through the secretory pathway. The pathway complexity, however, obfuscates its impact on the secretion of different proteins. Unraveling its impact on diverse proteins is particularly important for biopharmaceutical production. Here we delineate the core secretory pathway functions and integrate them with genome-scale metabolic reconstructions of human, mouse, and Chinese hamster ovary cells. The resulting reconstructions enable the computation of energetic costs and machinery demands of each secreted protein. By integrating additional omics data, we find that highly secretory cells have adapted to reduce expression and secretion of other expensive host cell proteins. Furthermore, we predict metabolic costs and maximum productivities of biotherapeutic proteins and identify protein features that most significantly impact protein secretion. Finally, the model successfully predicts the increase in secretion of a monoclonal antibody after silencing a highly expressed selection marker. This work represents a knowledgebase of the mammalian secretory pathway that serves as a novel tool for systems biotechnology.

Abstract is missing (Short communication)

Objective To estimate the risk of non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma (HL) in patients with inflammatory bowel disease (IBD).Design We undertook a two-country population cohort study with all patients diagnosed with IBD in Norway and Sweden from 1987 and 1993 through 2015 and 2016, respectively, and analysed the risk of NHL and HL. In Sweden, we also analysed prescriptions of thiopurines and anti-tumour necrosis factor (TNF)-α therapy from 2005. We calculated standardised incidence ratios (SIRs) with 95% CIs using the general populations as reference.Results Among 131 492 patients with IBD with a medium follow-up of 9.6 years, we identified 369 cases of NHL and 44 cases of HL. The SIR of NHL was 1.3 (95% CI 1.1 to 1.5) in ulcerative colitis and 1.4 (95% CI 1.2 to 1.7) in Crohn’s disease. We found no compelling heterogeneity in analyses stratified by patient characteristics. We found a similar pattern and magnitude of excess risks for HL. At 10 years, cumulative incidence was 0.26% (95% CI 0.23% to 0.30%) and 0.06% (95% CI 0.04% to 0.08%) for NHL and HL, respectively. Higher excess risks were found among patients with NHL with concomitant primary sclerosing cholangitis (SIR 3.4; 95% CI 2.1 to 5.2) and in those prescribed thiopurines alone (SIR 2.8; 95% CI 1.4 to 5.7) or with anti-TNF-α agents (SIR 5.7; 95% CI 2.7 to 11.9).Conclusion Patients with IBD have a statistically significant increased risk of malignant lymphomas compared with the general population, but the absolute risk remains low.

Objectives To determine the clinical and economic impact of a community-based, hybrid model of in-person and virtual care by comparing health-system performance of the rural jurisdiction where this model was implemented with neighbouring jurisdictions without such a model and the broader regional health system.Design A cross-sectional comparative study.Setting Ontario, Canada, with a focus on three largely rural public health units from 1 April 2018 until 31 March 2021.Participants All residents of Ontario, Canada under the age of 105 eligible for the Ontario Health Insurance Plan during the study period.Interventions An innovative, community-based, hybrid model of in-person and virtual care, the Virtual Triage and Assessment Centre (VTAC), was implemented in Renfrew County, Ontario on 27 March 2020.Main outcome measures Primary outcome was a change in emergency department (ED) visits anywhere in Ontario, secondary outcomes included changes in hospitalisations and health-system costs, using per cent changes in mean monthly values of linked health-system administrative data for 2 years preimplementation and 1 year postimplementation.Results Renfrew County saw larger declines in ED visits (−34.4%, 95% CI −41.9% to −26.0%) and hospitalisations (−11.1%, 95% CI −19.7% to −1.5%) and slower growth in health-system costs than other rural regions studied. VTAC patients’ low-acuity ED visits decreased by −32.9%, high-acuity visits increased by 8.2%, and hospitalisations increased by 30.0%.Conclusion After implementing VTAC, Renfrew County saw reduced ED visits and hospitalisations and slower health-system cost growth compared with neighbouring rural jurisdictions. VTAC patients experienced reduced unnecessary ED visits and increased appropriate care. Community-based, hybrid models of in-person and virtual care may reduce the burden on emergency and hospital services in rural, remote and underserved regions. Further study is required to evaluate potential for scale and spread.

