Notes

Dataset with regard to Get varieties classification.
Inhaled long-acting β-adrenergic agonists (LABAs) and short-acting β-adrenergic agonists are approved for the treatment of obstructive lung disease via actions mediated by β2 adrenergic receptors (β2-ARs) that increase cellular cAMP synthesis. This review discusses the potential of β2-AR agonists, in particular LABAs, for the treatment of acute respiratory distress syndrome (ARDS). We emphasize ARDS induced by pneumonia and focus on the pathobiology of ARDS and actions of LABAs and cAMP on pulmonary and immune cell types. β2-AR agonists/cAMP have beneficial actions that include protection of epithelial and endothelial cells from injury, restoration of alveolar fluid clearance, and reduction of fibrotic remodeling. β2-AR agonists/cAMP also exert anti-inflammatory effects on the immune system by actions on several types of immune cells. Early administration is likely critical for optimizing efficacy of LABAs or other cAMP-elevating agents, such as agonists of other Gs-coupled G protein-coupled receptors or cyclic nucleotide phosphodiesterase inhibitors. Clinical studies that target lung injury early, prior to development of ARDS, are thus needed to further assess the use of inhaled LABAs, perhaps combined with inhaled corticosteroids and/or long-acting muscarinic cholinergic antagonists. Such agents may provide a multipronged, repurposing, and efficacious therapeutic approach while minimizing systemic toxicity. SIGNIFICANCE STATEMENT Acute respiratory distress syndrome (ARDS) after pulmonary alveolar injury (e.g., certain viral infections) is associated with ∼40% mortality and in need of new therapeutic approaches. This review summarizes the pathobiology of ARDS, focusing on contributions of pulmonary and immune cell types and potentially beneficial actions of β2 adrenergic receptors and cAMP. Early administration of inhaled β2 adrenergic agonists and perhaps other cAMP-elevating agents after alveolar injury may be a prophylactic approach to prevent development of ARDS.
Hospital based follow-up has been the standard of care for endometrial cancer. Patient initiated follow-up is a useful adjunct for lower risk cancers. The purpose of this study was to evaluate outcomes of endometrial cancer patients after stratification into risk groupings, with particular attention to salvageable relapses.

All patients treated surgically for International Federation of Gynecology and Obstetrics (FIGO) stage I-IVA endometrial cancer of all histological subtypes, from January 2009 until March 2019, were analyzed. Patient and tumor characteristics, treatment details, relapse, death, and last follow-up dates were collected. Site of relapse, presence of symptoms, and whether relapses were salvageable were also identified. The European Society of Medical Oncology-European Society of Gynecological Oncology 2020 risk stratification was assigned, and relapse free and overall survival were estimated.

900 patients met the eligibility criteria. Median age was 66 years (range 28-96) and follow-up dptoms; prognosis after relapse remains favorable. Overall salvageable relapses were infrequent and cannot justify intensive hospital based follow-up. Use of patient initiated follow-up is therefore appropriate, as per the British Gynaecological Cancer Society's guidelines, for all risk groupings.
Quality of surgical care as a crucial component of a comprehensive multi-disciplinary management improves outcomes in patients with endometrial carcinoma, notably helping to avoid suboptimal surgical treatment. Quality indicators (QIs) enable healthcare professionals to measure their clinical management with regard to ideal standards of care.

In order to complete its set of QIs for the surgical management of gynecological cancers, the European Society of Gynaecological Oncology (ESGO) initiated the development of QIs for the surgical treatment of endometrial carcinoma.

QIs were based on scientific evidence and/or expert consensus. The development process included a systematic literature search for the identification of potential QIs and documentation of the scientific evidence, two consensus meetings of a group of international experts, an internal validation process, and external review by a large international panel of clinicians and patient representatives. QIs were defined using a structured format entation of surgical and pathological elements. Each QI was associated with a score. An assessment form including a scoring system was built as basis for ESGO accreditation of centers for endometrial cancer surgery.During the COVID-19 pandemic, pressures on clinical services required adaptation to how care was prioritised and delivered for women with gynecological cancer. This document discusses potential 'salvage' measures when treatment has deviated from the usual standard of care. The British Gynaecological Cancer Society convened a multidisciplinary working group to develop recommendations for the onward management and follow-up of women with gynecological cancer who have been impacted by a change in treatment during the pandemic. These recommendations are presented for each tumor type and for healthcare systems, and the impact on gynecological services are discussed. It will be important that patient concerns about the impact of COVID-19 on their cancer pathway are acknowledged and addressed for their ongoing care.
Scientific data on the safety and efficacy of flow diverter stents (FDS) for the treatment of unruptured internal carotid artery (ICA) aneurysms with compressive neuro-ophthalmological symptoms are scarce. We studied this subject in a retrospective international multicenter series, pooling data of 9 tertiary care neurointerventional departments.

To investigate, in a retrospective, multicentric cohort of patients presenting with visual or oculomotor symptoms attributed to a compressive carotid artery in an unruptured intracranial aneurysm, the safety and efficacy profiles of FDS, by analyzing neuro-opthalmologic symptom evolution following FDS placement, complications, and aneurysm obliteration rates.

