bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patient feedback for safety improvement in primary care: results from a feasibility study
Authors: Hernan Andrea L , Giles Sally J , Beks Hannah , McNamara Kevin , Kloot Kate , Binder Marley J , Versace Vincent 
Published: June 2020

ObjectivesPatient involvement in safety improvement is a developing area of research. The aim of this study was to investigate the feasibility of a patient feedback on safety intervention in primary care. Specifically, the intervention acceptability, fidelity, implementation enablers and barriers, scalability, and process of systematically collecting safety data were examined.Design, setting and participantsMixed-methods feasibility trial with six purposively selected Australian primary care practices.InterventionThe intervention comprised an iterative process with a cycle of measurement, learning, feedback, action planning and implementation period of 6 months.Primary and secondary outcomesQualitative and quantitative data relating to feasibility measures (acceptability, fidelity, enablers, barriers, scalability and process of collecting safety data) were collected and analysed.ResultsA total of n=1750 patients provided feedback on safety. There was a statistically significant increase in mean patient safety scores indicating improved safety (4.30–4.37, p=0.002). Staff deemed the intervention acceptable, with minor recommendations for improvement. Intervention fidelity was high and implementation enablers were attributed to the intervention structure and framework, use of intuitive problem-solving approaches, and multidisciplinary team involvement. Practice-based safety interventions resulted in sustainable and measurable changes to systems for safety, such as increased access to care and improved patient information accuracy.ConclusionsThe findings indicate that this innovative patient feedback on safety intervention is feasible for scale-up to a larger effectiveness trial and further spread into policy and practice. This intervention complements existing safety improvement strategies and activities, and integrates into current patient feedback service requirements for Australian primary care. Further research is needed to examine the intervention effects on safety incident reduction.
Improving transitions from acute care to home among complex older adults using the LACE Index and care coordination
Authors: Charles Lesley , Jensen Lisa , Torti Jacqueline M I , Parmar Jasneet , Dobbs Bonnie , Tian Peter George Jaminal 
Published: June 2020

BackgroundImproving transitions in care is a major focus of healthcare planning. The objective of this study was to determine the improvement in transitions from an intervention identifying complex older adult patients in acute care and supporting their discharge into the community.MethodsThis was a quality assurance study evaluating an intervention on high-risk patients admitted in an acute care hospital. In phase 1, theLength of Stay,Acuity of the Admission,Charlson Comorbidity Index Score, andEmergency Department Use (LACE Index) was selected to assess a patient’s risk for readmission and a standard discharge protocol was developed. In phase 2, the intervention was implemented: (1) all patients were screened for the risk of readmission using the LACE Index; and (2) the high-risk patients were provided care coordination including follow-up phone calls focused on medications, equipment and homecare services. Emergency department (ED) revisits and hospital readmissions were measured.ResultsThe LACE Index identified 433/1621 (27%) patients at high risk for readmission. Care coordination was achieved within 72 hours in 79% of patients. The 433 high-risk patients receiving the intervention, compared with a group without intervention (n=231), had lower lengths of stay (12.7 days vs 16.6 days); similar 7-day ED revisits (10.6% vs 10.8%) and 30-day ED revisits (30.5% vs 33.3%); lower 90-day readmissions (39.3% vs 44.6%); and lower 6-month readmissions (50.9% vs 58.4%). The 7-day and 30-day readmissions were similar in both groups.ConclusionsIdentifying complex patients at high risk for readmission and supporting them during transitions from acute care to home potentially decreases lengths of hospital stay and prevents short-term ED revisits and long-term readmissions.
DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy
Authors: Ged Yasser , Chaim Joshua L , DiNatale Renzo G , Knezevic Andrea , Kotecha Ritesh R , Carlo Maria I , Lee Chung-Han , Foster Ashley , Feldman Darren R , Teo Min Yuen , Iyer Gopakumar , Chan Timothy , Patil Sujata , Motzer Robert J , Hakimi A Ari , Voss Martin H 
Published: June 2020