Abstract Objective Gout and diabetes mellitus type 2 (DM) frequently co-exist. The pharmacological effects of metformin may include anti-inflammatory and urate lowering effects. The objective of this study was to test these effects in patients with gout starting uric acid lowering treatment (ULT) in secondary care. Methods Retrospective cohort study including patients with gout and DM starting ULT. Differences in the incidence density of gout flares, proportion of patients reaching target sUA in the first six months after starting ULT, and difference in mean allopurinol dose at sUA target were compared between users of metformin and users of other or no anti-diabetic drugs (control group). Correction for confounding was applied. Results A total of 307 patients were included, of whom 160 (52.1%) used metformin. The incidence of flares was 1.61 and 1.70 in the first six months for respectively the metformin group and control group. The incidence rate ratio for gout flares was not significant (0.95, 95% CI 0.78 to 1.14). At six months, 62.8% and 54.9% reached target sUA in the metformin and control group respectively, corrected odds ratio of 1.09 (95% CI 0.66 to 1.80). There was no difference in mean allopurinol dose at sUA target 266 mg for metformin users and 236 mg for the control group, difference 30 mg (95% CI − 4.7 to 65.5). Conclusions In conclusion we could not confirm a clinically relevant anti-inflammatory or urate lowering effect of metformin in patients starting ULT treatment and receiving usual care flare prophylaxis.

Background: Modulation of pathological neural circuit activity in the brain with a minimum of complications is an area of intense interest. Objective: The goal of the study was to alter neurons' physiological states without apparent damage of cellular integrity using stereotactic radiosurgery (SRS). Methods: We treated a 7.5 mm-diameter target on the visual cortex of Göttingen minipigs with doses of 40, 60, 80, and 100 Gy. Six months post-irradiation, the pigs were implanted with a 9 mm-wide, eight-shank multi-electrode probe, which spanned the radiation focus as well as the low-exposure neighboring areas. Results: Doses of 40 Gy led to an increase of spontaneous firing rate, six months post-irradiation, while doses of 60 Gy and greater were associated with a decrease. Subjecting the animals to visual stimuli resulted in typical visual evoked potentials (VEP). At 40 Gy, a significant reduction of the P1 peak time, indicative of higher network excitability was observed. At 80 Gy, P1 peak time was not affected, while a minor reduction at 60 Gy was seen. No distance-dependent effects on spontaneous firing rate, or on VEP were observed. Post-mortem histology revealed no evidence of necrosis at doses below 60 Gy. In an in vitro assay comprising of iPS-derived human neuron-astrocyte co-cultures, we found a higher vulnerability of inhibitory neurons than excitatory neurons with respect to radiation, which might provide the cellular mechanism of the disinhibitory effect observed in vivo. Conclusion: We provide initial evidence for a rather circuit-wide, long-lasting disinhibitory effect of low sub-ablative doses of SRS.