All patients treated since 2015 with a FDS for an unruptured aneurysm of the ICA with signs of compressive cranial nerve symptoms (CN II, III, IV, VI) were included.

We treated 55 patients with 55 aneurysms; 21 (38.2%) patients had oculomotor and 15 (27.3%) visual symptoms only; 19 (34.5%) presented with are not rare.
FDS are effective to treat patients with compressive aneurysms of the ICA causing neuro-ophthalmological symptoms, especially when treatment is initiated early after symptom onset, and aneurysm occlusion is adequate. However, serious complications are not rare.Containing the COVID-19 pandemic in the United States requires mobilizing a large majority of the mass public to vaccinate, but many Americans are hesitant or opposed to vaccination. A significant predictor of vaccine attitudes in the United States is religiosity, with more-religious individuals expressing more distrust in science and being less likely to get vaccinated. Here, we test whether explicit cues of common religious identity can help medical experts build trust and increase vaccination intentions. In a preregistered survey experiment conducted with a sample of unvaccinated American Christians (n = 1,765), we presented participants with a vaccine endorsement from a prominent medical expert (NIH Director Francis Collins) and a short essay about doctors' and scientists' endorsement of the vaccines. In the common religious identity condition, these materials also highlighted the religious identity of Collins and many medical experts. Unvaccinated Christians in the common identity condition expressed higher trust in medical experts, greater intentions to vaccinate, and greater intentions to promote vaccination to friends and family than those who did not see the common identity cue. These effects were moderated by religiosity, with the strongest effects observed among the most religious participants, and statistically mediated by heightened perceptions of shared values with the medical expert endorsing the vaccine. These findings demonstrate the efficacy of common identity cues for promoting vaccination in a vaccine-hesitant subpopulation. More generally, the results illustrate how trust in science can be built through the invocation of common group identities, even identities often assumed to be in tension with science.The vast majority of a bacterial population is killed when treated with a lethal concentration of antibiotics. The time scale of this killing is often comparable with the bacterial generation time before the addition of antibiotics. Yet, a small subpopulation typically survives for an extended period. However, the long-term killing dynamics of bacterial cells has not been fully quantified even in well-controlled laboratory conditions. We constructed a week-long killing assay and followed the survival fraction of Escherichia coli K12 exposed to a high concentration of ciprofloxacin. We found that long-term survivors were formed during exponential growth, with some cells surviving at least 7 d. The long-term dynamics contained at least three time scales, which greatly enhances predictions of the population survival time compared with the biphasic extrapolation from the short-term behavior. Furthermore, we observed a long memory effect of a brief starvation pulse, which was dependent on the (p)ppGpp synthase relA Specifically, 1 h of carbon starvation before antibiotics exposure increased the surviving fraction by nearly 100-fold even after 4 d of ciprofloxacin treatment.Introduction Transarterial radioembolization (TARE) is a loco-regional radiopharmaceutical therapy based on the delivery of radioactive yttrium-90 (90Y) microspheres to liver tumors. The importance of personalized dosimetry to make TARE safer and more effective has been demonstrated in recent clinical studies, stressing the need for quantification of the dose-response relationship to ultimately optimize the administered activity pre-treatment and image it post-treatment. 90Y dosimetric studies are challenging due to the lack of accurate and precise methods but best realized with positron emission tomography combined with Monte Carlo simulations and other image modalities to calculate a segmental dose distribution. Methods Two PET/CT scanners were evaluated in this study the Biograph mCT and the total-body uEXPLORER. The reconstructions of a NEMA IQ phantom and two patient images were performed using our standard clinical oncology protocol. A late portal phase CECT was used to contour the liver segments and cretry. The uEXPLORER scanner showed a better signal-to-noise ratio than mCT especially in lower count regions of interest, which is expected to improve dose quantification and tumor dosimetry.Quantitative dynamic PET with compartmental modeling has the potential to enable multiparametric imaging and more accurate quantification as compared to static PET imaging. Conventional methods for parametric imaging commonly use a single kinetic model for all image voxels and neglect the heterogeneity of physiological models, which can work well for single-organ parametric imaging but may significantly compromise total-body parametric imaging on long axial field-of-view scanners. In this paper, we evaluate the necessity of voxel-wise compartmental modeling strategies, including time delay correction and model selection, for total-body multiparametric imaging. Methods Ten subjects (5 patients with metastatic cancer and 5 healthy volunteers) were scanned on the uEXPLORER total-body PET/CT system following injection of 370 MBq 18F-fluorodeoxyglucose (FDG). Dynamic data were acquired for 60 minutes. Total-body parametric imaging was performed using two approaches. One is the conventional method that uses a single irreversible two-tissue compartmental model with and without time delay correction. The second approach selects the best kinetic model from three candidate models for individual voxels. The differences between the two approaches were evaluated for parametric imaging of micro kinetic parameters and FDG net influx rate Ki Results Time delay correction had a non-negligible effect on kinetic quantification of various organs and lesions. The effect was larger in lesions with higher blood volume. Parametric imaging of Ki with the standard two-tissue model introduced artifacts in vascular regions, which was overcome by the voxel-wise model selection strategy. Conclusion The time delay and appropriate kinetic model vary in different organs and lesions. Modeling of the time delay of the blood input function and model selection improved total-body multiparametric imaging.Progressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterised by neuro-glial tau pathology. A new staging system for PSP pathology at post-mortem has been described and validated. We used a data-driven approach to test whether post-mortem pathological staging in PSP can be reproduced in vivo with 18F-flortaucipir PET. Methods N = 42 patients with probable PSP and N = 39 controls underwent 18F-flortaucipir PET. Conditional inference tree analyses on regional binding potential values identified absent/present pathology thresholds to define in vivo staging. Following the staging system for PSP pathology, the combination of absent/present values across all regions was evaluated to assign each participant to in vivo stages. Analysis of variance was applied to analyse differences among means of disease severity between stages. In vivo staging was compared with post-mortem staging in N = 9 patients who also had post-mortem confirmation of the diagnosis and stage. Results Stage assignment was estimable in 41 patients N = 10 patients were classified in stage I/II, N = 26 in stage III/IV, N = 5 in stage V/VI, while N = 1 was not classifiable. An explorative sub-staging identified N = 2 patients in stage I, N = 8 in stage II, N = 9 in stage III, N = 17 in stage IV and N = 5 in stage V. However, the nominal 18F-flortaucipir derived stage was not associated with clinical severity and was not indicative of pathology staging at post-mortem. Conclusion 18F-flortaucipir PET in vivo does not correspond to neuropathological staging in PSP. This analytic approach, seeking to mirror in vivo the neuropathology staging with PET-to-autopsy correlational analyses might enable in vivo staging with next-generation PET tracers for tau, but further evidence and comparison with post-mortem data are needed.Alpha-particle radiotherapy has already been shown to be impervious to most resistance mechanisms. However, in established (i.e. large, vascularized) soft-tissue lesions, the diffusion-limited penetration depths of radiolabeled antibodies and/or nanocarriers (up to 50-80µm) combined with the short range of α-particles (4-5 cell diameters) may result in only partial tumor irradiation potentially limiting treatment efficacy. To address this challenge, we combined carriers with complementary intratumoral microdistributions of the delivered α-particles. We use the α-particle generator Actinium-225 (225Ac), and we combine (1) a tumor-responsive liposome that upon tumor uptake releases in the interstitium a highly-diffusing form of its radioactive payload (225Ac-DOTA), which may penetrate the deeper parts of tumors where antibodies do not reach, with (2) a separately administered, less-penetrating radiolabeled-antibody irradiating the tumor perivascular regions from where liposome contents clear too fast. Methods Ower tumor delivered doses. Augmentation of antibody-targeted α-particle therapies with tumor-responsive liposomes may address partial tumor irradiation improving therapeutic effects.Quantitative SPECT/CT imaging is currently the state-of-the-art for peri-therapeutic monitoring of radiopharmaceutical distributions. Due to poor resolution, however, the verification of SPECT/CT-based activity distributions is of particular importance. Due to the lack of a ground truth in patient measurements, phantoms are commonly used as a substitute for clinical validation of quantitative SPECT/CT. Due to the time-consuming and erroneous preparation of multi-compartment phantoms, e.g. for the kidney, the usually very complex internal activity distributions are typically replaced by one- or two-compartment models. To provide a simplified solution for generating inhomogeneous activity distributions, this work presents a methodology for designing single-compartment phantoms that mimic inhomogeneous spatial activity distributions by internal filling structures of different volume fractions. Methods A series of phantoms with different filling structures was designed, 3D printed, and measured. After assessing tn combinations of filling structure and reconstruction, a histogram analysis indicated an even more complex activity distribution in the patient than represented by the two compartments assumed in our model. Conclusion The proposed methodology provides patient-specific phantoms mimicking inhomogeneous activity distributions while using a single stock solution, thus simplifying the filling process and reducing uncertainties in the activity determination. This enables an unprecedented possibility for patient-specific evaluation of radiopharmaceutical uptake, reducing uncertainties in internal dosimetry and individualized treatments.
To evaluate the impact of timing of initiation of parenteral nutrition (PN) after birth in very preterm infants.