BackgroundLoss-of-function alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may determine benefit from immune-oncology (I/O) agents as shown in colon cancer. However, biologic significance and relevance to I/O in metastatic clear cell RCC (ccRCC) are unknown.MethodsGenomic data and treatment outcomes were retrospectively collected for patients with metastatic ccRCC. Tumor and germline DNA were subject to targeted next generation sequencing across >400 genes of interest, including 34 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) deleterious DDR gene alterations present (Del DDR); (2) wild-type (WT) and variants of unknown significance (VUS) DDR gene alterations present (WT/VUS DDR). Association between DDR status and therapeutic benefit was investigated separately for I/O and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy.ResultsDel DDR were detected in 43/229 patients (19%). The most frequently altered genes wereCHEK2andATM. Clonality analysis was performed in 27 somatic DDR mutations and 17 were clonal (63%). For patients with I/O treatment, Del DDR status was associated with superior overall survival (log-rank p=0.049); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Del DDR was 0.41 (95% CI: 0.14–1.14; p=0.09). No association was seen with VEGF-TKI treatment (log-rank p=0.903).ConclusionDel DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Loss-of-function events in these genes may affect outcome with I/O therapy in metastatic RCC, and these hypothesis-generating results deserve further study.
Nivolumab-induced synovitis is characterized by florid T cell infiltration and rapid resolution with synovial biopsy-guided therapy
Authors: Murray-Brown William , Wilsdon Tom D , Weedon Helen , Proudman Susanna , Sukumaran Shawgi , Klebe Sonja , Walker Jennifer G , Smith Malcolm D , Wechalekar Mihir D 
Published: June 2020

BackgroundImmune checkpoint inhibitors (ICIs) are associated with rheumatic and musculoskeletal immune-related adverse events (irAEs) in 5%–20% of patients. Currently, patients refractory to corticosteroids and conventional disease-modifying antirheumatic drugs (cDMARD) are treated with biological DMARDs (bDMARDs) targeting tumor necrosis factor α (TNFα) and interleukin-6, although without a clear biological rationale. Synovial tissue (ST) biopsy presents a valuable opportunity to investigate irAE pathogenesis and appropriately stratify bDMARD use in refractory irAE patients.Case presentationWe provide the first report of comparative, parallel ST and synovial fluid (SF) analyses of severe, cDMARD-refractory, seronegative polyarthritis, classified as a grade 3 irAE occurring in response to nivolumab treatment for metastatic squamous cell lung cancer, in comparison with ST and SF from patients with untreated rheumatoid arthritis (RA). We investigated immunohistochemical labeling of ST cytokine expression as a biological rationale for selecting therapy. Flow cytometric analysis of lymphocytes from ST, SF and blood collected before and after synovial biopsy-guided therapy, in comparison with RA, were evaluated for insights into the immunopathogenesis of irAE. Immunolabeling of ST demonstrated an excess of TNFα cytokine expression. Subsequent treatment with infliximab resulted in resolution of inflammatory symptoms and a significant reduction in C reactive protein levels. Flow cytometric analysis of synovial infiltrates indicated absence of programmed cell death protein-1 (PD-1) receptor positivity despite cessation of nivolumab approximately 200 days prior to the analyzes.ConclusionsA deeper understanding of the immunopathogenetic basis of immune activation in irAEs is required in order to select therapy that is likely to be the most effective. This is the first report investigating parallel blood, ST and SF in ICI-induced severe rheumatic irAE. Use of a bDMARD directed by the dominant inflammatory cytokine achieved resolution of synovitis while maintaining cancer remission.
Targeting the coding sequence: opposing roles in regulating classical and non-classical MHC class I molecules by miR-16 and miR-744
Authors: Friedrich Michael , Vaxevanis Christoforos K , Biehl Katharina , Mueller Anja , Seliger Barbara 
Published: June 2020

