A cluster randomized controlled trial comparing Virtual Learning Collaborative and Technical Assistance strategies to implement an early palliative care program for patients with advanced cancer and their caregivers: a study protocol

Background: Virtual Learning Collaboratives (VLC), learning communities focused on a common purpose, are used frequently in healthcare settings to implement best practices. Yet, there is limited research testing the effectiveness of this approach compared to other implementation strategies. This study evaluates the effectiveness of a VLC compared to Technical Assistance (TA) among community oncology practices implementing ENABLE (Educate, Nurture, Advise, Before Life Ends), an evidence-based, early palliative care telehealth, psycho-educational intervention for patients with newly diagnosed advanced cancer and their caregivers. Methods: Using Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) and Proctor’s Implementation Outcomes Frameworks, this two-arm hybrid type-III cluster-randomized controlled trial (RCT) will compare two implementation strategies, VLC versus TA, among the 48 National Cancer Institute Community Oncology Research Program (NCORP) practice clusters that have not historically provided palliative care to all patients with advanced cancer. Three cohorts of practice clusters will be randomized to the study arms. Each practice cluster will recruit 15–27 patients and a family caregiver to participate in ENABLE. The primary study outcome is ENABLE uptake (patient level), i.e., the proportion of eligible patients who complete the ENABLE program (receive a palliative care assessment and complete the six ENABLE sessions over 12 weeks). The secondary outcome is overall program implementation (practice cluster level), as measured by the General Organizational Index at baseline, 6, and 12 months. Exploratory aims assess patient and caregiver mood and quality of life outcomes at baseline, 12, and 24 weeks. Practice cluster randomization will seek to keep the proportion of rural practices, practice sizes, and minority patients seen within each practice balanced across the two study arms. Discussion: This study will advance the field of implementation science by evaluating VLC effectiveness, a commonly used but understudied, implementation strategy. The study will advance the field of palliative care by building the capacity and infrastructure to implement an early palliative care program in community oncology practices. Trial registration: Clinicaltrials.gov. NCT04062552; Pre-results. Registered: August 20, 2019. https://clinicaltrials.gov/ct2/show/NCT04062552?term=NCT04062552&draw=2&rank=

Risk of mortality and cardiovascular events following macrolide prescription in chronic rhinosinusitis patients: a cohort study using linked primary care electronic health records

Background: Macrolide antibiotics have demonstrated important anti-inflammatory and immunomodulatory properties in chronic rhinosinusitis (CRS) patients. However, reports of increased risks of cardiovascular events have led to safety concerns. We investigated the risk of all-cause and cardiac death, and cardiovascular outcomes, associated with macrolide use. Methodology: Observational cohort (1997-2016) using linked data from the Clinical Practice Research Datalink, Hospital Episodes Statistics, and the Office for National Statistics. Patients aged 16-80 years with CRS prescribed a macrolide antibiotic or penicillin were included, comparing prescriptions for macrolide antibiotics to penicillin. Outcomes were all-cause mortality, cardiac death, myocardial infarction, stroke, diagnosis of peripheral vascular disease, and cardiac arrhythmia. Results: Analysis included 320,798 prescriptions received by 66,331 patients. There were 3,251 deaths, 815 due to cardiovascular causes, 925 incident myocardial infarctions, 859 strokes, 637 diagnoses of peripheral vascular disease, and 1,436 cardiac arrhythmias. A non-statistically significant trend towards increased risk of myocardial infarction during the first 30 days following macrolide prescription was observed (fully adjusted hazard ratio 1.60, 95% confidence interval: 0.95, 2.68, p=0.08). No statistically significant short- or long-term risks were observed for macrolide prescription. No significant risks were identified for clarithromycin in particular. Conclusions: Although not statistically significant, our best estimates suggest an increased short-term risk of myocardial infarction in patients with CRS following macrolide prescription, supporting previous observational evidence. However, confounding by indication remains a possible explanation for this apparent increased risk. We found no evidence of longer term increased risks

Expert panel process to optimise the design of a randomised controlled trial in chronic rhinosinusitis (the MACRO programme).

BACKGROUND: MACRO (Defining best Management for Adults with Chronic RhinOsinusitis) is an NIHR-funded programme of work designed to establish best practice for adults with chronic rhinosinusitis (CRS). The 7-year programme comprises three consecutive workstreams, designed to explore NHS care pathways through analysis of primary and secondary data sources, and to undertake a randomised controlled trial to evaluate a longer-term course of macrolide antibiotics and endoscopic sinus surgery for patients with CRS. A number of outstanding elements still required clarification at the funding stage. This paper reports an expert panel review process designed to agree and finalise the MACRO trial design, ensuring relevance to patients and clinicians whilst maximising trial recruitment and retention. METHODS: An expert panel, consisting of the MACRO Programme Management Group, independent advisors, and patient contributors, was convened to review current evidence and the mixed-method data collected as part of the programme, and reach agreement on MACRO trial design. Specifically, agreement was sought for selection of macrolide antibiotic, use of orally administered steroids, inclusion of CRS phenotypes (with/without nasal polyps), and overall trial design. RESULTS: A 12-week course of clarithromycin was agreed as the main trial comparator due to its increasing use as a first- and second-line treatment for patients with CRS, and the perceived need to establish its role in CRS management. Orally administered steroids will be used as a rescue medication during the trial, rather than routinely either pre or post trial randomisation, to limit any potential effects on surgical outcomes and better reflect current UK prescribing habits. Both CRS phenotypes will be included in a single trial to ensure that the MACRO trial is both pragmatic and generalisable to primary care. A modified, three-arm trial design was agreed after intense discussions and further exploratory work. Inclusion criteria were amended to ensure that the patients recruited would be considered eligible for the treatment offered in the trial due to having already received appropriate medical therapy as deemed suitable by their ENT surgeon. A proposed 6-week run-in period prior to randomisation was removed due to the new criteria prior to randomisation. CONCLUSION: The expert panel review process resulted in agreement on key elements and an optimal design for the MACRO trial, considered most likely to be successful in terms of both recruitment potential and ability to establish best management of patients with CRS

nucleAIzer : A Parameter-free Deep Learning Framework for Nucleus Segmentation Using Image Style Transfer