Propensity-matched analysis of data from the UK National Neonatal Research Database.

65 033 babies <31 weeks gestation admitted to neonatal units in England and Wales between 2008 and 2019.

PN initiated in the first 2 days (early) versus after the second postnatal day (late). Babies who died in the first 2 days without receiving PN were analysed as 'late'.

The main outcome measure was morbidity-free survival to discharge. The secondary outcomes were survival to discharge, growth and other core neonatal outcomes.

No difference was found in the primary outcome (absolute rate difference (ARD) between early and late 0.50%, 95% CI -0.45 to 1.45, p=0.29). The early group had higher rates of survival to discharge (ARD 3.3%, 95% CI 2.7 to 3.8, p<0.001), late-onset sepsis (ARD 0.84%, 95% CI 0.48 to 1.2, p<0.001), bronchopulmonary dysplasia (ARD 1.24%, 95% CI 0.30 to 2.17, p=0.01), treated retinopathy of prematurity (ARD 0.50%, 95% CI 0.17 to 0.84, p<0.001), surgical procedures (ARD 0.80%, 95% CI 0.20 to 1.40, p=0.01) and greater drop in weight z-score between birth and discharge (absolute difference 0.019, 95% CI 0.003 to 0.035, p=0.02). Of 4.9% of babies who died in the first 2 days, 3.4% were in the late group and not exposed to PN.