BackgroundTo control gene expression, microRNAs (miRNAs) are of key importance and their deregulation is associated with the development and progression of various cancer types. In this context, a discordant messenger RNA/protein expression pointing to extensive post-transcriptional regulation of major histocompatibility complex (MHC) class I molecules was already shown. However, only a very limited number of miRNAs targeting these molecules have yet been identified. Despite an increasing evidence of coding sequence (CDS)-located miRNA binding sites, there exists so far, no detailed study of the interaction of miRNAs with the CDS of MHC class I molecules.MethodsUsing an MS2-tethering approach in combination with small RNA sequencing, a number of putative miRNAs binding to the CDS of human leukocyte antigen (HLA)-G were identified. These candidate miRNAs were extensively screened for their effects in the HLA-G-positive JEG3 cell line. Due to the high sequence similarity between HLA-G and classical MHC class I molecules, the impact of HLA-G candidate miRNAs on HLA class I surface expression was also analyzed. The Cancer Genome Atlas data were used to correlate candidate miRNAs and HLA class I gene expression.ResultsTransfection of candidate miRNAs revealed that miR-744 significantly downregulates HLA-G protein levels. In contrast, overexpression of the candidate miRNAs miR-15, miR-16, and miR-424 sharing the same seed sequence resulted in an unexpected upregulation of HLA-G. Comparable results were obtained for classical MHC class I members after transfection of miRNA mimics into HEK293T cells. Analyses of The Cancer Genome Atlas data sets for miRNA and MHC class I expression further validated the results.ConclusionsOur data expand the knowledge about MHC class I regulation and showed for the first time an miRNA-dependent control of MHC class I antigens mediated by the CDS. CDS-located miRNA binding sites could improve the general use of miRNA-based therapeutic approaches as these sites are highly independent of structural variations (e.g. mutations) in the gene body. Surprisingly, miR-16 family members promoted MHC class I expression potentially in a gene activation-like mechanism.
Clinical spectrum and genetic variations of LMNA-related muscular dystrophies in a large cohort of Chinese patients
Authors: Fan Yanbin , Tan Dandan , Song Danyu , Zhang Xu , Chang Xingzhi , Wang Zhaoxia , Zhang Cheng , Chan Sophelia Hoi-Shan , Wu Qixi , Wu Liwen , Wang Shuang , Yan Hui , Ge Lin , Yang Haipo , Mao Bing , Bönnemann Carsten , Liu Jingying , Wang Suxia , Yuan Yun , Wu Xiru , Zhang Hong , Xiong Hui 
Published: June 2020

BackgroundLMNA-related muscular dystrophy is caused by mutations in LMNA gene. We aimed to identify genetic variations and clinical features in a large cohort of Chinese patients with LMNA mutations in an attempt to establish genotype-phenotype correlation.MethodsThe clinical presentations of patients with LMNA-related muscular dystrophy were recorded using retrospective and prospective cohort study. LMNA mutation analysis was performed by Sanger sequencing or next-generation sequencing. Mosaicism was detected by personal genome machine amplicon deep sequencing for mosaicism.ResultsEighty-four patients were identified to harbour LMNA mutations. Forty-one of those were diagnosed with LMNA-related congenital muscular dystrophy (L-CMD), 32 with Emery-Dreifuss muscular dystrophy (EDMD) and 11 with limb-girdle muscular dystrophy type 1B (LGMD1B). We identified 21 novel and 29 known LMNA mutations. Two frequent mutations were identified: c.745C>T and c.1357C>T. A correlation between the location of mutation and the clinical phenotype was observed: mutations affecting the head and coil 2A domains mainly occurred in L-CMD, while the coil 2B and Ig-like domains mainly related to EDMD and LGMD1B. We found somatic mosaicism in one parent of four probands. Muscle biopsies revealed 11 of 20 biopsied L-CMD exhibited inflammatory changes, and muscle cell ultrastructure showed abnormal nuclear morphology.ConclusionsOur detailed clinical and genetic analysis of 84 patients with LMNA-related muscular dystrophy expands clinical spectrum and broadens genetic variations caused by LMNA mutations. We identified 21 novel and 29 known LMNA mutations and found two frequent mutations. A correlation between the location of mutation and the clinical severity was observed. Preliminary data suggested that low-dose corticosteroid treatment may be effective.
Defining the phenotypical spectrum associated with variants in TUBB2A
Authors: Brock Stefanie , Vanderhasselt Tim , Vermaning Sietske , Keymolen Kathelijn , Régal Luc , Romaniello Romina , Wieczorek Dagmar , Storm Tim Matthias , Schaeferhoff Karin , Hehr Ute , Kuechler Alma , Krägeloh-Mann Ingeborg , Haack Tobias B , Kasteleijn Esmee , Schot Rachel , Mancini Grazia Maria Simonetta , Webster Richard , Mohammad Shekeeb , Leventer Richard J , Mirzaa Ghayda , Dobyns William B , Bahi-Buisson Nadia , Meuwissen Marije , Jansen Anna C , Stouffs Katrien 
Published: June 2020