Single-cell segmentation is typically a crucial task of image-based cellular analysis. We present nucleAIzer, a deep-learning approach aiming toward a truly general method for localizing 2D cell nuclei across a diverse range of assays and light microscopy modalities. We outperform the 739 methods submitted to the 2018 Data Science Bowl on images representing a variety of realistic conditions, some of which were not represented in the training data. The key to our approach is that during training nucleAIzer automatically adapts its nucleus-style model to unseen and unlabeled data using image style transfer to automatically generate augmented training samples. This allows the model to recognize nuclei in new and different experiments efficiently without requiring expert annotations, making deep learning for nucleus segmentation fairly simple and labor free for most biological light microscopy experiments. It can also be used online, integrated into CellProfiler and freely downloaded at www.nucleaizer.org. A record of this paper's transparent peer review process is included in the Supplemental Information.Peer reviewe

Genotype and Cardiovascular Phenotype Correlations With TBX1 in 1,022 Velo-Cardio-Facial/Digeorge/22q11.2 Deletion Syndrome Patients

Haploinsufficiency of TBX1, encoding a T-box transcription factor, is largely responsible for the physical malformations in velo-cardio-facial /DiGeorge/22q11.2 deletion syndrome (22q11DS) patients. Cardiovascular malformations in these patients are highly variable, raising the question as to whether DNA variations in the TBX1 locus on the remaining allele of 22q11.2 could be responsible. To test this, a large sample size is needed. The TBX1 gene was sequenced in 360 consecutive 22q11DS patients. Rare and common variations were identified. We did not detect enrichment in rare SNP (single nucleotide polymorphism) number in those with or without a congenital heart defect. One exception was that there was increased number of very rare SNPs between those with normal heart anatomy compared to those with right-sided aortic arch or persistent truncus arteriosus, suggesting potentially protective roles in the SNPs for these phenotype-enrichment groups. Nine common SNPs (minor allele frequency, MAF \u3e 0.05) were chosen and used to genotype the entire cohort of 1,022 22q11DS subjects. We did not find a correlation between common SNPs or haplotypes and cardiovascular phenotype. This work demonstrates that common DNA variations in TBX1 do not explain variable cardiovascular expression in 22q11DS patients, implicating existence of modifiers in other genes on 22q11.2 or elsewhere in the genome

The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD

Inhibition of resistance-refractory P. falciparum kinase PKG delivers prophylactic, blood stage, and transmission-blocking antiplasmodial activity

The search for antimalarial chemotypes with modes of action unrelated to existing drugs has intensified with the recent failure of first-line therapies across Southeast Asia. Here, we show that the trisubstituted imidazole MMV030084 potently inhibits hepatocyte invasion by Plasmodium sporozoites, merozoite egress from asexual blood stage schizonts, and male gamete exflagellation. Metabolomic, phosphoproteomic, and chemoproteomic studies, validated with conditional knockdown parasites, molecular docking, and recombinant kinase assays, identified cGMP-dependent protein kinase (PKG) as the primary target of MMV030084. PKG is known to play essential roles in Plasmodium invasion of and egress from host cells, matching MMV030084's activity profile. Resistance selections and gene editing identified tyrosine kinase-like protein 3 as a low-level resistance mediator for PKG inhibitors, while PKG itself never mutated under pressure. These studies highlight PKG as a resistance-refractory antimalarial target throughout the Plasmodium life cycle and promote MMV030084 as a promising Plasmodium PKG-targeting chemotype

BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 are implicated in tau pathology

Background Identified as an Alzheimer’s disease (AD) susceptibility gene by genome wide-association studies, BIN1 has 10 isoforms that are expressed in the Central Nervous System (CNS). The distribution of these isoforms in different cell types, as well as their role in AD pathology still remains unclear. Methods Utilizing antibodies targeting specific BIN1 epitopes in human post-mortem tissue and analyzing mRNA expression data from purified microglia, we identified three isoforms expressed in neurons and astrocytes (isoforms 1, 2 and 3) and four isoforms expressed in microglia (isoforms 6, 9, 10 and 12). The abundance of selected peptides, which correspond to groups of BIN1 protein isoforms, was measured in dorsolateral prefrontal cortex, and their relation to neuropathological features of AD was assessed. Results Peptides contained in exon 7 of BIN1’s N-BAR domain were found to be significantly associated with AD-related traits and, particularly, tau tangles. Decreased expression of BIN1 isoforms containing exon 7 is associated with greater accumulation of tangles and subsequent cognitive decline, with astrocytic rather than neuronal BIN1 being the more likely culprit. These effects are independent of the BIN1 AD risk variant. Conclusions Exploring the molecular mechanisms of specific BIN1 isoforms expressed by astrocytes may open new avenues for modulating the accumulation of Tau pathology in AD