Residual confounding and survival bias cannot be excluded and justify the need for a randomised controlled trial powered to detect differences in important functional outcomes.
Residual confounding and survival bias cannot be excluded and justify the need for a randomised controlled trial powered to detect differences in important functional outcomes.The FDA approval of immune checkpoint inhibitors for cancers with tumor mutation burden (TMB) of at least 10 mut/Mb is postulated to reduce healthcare disparities by broadly expanding treatment eligibility. In a cohort of 39,400 patients with available genomic and race data, black and Asian patients were less likely to have TMB-high cancers in multiple types of malignancies based on the currently approved cut-off. Decreasing TMB thresholds preferentially increased the eligibility of minority patients for immune checkpoint inhibitors while retaining predictive value of treatment benefit in a cohort of immune checkpoint inhibitor treated patients. This study highlights differing distributions of TMB-high cancers between racial groups and provides guidance in developing more rational eligibility criteria for immune checkpoint inhibitors.Glioblastoma is the the most common primary brain tumor in adults. Onset of disease is followed by a uniformly lethal prognosis and dismal overall survival. While immunotherapies have revolutionized treatment in other difficult-to-treat cancers, these have failed to demonstrate significant clinical benefit in patients with glioblastoma. Obstacles to success include the heterogeneous tumor microenvironment (TME), the immune-privileged intracranial space, the blood-brain barrier (BBB) and local and systemic immunosuppressions. Monoclonal antibody-based therapies have failed at least in part due to their inability to access the intracranial compartment. Bispecific T-cell engagers are promising antibody fragment-based therapies which can bring T cells close to their target and capture them with a high binding affinity. They can redirect the entire repertoire of T cells against tumor, independent of T-cell receptor specificity. However, the multiple challenges posed by the TME, immune privilege and the BBB suggest that a single agent approach may be insufficient to yield durable, long-lasting antitumor efficacy. In this review, we discuss the mechanism of action of T-cell engagers, their preclinical and clinical developments to date. We also draw comparisons with other classes of multispecific antibodies and potential combinations using these antibody fragment therapies.
To assess the additive value of dual-energy CT (DECT) over single-energy CT (SECT) to radiomics-based response prediction in patients with metastatic melanoma preceding immunotherapy.

A total of 140 consecutive patients with melanoma (58 female, 63±16 years) for whom baseline DECT tumor load assessment revealed stage IV and who were subsequently treated with immunotherapy were included. Best response was determined using the clinical reports (81 responders 27 complete response, 45 partial response, 9 stable disease). Individual lesion response was classified manually analogous to RECIST 1.1 through 1291 follow-up examinations on a total of 776 lesions (6.7±7.2 per patient). The patients were sorted chronologically into a study and a validation cohort (each n=70). The baseline DECT was examined using specialized tumor segmentation prototype software, and radiomic features were analyzed for response predictors. Significant features were selected using univariate statistics with Bonferroni correction and mulethod of DECT-specific radiomic analysis provides a significant additive value over SECT radiomics approaches for response prediction in patients with metastatic melanoma preceding immunotherapy, especially on a lesion-based level. As mixed tumor response is not uncommon in metastatic melanoma, this lends a powerful tool for clinical decision-making and may potentially be an essential step toward individualized medicine.
The new method of DECT-specific radiomic analysis provides a significant additive value over SECT radiomics approaches for response prediction in patients with metastatic melanoma preceding immunotherapy, especially on a lesion-based level. As mixed tumor response is not uncommon in metastatic melanoma, this lends a powerful tool for clinical decision-making and may potentially be an essential step toward individualized medicine.
Recently, immunotherapy with immune checkpoint inhibitors (ICIs) has shown promising efficacy in biliary tract cancer (BTC), which includes gallbladder cancer (GBC) and cholangiocarcinoma (CHOL). Understanding the association between immunotherapy outcomes and the genomic profile of advanced BTC may further improve the clinical benefits from immunotherapy.

Genomic tumor DNA was isolated from 98 Chinese patients with advanced BTC and used for targeted next-generation sequencing of 416 cancer-related genes to identify the genomic alterations common to advanced BTC. Thirty-four patients had received ICI camrelizumab plus gemcitabine and oxaliplatin (from the NCT03486678 trial) as a first-line treatment. Tumor-infiltrating immune cells were evaluated using immunofluorescence staining.

KRAS and TP53 mutations were much more frequent in the advanced-stage BTC cohort than in other cohorts with mostly early stage disease. Specifically, KRAS-TP53 co-mutations were favored in advanced CHOL, with a favorable respotratification of immunotherapy outcomes.
Genomic alterations in advanced BTC were associated with specific prognosis and immunotherapy outcomes. Combining genomic classification with TME evaluation further improved the stratification of immunotherapy outcomes.
Patients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples.

We established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort.

Two patients were super-responders, and the otherICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer.
The TIGIT/CD155 axis mediates resistance to ICIs in patients with melanoma with an inflamed TME, promoting the development of TIGIT blockade therapies in such patients with cancer.
Tumors can influence peripheral immune macroenvironment, thereby creating opportunities for non-invasive serum/plasma immunobiomarkers for immunostratification and immunotherapy designing. However, current approaches for immunobiomarkers' detection are largely quantitative, which is unreliable for assessing functional peripheral immunodynamics of patients with cancer. Hence, we aimed to design a functional biomarker modality for capturing peripheral immune signaling in patients with cancer for reliable immunostratification.