BackgroundVariants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis.MethodsIn order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed.ResultsWe report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy.ConclusionThe imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype–phenotype correlations could be established, suggesting the role of additional modifiers.
Novel loss-of-function mutation in HERC2 is associated with severe developmental delay and paediatric lethality
Authors: Elpidorou Marilena , Best Sunayna , Poulter James A , Hartill Verity , Hobson Emma , Sheridan Eamonn , Johnson Colin A 
Published: June 2020

BackgroundThe HERC2 gene encodes a 527 kDa E3 ubiquitin protein ligase that has key roles in cell cycle regulation, spindle formation during mitosis, mitochondrial functions and DNA damage responses. It has essential roles during embryonic development, particularly for neuronal and muscular functions. To date, missense mutations in HERC2 have been associated with an autosomal recessive neurodevelopmental disorder with some phenotypical similarities to Angelman syndrome, and a homozygous deletion spanning HERC2 and OCA2 causing a more severe neurodevelopmental phenotype.Methods and resultsWe ascertained a consanguineous family with a presumed autosomal recessive severe neurodevelopmental disorder that leads to paediatric lethality. In affected individuals, we identified a homozygous HERC2 frameshift variant that results in a premature stop codon and complete loss of HERC2 protein. Functional characterisation of this variant in fibroblasts, from one living affected individual, revealed impaired mitochondrial network and function as well as disrupted levels of known interacting proteins such as XPA.ConclusionThis study extends the genotype–phenotype correlation for HERC2 variants to include a distinct lethal neurodevelopmental disorder, highlighting the importance of further characterisation for HERC2-related disorders.
Haploinsufficiency of theNF1gene is associated with protection against diabetes
Authors: Kallionpää Roope A , Peltonen Sirkku , Leppävirta Jussi , Pöyhönen Minna , Auranen Kari , Järveläinen Hannu , Peltonen Juha 
Published: June 2020