Abstract Background The shortage of available organs for life-saving transplants persists worldwide. While a majority support donating their organs or tissue when they die, many have not registered their wish to do so. When registered, next of kin are much more likely to follow-through with the decision to donate. In many countries, most people visit their family physician office each year and this setting is a promising, yet underused, site where more people could register for deceased organ donation. Our primary aim was to evaluate the effectiveness of an intervention to promote organ donation registration in family physician’s offices. Methods We developed an intervention to address barriers and enablers to organ donation registration that involved physician office reception staff inviting patients to register on a tablet in the waiting room while they waited for their appointment. We conducted a cross-sectional stepped-wedge cluster randomized controlled registry trial to evaluate the intervention. We recruited six family physician offices in Canada. All offices began with usual care and then every two weeks, one office (randomly assigned) started the intervention until all offices delivered the intervention. The primary outcome was registration for deceased organ donation in the provincial organ registration registry, assessed within the 7 days of the physician visit. At the end of the trial, we also conducted interviews with clinic staff to assess any barriers and enablers to delivering the intervention. Results The trial involved 24,616 patient visits by 13,562 unique patients: 12,484 visits in the intervention period and 12,132 in the control period. There was no statistically significant difference in the percentage of patients registered for deceased organ donation in the intervention versus control period (48.0% vs 46.2%; absolute difference after accounting for the secular trend: 0.12%; 95% CI: − 2.30, 2.54; p=0.92). Interviews with clinic staff indicated location of the tablet within a waiting room, patient rapport, existing registration, confidence and motivation to deliver the intervention and competing priorities as barriers and enablers to delivery. Conclusions Our intervention did not increase donor registration. Nonetheless, family physician offices may still remain a promising setting to develop and evaluate better interventions to increase organ donation registration. Trial registration NCT03213171

Abstract Lymphoblastoid cell lines (LCLs) derive from blood infected in vitro by Epstein–Barr virus and were used in several genetic, transcriptomic and epigenomic studies. Although few changes were shown between LCL and blood genotypes (SNPs) validating their use in genetics, more were highlighted for other genomic features and/or in their transcriptome and epigenome. This could render them less appropriate for these studies, notably when blood DNA could still be available. Here we developed a simple, high-throughput and cost-effective real-time PCR approach allowing to distinguish blood from LCL DNA samples based on the presence of EBV relative load and rearranged T-cell receptors γ and β. Our approach was able to achieve 98.5% sensitivity and 100% specificity on DNA of known origin (458 blood and 316 LCL DNA). It was further applied to 1957 DNA samples from the CEPH Aging cohort comprising DNA of uncertain origin, identifying 784 blood and 1016 LCL DNA. A subset of these DNA was further analyzed with an epigenetic clock indicating that DNA extracted from blood should be preferred to LCL for DNA methylation-based age prediction analysis. Our approach could thereby be a powerful tool to ascertain the origin of DNA in old collections prior to (epi)genomic studies.

Objective: Long‐term gout management is based on reducing serum urate by using urate‐lowering therapy (ULT). A lifelong treat‐to‐target approach is advocated, although a ULT (taper to) stop attempt can be considered (treat‐to‐avoid symptoms approach) during remission. Exploring the beliefs of patients with gout on long‐term ULT strategies during remission is important for optimizing gout management. We aimed to identify factors that influence the decision for continuation or discontinuation of ULT and to determine their relative importance according to patients with gout in remission. Methods: A mixed‐methods design was used. First, semistructured interviews (substudy 1) were conducted to identify barriers and facilitators for the (dis)continuation of ULT using inductive thematic analysis. Afterwards, these barriers/facilitators were summarized into neutrally phrased items and used in a maximum difference scaling study (substudy 2) to determine their relative importance using the rescaled probability score. Results: Substudies 1 and 2 included 18 and 156 patients, respectively. Substudy 1 yielded 22 items within 10 overarching themes. Substudy 2 revealed that the perceived risk of joint damage and gout flares and that ULT use gives some assurance were the most important items. The costs, ease of receiving ULT, and its practical use were the least important items. Conclusion: These results can aid shared decision‐making and provide input for what is important to discuss with patients with gout in remission when they consider ULT discontinuation. The emphasis should be on the risk of having gout flares and joint damage, not so much on facilitating how easily medication is received. [ABSTRACT FROM AUTHOR]