We used a data-driven
framework, integrating existing tumor/blood bulk-RNAseq or single-cell (sc)RNAseq datasets of patients with cancer, to inform the design of an innovative serum-screening modality, that is, serum-functional immunodynamic status (sFIS) assay. Next, we pursued proof-of-concept analyses via multiparametric serum profiling of patients with ovarian cancer (OV) with sFIS assay combined with Luminex (cytokines/soluble immune checkpoints), CA125-antigen detection, and wies.
We established sFIS assay as a novel biomarker resource for serum screening in patients with OV to evaluate peripheral immunodynamics, patient survival trends and malignancy risk, and to design preclinical chemo-immunotherapy strategies.
It is well-known that finding an optimum medication at the correct dose for elderly patients is challenging for the practitioner. This study aimed to examine the main trends in prescribing medications for elderly patients and their compliance with the principles of rational pharmacotherapy, and to establish the main factors affecting adherence to treatment in these patients.

956 records of outpatients over 60 years of age were examined. The groups of medications prescribed, the dosage simultaneously prescribed to one patient, the structure of nosologies among elderly patients, and the frequency of side effects were studied. The second stage of the study with 147 patients involved examining the adherence to medications by elderly patients using the Brief Medication Questionnaire.

A total of 147 patients (79 (53.7%) women and 68 (46.3%) men) aged over 60 years who were taking ≥4 medications for primary and concomitant diseases were surveyed. The phenomenon of polypragmasy is clearly seen when prescribing liarities of the pharmacodynamics and pharmacokinetics of drugs prescribed, the presence of polymorbidity, the prevalence of polypragmasy, and the low adherence to treatment.
Pharmacy automation is increasing in hospitals. The aim of this systematic review was to identify and evaluate the literature on automated unit dose dispensing systems (UDDS) producing individually packaged and labelled drugs for inpatients.

The search was conducted on eight electronic databases, including Scopus, Medline Ovid, and Cinahl, and limited to peer reviewed articles with English abstracts published 2000-2020. Studies were included in the review if drug dispensing was performed by an automated UDDS where individually packaged and labelled unit doses were subsequently assembled patient specifically for inpatients. All outcomes related to UDDS functionality were included with specific interest in medication safety, cost-efficiency and stock management. Outcomes were categorised and results synthesised qualitatively.

664 publications were screened, one article identified manually, resulting in eight included articles. Outcomes of the studies were categorised as medication administration errors (Mable knowledge for hospital decision makers on the cost-benefit of the investment and to support decision making.
UDDS improved patient safety. However, automation is a costly investment and the implementation process is complex and time consuming. Further controlled studies are needed on the clinical and economical outcomes of automated UDDS to produce reliable knowledge for hospital decision makers on the cost-benefit of the investment and to support decision making.
unCoVer-Unravelling data for rapid evidence-based response to COVID-19-is a Horizon 2020-funded network of 29 partners from 18 countries capable of collecting and using real-world data (RWD) derived from the response and provision of care to patients with COVID-19 by health systems across Europe and elsewhere. unCoVer aims to exploit the full potential of this information to rapidly address clinical and epidemiological research questions arising from the evolving pandemic.

From the onset of the COVID-19 pandemic, partners are gathering RWD from electronic health records currently including information from over 22 000 hospitalised patients with COVID-19, and national surveillance and screening data, and registries with over 1 900 000 COVID-19 cases across Europe, with continuous updates. These heterogeneous datasets will be described, harmonised and integrated into a multi-user data repository operated through Opal-DataSHIELD, an interoperable open-source server application. Federated data analyses, withons.
After strict ethical considerations, databases will be available through a federated data analysis platform that allows processing of available COVID-19 RWD without disclosing identification information to analysts and limiting output to data aggregates. Dissemination of unCoVer's activities will be related to the access and use of dissimilar RWD, as well as the results generated by the pooled analyses. Dissemination will include training and educational activities, scientific publications and conference communications.
This study aims to implement a version of patient-centred labels (PCL) consistent with current labelling practice in Australia; assess the effectiveness of PCL in relation to the proportion of participants that correctly comprehend dosing instructions, and explore the proportion of correct comprehension of PCL in participants with both low and high health literacy.

Randomised controlled trial.

A large tertiary care hospital in Brisbane, Queensland, Australia.

121 participants with a majority born in Australia (65.3%), New Zealand (14.0%), the UK (6.6%) and Ireland (2.5%).

Participants were randomly assigned to either a panel of three PCL (n=61) or three standard labels (n=60) and asked to comprehend their assigned panel of labels.

Difference in the proportion of participants that correctly comprehend dosing instructions provided on PCL compared with standard labels. The two-proportion test was used to measure the impact of PCL on the proportion of participants correctly comprehending dosing instructions.