BackgroundThe hereditary predisposition to diabetes is only partially explained by genes identified so far. Neurofibromatosis type 1 (NF1) is a rare monogenic dominant syndrome caused by aberrations of theNF1gene. Here, we used a cohort of 1410 patients with NF1 to study the association of theNF1gene with type 1 (T1D) and type 2 diabetes (T2D).MethodsA total of 1410 patients were confirmed to fulfil the National Institutes of Health diagnostic criteria for NF1 by individually reviewing their medical records. The patients with NF1 were compared with 14 017 controls matched for age, sex and area of residence as well as 1881 non-NF1 siblings of the patients with NF1. Register-based information on purchases of antidiabetic medication and hospital encounters related to diabetes were retrieved. The Cox proportional hazards model was used to calculate the relative risk for diabetes in NF1.ResultsPatients with NF1 showed a lower rate of T2D when compared with a 10-fold control cohort (HR 0.27, 95% CI 0.17 to 0.43) or with their siblings without NF1 (HR 0.28, 95% CI 0.16 to 0.47). The estimates remained practically unchanged after adjusting the analyses for history of obesity and dyslipidaemias. The rate of T1D in NF1 was decreased although statistically non-significantly (HR 0.58, 95% CI 0.27 to 1.25).ConclusionHaploinsufficiency of theNF1gene may protect against T2D and probably T1D. SinceNF1negatively regulates the Ras signalling pathway, the results suggest that the Ras pathway may be involved in the pathogenesis of diabetes.
Revisiting the equity debate in COVID-19: ICU is no panacea
Authors: Ballantyne Angela , Rogers Wendy A , Entwistle Vikki , Towns Cindy 
Published: June 2020

Throughout March and April 2020, debate raged about how best to allocate limited intensive care unit (ICU) resources in the face of a growing COVID-19 pandemic. The debate was dominated by utility-based arguments for saving the most lives or life-years. These arguments were tempered by equity-based concerns that triage based solely on prognosis would exacerbate existing health inequities, leaving disadvantaged patients worse off. Central to this debate was the assumption that ICU admission is a valuable but scarce resource in the pandemic context.In this paper, we argue that the concern about achieving equity in ICU triage is problematic for two reasons. First, ICU can be futile and prolong or exacerbate suffering rather than ameliorate it. This may be especially true in patients with COVID-19 with emerging data showing that most who receive access to a ventilator will still die. There is no value in admitting patients with poor prognostic indicators to ICU to meet an equity target when intensive critical care is contrary to their best interests. Second, the focus on ICU admission shifts focus away from important aspects of COVID-19 care where there is greater opportunity for mitigating suffering and enhancing equitable care.We propose that the focus on equity concerns during the pandemic should broaden to include providing all people who need it with access to the highest possible standard of end-of-life care. This requires attention to culturally safe care in the following interlinked areas: palliative care, communication and decision support and advanced care planning.
Role for machine learning in sex-specific prediction of successful electrical cardioversion in atrial fibrillation?
Authors: Vinter Nicklas , Frederiksen Anne Sofie , Albertsen Andi Eie , Lip Gregory Y H , Fenger-Grøn Morten , Trinquart Ludovic , Frost Lars , Møller Dorthe Svenstrup 
Published: June 2020

ObjectiveElectrical cardioversion is frequently performed to restore sinus rhythm in patients with persistent atrial fibrillation (AF). However, AF recurs in many patients and identifying the patients who benefit from electrical cardioversion is difficult. The objective was to develop sex-specific prediction models for successful electrical cardioversion and assess the potential of machine learning methods in comparison with traditional logistic regression.MethodsIn a retrospective cohort study, we examined several candidate predictors, including comorbidities, biochemistry, echocardiographic data, and medication. The outcome was successful cardioversion, defined as normal sinus rhythm immediately after the electrical cardioversion and no documented recurrence of AF within 3 months after. We used random forest and logistic regression models for sex-specific prediction.ResultsThe cohort comprised 332 female and 790 male patients with persistent AF who underwent electrical cardioversion. Cardioversion was successful in 44.9% of the women and 49.9% of the men. The prediction errors of the models were high for both women (41.0% for machine learning and 48.8% for logistic regression) and men (46.0% for machine learning and 44.8% for logistic regression). Discrimination was modest for both machine learning (0.59 for women and 0.56 for men) and logistic regression models (0.60 for women and 0.59 for men), although the models were well calibrated.ConclusionsSex-specific machine learning and logistic regression models showed modest predictive performance for successful electrical cardioversion. Identifying patients who will benefit from cardioversion remains challenging in clinical practice. The high recurrence rate calls for thoroughly informed shared decision-making for electrical cardioversion.