Introduction: Hindfoot varus deformity is common in people with unilateral upper motor neuron syndrome (UMNS) and can be dynamic or persistent. The aims of this study were (1) to gain insight into plantar pressure characteristics of people with chronic UMNS in relation to hindfoot varus and (2) to propose a quantitative outcome measure, based on plantar pressure, for the scientific evaluation of surgical interventions. Methods: In this retrospective study, a cohort comprising plantar pressure data of 49 people with UMNS (22 "no hindfoot varus", 18 "dynamic hindfoot varus", and 9 "persistent hindfoot varus"), and 586 healthy controls was analyzed. As an indication of plantigrade foot contact, the ratio between the plantar contact area of the affected and the non‐affected foot was calculated. To investigate spatial and temporal aspects of plantar pressure, normalized plantar pressure patterns and center of pressure trajectories were computed. Results: People with UMNS had lower plantar pressure area ratios compared to healthy controls. Additionally, increased plantar pressure underneath the lateral foot was found in people with a persistent hindfoot varus. Center of pressure trajectories were more lateral during the first 26% of the stance phase in people with a dynamic hindfoot varus and during the first 82% of the stance phase in people with a persistent hindfoot varus compared to healthy controls. Conclusion: Spatial and temporal differences in plantar pressure were found in people with dynamic or persistent hindfoot varus deformity. We propose to primarily use the medio‐lateral center of pressure trajectory as outcome measure for the scientific evaluation of surgical interventions targeting hindfoot varus. [ABSTRACT FROM AUTHOR]

Background: Ambient fine particulate matter (PM2.5) causes millions of deaths every year worldwide. Identification of the most harmful types of PM2.5 would facilitate efficient prevention strategies. Objectives: The aim of this study was to investigate associations between components of PM2.5 and mortality in a nation-wide Danish population. Methods: Our study base was Danes born 1921–1985 and aged 30–85 years, who were followed up for mortality from 1991 to 2015. We included 678,465 natural cause mortality cases and selected five age, sex and calendar time matched controls to each case from the study base. We retrieved the address history of the study population from Danish registries and assessed five-year average concentrations of eight PM2.5 components using deterministic Chemistry-Transport Models air pollution models. We estimated mortality rate ratios (MRRs) by conditional logistic regression and adjusted for socio-demographical factors at individual and neighborhood level. Results: Single pollutant models showed the strongest associations between natural cause mortality and an interquartile increase in sulfate particles (SO4−-) (MRR: 1.123; 95 % CI: 1.100–1.147 per 1.5 µg/m3) and secondary organic aerosol (SOA) (MRR: 1.054; 95 % CI: 1.048–1.061 per 0.050 µg/m3). Two-pollutant models showed robust associations between SO4−− and SOA and natural cause mortality. Elemental carbon and mineral dust showed robust associations with higher respiratory and lung cancer mortality. Conclusion: This nation-wide study found robust associations between natural cause mortality and SO4−− particles and SOA, which is in line with the results of previous studies. Elemental carbon and mineral dust showed robust associations with higher respiratory and lung cancer mortality.

Functional characterization of regulatory DNA elements in broad genetic contexts is a prerequisite for forward engineering of biological systems. Translation initiation site (TIS) sequences are attractive to use for regulating gene activity and metabolic pathway fluxes because the genetic changes are minimal. However, limited knowledge is available on tuning gene outputs by varying TISs in different genetic and environmental contexts. Here, we created TIS hexamer libraries in baker's yeast Saccharomyces cerevisiae directly 5' end of a reporter gene in various promoter contexts and measured gene activity distributions for each library. Next, selected TIS sequences, resulted in almost 10-fold changes in reporter outputs, were experimentally characterized in various environmental and genetic contexts in both yeast and mammalian cells. From our analyses, we observed strong linear correlations (R2 = 0.75-0.98) between all pairwise combinations of TIS order and gene activity. Finally, our analysis enabled the identification of a TIS with almost 50% stronger output than a commonly used TIS for protein expression in mammalian cells, and selected TISs were also used to tune gene activities in yeast at a metabolic branch point in order to prototype fitness and carotenoid production landscapes. Taken together, the characterized TISs support reliable context-independent forward engineering of translation initiation in eukaryotes.