A greater proportion of participants were able to accurately comprehend PCL compared with standard labels. The proportion of participants who were able to correctly comprehend dose instructions provided on all three labels was significantly higher in the group that received PCL; 23.3% standard vs 83.6% PCL, p<0.001. The effect was observed in both low and high health literacy participants. The proportion of participants with accurate label comprehension was higher in participants with low Newest Vital Signs scores (8.3% standard vs 85.7% PCL, p<0.001) and low Rapid Estimate of Adult Literacy in Medicine scores (10.5% standard vs 96.0% PCL, p<0.001) who received PCL.

This study supports the use of PCL in Australian pharmacy practice. PCL provide simple, clear and explicit dosing instructions to patients. Implementing PCL may reduce the risk of misinterpreting dosing instructions by patients and improve quality use of medicines.

ACTRN12621000083897; Results.
ACTRN12621000083897; Results.
Despite firearms contributing to significant morbidity and mortality globally, firearm injury epidemiology is seldom described outside of the USA. We examined firearm injuries among youth in Canada, including weapon type, and intent.

Population-based, pooled cross-sectional study using linked health administrative and demographic databases.

Ontario, Canada.

All children and youth from birth to 24 years, residing in Ontario from 1 April 2003 to 31 March 2018.

Firearm injury intent and weapon type using the International Classification of Disease-10 CM codes with Canadian enhancements. Secondary exposures were sociodemographics including age, sex, rurality and income.

Any hospital or death record of a firearm injury with counts and rates of firearm injuries described overall and stratified by weapon type and injury intent. Multivariable Poisson regression stratified by injury intent was used to calculate rate ratios of firearm injuries by weapon type.

Of 5486 children and youth with a firearm injuaths and should be a focus of prevention efforts.
Firearm injuries are a preventable public health problem among youth in Ontario, Canada. Unintentional injuries and those caused by non-powdered firearms were most common and assault and self-injury contributed to substantial firearm-related deaths and should be a focus of prevention efforts.
Opioid and benzodiazepine co-prescribing is associated with a substantial increase in opioid overdose deaths. In this study, we examine the prescribing trends of substitutes of opioids and benzodiazepines alone or in combination, compared with opioids and benzodiazepines.

Retrospective cohort study.

Data were collected using a 20% national sample of Medicare beneficiaries from 2013 to 2018.

4.1-4.3 million enrollees each year from 2013 to 2018.

None.

We employ a generalised linear mixed models to calculate ORs for opioid use, benzodiazepine or Z-drug (benzos/Z-drugs) use, opioid/benzos/Z-drugs 30-day use, gabapentinoid use and (selective serotonin reuptake inhibitors (SSRI) and serotonin norepinephrine reuptake inhibitors (SNRIs)) use, adjusted for the repeated measure of patient. We then created two models to calculate the ORs for each year and comparing to 2013.

Opioid and benzos/Z-drugs use decreased by 2018 (aOR 0.626; 95% CI 0.622 to 0.630) comparing to 2013. We demonstrate a 36.3% and 9.9%ety. It is unclear if this trend towards opioid/benzos/Z-drugs alternatives is associated with fewer drug overdose death, better control of pain and comorbid anxiety, and improved quality of life.
To develop a population-based risk stratification model (COVID-19 Vulnerability Score) for predicting severe/fatal clinical manifestations of SARS-CoV-2 infection, using the multiple source information provided by the healthcare utilisation databases of the Italian National Health Service.

Retrospective observational cohort study.

Population-based study using the healthcare utilisation database from five Italian regions.

Beneficiaries of the National Health Service, aged 18-79 years, who had the residentship in the five participating regions. Residents in a nursing home were not included. The model was built from the 7 655 502 residents of Lombardy region.

The score included gender, age and 29 conditions/diseases selected from a list of 61 conditions which independently predicted the primary outcome, that is, severe (intensive care unit admission) or fatal manifestation of COVID-19 experienced during the first epidemic wave (until June 2020). The score performance was validated by applying the modelntify high-risk citizens who need early preventive or treatment interventions.
A score based on data used for public health management accurately predicted the occurrence of severe/fatal manifestations of COVID-19. Use of this score may help health decision-makers to more accurately identify high-risk citizens who need early preventive or treatment interventions.
The aim of this study was to identify prehospital and early hospital risk factors associated with 30-day mortality in patients with blood culture-confirmed community-acquired bloodstream infection (CA-BSI) in Sweden.

A retrospective case-control study of 1624 patients with CA-BSI (2015-2016), 195 non-survivors satisfying the inclusion criteria were matched 11 with 195 survivors for age, gender and microorganism. All forms of contact with a healthcare provider for symptoms of infection within 7 days prior CA-BSI episode were registered. Logistic regression was used to analyse risk factors for 30-day all-cause mortality.

Of the 390 patients, 61% (115 non-survivors and 121 survivors) sought prehospital contact. The median time from first prehospital contact till hospital admission was 13 hours (6-52) for non-survivors and 7 hours (3-24) for survivors (p<0.01). Several risk factors for 30-day all-cause mortality were identified prehospital delay OR=1.26 (95% CI 1.07 to 1.47), p<0.01; severity of illney hospital care is critical for rapid initiation of adequate management and antibiotic treatment.
The global COVID-19 pandemic has reported to have a negative impact on the mental health and well-being of individuals around the world. Mental health system infrastructure, primarily developed to support individuals through in-person care, struggled to meet rising demand for services even prior to COVID-19. With public health guidelines requiring the use of physical distancing during the pandemic, digital mental health supports may be one way to address the needs of the population. Despite this, barriers exist in promoting and supporting access to existing and emerging digital resources. Text messaging may address some of these barriers, extending the potential reach of these digital interventions across divides that may separate some vulnerable or disadvantaged groups from essential mental health supports. Building on an existing knowledge synthesis project identifying key digital resources for improved mental health, this research will establish low-tech connections to assess need and better match accessapproach will be used to integrate both qualitative and quantitative data collected to understand the overall acceptability, satisfaction and perceived benefit of the text messaging service. Thematic analysis and descriptive statistics will be used as analytic methods.

This study has received approval from the Research Ethics Board at the University of Saskatchewan. A knowledge dissemination plan has been developed that includes traditional academic approaches such as conference presentations, and academic publications, as well as mainstream approaches such as social media, radio and dissemination through the advisory committee.
This study has received approval from the Research Ethics Board at the University of Saskatchewan. A knowledge dissemination plan has been developed that includes traditional academic approaches such as conference presentations, and academic publications, as well as mainstream approaches such as social media, radio and dissemination through the advisory committee.
To explore factors perceived as positive or negative among young people with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) in relation to school and everyday life.

A qualitative study with semistructured individual interviews performed at the local hospital or at the informants' homes between September 2017 and January 2018, with an additional telephone interview to collect data on experiences from the COVID-19 pandemic, conducted in September 2020. Data were analysed using a grounded theory approach.

The informants were recruited from two university hospitals that offer interdisciplinary assessments of young people with CFS/ME from various parts of Norway.

Five males and 13 females aged 13-21 years with CFS/ME diagnosed 3-56 months prior to the interviews participated.

The informants were concerned about a lack of educational adaptations and missed social life at school. Educational and social adaptations could improve schooling and health among young people with CFS/ME. Negative expecial interaction with peers. From the participants' view, factors that limit learning and socialisation include a lack of knowledge about CFS/ME among teachers and school personnel, expectations from teachers of doing more than they could manage at school, feeling alone coping with the disease and not recognising their own limitations regarding what they are able to do. Suggested factors perceived to enhance learning and socialisation were a better understanding of the disease among school personnel and peers, suitable educational adaptations and being able to socialise with peers.
Quality of life (QoL) outcomes are used to monitor quality of care for older adults accessing aged care services, yet it remains unclear which QoL instruments best meet older adults', providers' and policymakers' needs. This review aimed to (1) identify QoL instruments used in aged care and describe them in terms of QoL domains measured and logistical details; (2) summarise in which aged care settings the instruments have been used and (3) discuss factors to consider in deciding on the suitability of QoL instruments for use in aged care services.

Systematic review.

MEDLINE, EMBASE, PsycINFO, Cochrane Library and CINAHL from inception to 2021.

Instruments were included if they were designed for adults (>18 years), available in English, been applied in a peer-reviewed research study examining QoL outcomes in adults >65 years accessing aged care (including home/social care, residential/long-term care) and had reported psychometrics.

Two researchers independently reviewed the measures and extracte settings, depending on needs and interests of users.
A comprehensive list of QoL instruments and their characteristics is provided to inform instrument choice for use in research or for care quality assurance in aged care settings, depending on needs and interests of users.
Prostate cancer (PCa), as a malignant tumour with rapid development in recent years, significantly affects men's health, work, life and economy. Androgen deprivation therapy (ADT) plays an important role in the treatment of PCa and can be used as a complementary therapy in the late stage of castration-resistant prostate cancer. Though ADT targeting PCa shows an effective therapeutic effect, the underlying side effects (cognitive disorder, hot flashes, a decrease in sexuality) cannot be ignored. At present, cognitive behavioural therapy (CBT) has been widely used for patients with PCa after ADT due to its confirmed efficacy, fewer side effects and lower economic burden. However, the effectiveness of CBT for patients with PCa after ADT is still controversial. Therefore, we will conduct a systematic review and meta-analysis of the effectiveness of CBT for patients with PCa after ADT.

Literatures will be searched from establishment of the database to 31 May 2021 with the language restrictions of English and C
DOI 10.17605/OSF.IO/FUVEA.
Systemic therapy with androgen deprivation therapy (ADT) and intensification with agents such as docetaxel, abiraterone acetate and enzalutamide has resulted in improved overall survival in men with
synchronous metastatic hormone-sensitive prostate cancer (mHSPC). Novel local cytoreductive treatments and metastasis-directed therapy are now being evaluated. Such interventions may provide added survival benefit or delay the requirement for further systemic agents and associated toxicity but can confer additional harm. Understanding men's preferences for treatment options in this disease state is crucial for patients, clinicians, carers and future healthcare service providers.

Using a prospective, multicentre discrete choice experiment (DCE), we aim to determine the attributes associated with treatment that are most important to men with mHSPC. Furthermore, we plan to determine men's preferences for, and trade-offs between, the attributes (survival and side effects) of different treatment options includinence 20/EE/0194). Project information will be reported on the publicly available Imperial College London website and the Heath Economics Research Unit (HERU website including the HERU Blog). We will use the social media accounts of IP5-MATTER, Imperial Prostate London, HERU and the individual researchers to disseminate key findings following publication. Findings from the study will be presented at national/international conferences and peer-reviewed journals. Authorship policy will follow the recommendations of the International Committee of Medical Journal Editors.

NCT04590976.
NCT04590976.
To describe opioid agonist treatment prescribing rates in provincial prisons and compare with community prescribing rates.

We used quarterly, cross-sectional data on the number and proportion of people prescribed opioid agonist treatment in prison populations. Trends were compared with Ontario surveillance data from prescribers, reported on a monthly basis.

Provincial prisons and general population in Ontario, Canada between 2015 and 2018.

Adults incarcerated in provincial prisons and people ages 15 years and older in Ontario.

Opioid agonist treatment prescribing prevalence, defined as treatment with methadone or buprenorphine/naloxone.

In prison, 6.9%-8.4% of people were prescribed methadone; 0.8% to 4.8% buprenorphine/naloxone; and 8.2% to 13.2% either treatment over the study period. Between 2015 and 2018, methadone prescribing prevalence did not substantially change in prisons or in the general population. The prevalence rate of buprenorphine/naloxone prescribing increased in prisons by 1.70 times per year (95% CI 1.47 to 1.96), which was significantly higher than the increase in community prescribing 1.20 (95% CI 1.19 to 1.21). Buprenorphine/naloxone prescribing prevalence was significantly different across prisons.

The increase in opioid agonist treatment prescribing between 2015 and 2018 in provincial prisons shows that efforts to scale up access to treatment in the context of the opioid overdose crisis have included people who experience incarceration in Ontario. Further work is needed to understand unmet need for treatment and treatment impacts.
The increase in opioid agonist treatment prescribing between 2015 and 2018 in provincial prisons shows that efforts to scale up access to treatment in the context of the opioid overdose crisis have included people who experience incarceration in Ontario. Further work is needed to understand unmet need for treatment and treatment impacts.
COVID-19 is associated with a marked systemic inflammatory response with concomitant cardiac injury and remodelling, but it is currently unknown whether the latter is reversible. Given that high-intensity interval training (HIIT) is a powerful stimulus to improve cardiorespiratory fitness while also eliciting marked anti-inflammatory effects, it may be an important countermeasure of reducing cardiopulmonary morbidity following COVID-19.

40 COVID-19 survivors who have been discharged from hospital will be included in this investigator-blinded randomised study with a 12-week HIIT intervention. Patients will be 11 block-randomised by sex to either a supervised HIIT exercise group or standard care (control group). The main hypothesis is that a 12-week HIIT scheme is a safe way to improve loss of cardiac mass and associated cardiorespiratory fitness, despite hypothesised limited HIIT-induced changes in conventional lung function indices per se. Ultimately, we hypothesise that the HIIT scheme will reduce post-COVID-19 symptoms and improve quality of life.

This study is approved by the Scientific Ethical Committee at the Capital Region of Denmark (H-20033733, including amendments 75068 and 75799) and registered at ClinicalTrials.gov (NCT04647734, pre-results). The findings will be published in a peer-reviewed journal, including cases of positive, negative and inconclusive results.
NCT04549337.
This study is approved by the Scientific Ethical Committee at the Capital Region of Denmark (H-20033733, including amendments 75068 and 75799) and registered at ClinicalTrials.gov (NCT04647734, pre-results). The findings will be published in a peer-reviewed journal, including cases of positive, negative and inconclusive results.Trial registration number NCT04549337.
Bioprosthetic aortic valves with an extended subannular component, such as transcatheter valves, exert increased compression on the cardiac conduction system and increase the risk for permanent pacemaker implantation. It is unknown if the On-X mechanical prosthetic valve, which has an elongated subannular valve housing, increases the risk of permanent pacemaker implantation following aortic valve replacement.

Observational nationwide cohort study.

Swedish population-based study.

All patients aged 18-65 years who underwent primary mechanical aortic valve replacement in Sweden between 2005 and 2018. We used the Swedish Web system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies register and other Swedish national health-data registers.

Patients implanted with an On-X valve versus patients implanted with other bileaflet mechanical valves.

Primary outcome measure was permanent pacemaker implantation within 30 days of surgery.

A totaventional bileaflet mechanical valves. The On-X elongated subannular valve housing does not interfere with the cardiac conduction system.
Aphasia is an impairment of language that occurs in 30%-40% of stroke survivors. This often chronic condition results in poor outcomes for the individual with aphasia and their family. Long-term aphasia management is limited, with few people receiving sufficient services by 6-12 months postonset. We present a protocol for the development of coproduced aphasia service elements. We will use experience-based codesign (EBCD), an approach that enables service users and providers to collaboratively develop services and care pathways. Drawing on the experiences of people with aphasia, their families and clinicians we will establish priorities for the development of new services and later work together to codesign them.

This research will be coproduced with people with aphasia (n=30-60), their families (n=30-60) and speech pathologists (n=30-60) in Queensland, Australia, using EBCD. A consumer advisory committee will provide oversight and advice throughout the research. In phase 1, we will use semistructured interviews and the nominal group technique to explore experiences and unmet needs in aphasia rehabilitation.
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