Selective autophagy of the adaptor TRIF regulates innate inflammatory signaling.

Defective autophagy is linked to diseases such as rheumatoid arthritis, lupus and inflammatory bowel disease (IBD). However, the mechanisms by which autophagy limits inflammation remain poorly understood. Here we found that loss of the autophagy-related gene Atg16l1 promoted accumulation of the adaptor TRIF and downstream signaling in macrophages. Multiplex proteomic profiling identified SQSTM1 and Tax1BP1 as selective autophagy-related receptors that mediated the turnover of TRIF. Knockdown of Tax1bp1 increased production of the cytokines IFN-ß and IL-1ß. Mice lacking Atg16l1 in myeloid cells succumbed to lipopolysaccharide-mediated sepsis but enhanced their clearance of intestinal Salmonella typhimurium in an interferon receptor-dependent manner. Human macrophages with the Crohn's disease-associated Atg16l1 variant T300A exhibited more production of IFN-ß and IL-1ß. An elevated interferon-response gene signature was observed in patients with IBD who were resistant to treatment with an antibody to the cytokine TNF. These findings identify selective autophagy as a key regulator of signaling via the innate immune system.

Decoding disease: from genomes to networks to phenotypes.

Interpreting the effects of genetic variants is key to understanding individual susceptibility to disease and designing personalized therapeutic approaches. Modern experimental technologies are enabling the generation of massive compendia of human genome sequence data and associated molecular and phenotypic traits, together with genome-scale expression, epigenomics and other functional genomic data. Integrative computational models can leverage these data to understand variant impact, elucidate the effect of dysregulated genes on biological pathways in specific disease and tissue contexts, and interpret disease risk beyond what is feasible with experiments alone. In this Review, we discuss recent developments in machine learning algorithms for genome interpretation and for integrative molecular-level modelling of cells, tissues and organs relevant to disease. More specifically, we highlight existing methods and key challenges and opportunities in identifying specific disease-causing genetic variants and linking them to molecular pathways and, ultimately, to disease phenotypes.

Effect of Cangrelor on Infarct Size in ST-Segment Elevation Myocardial Infarction Treated By Primary Percutaneous Coronary Intervention: A Randomized Controlled Trial (The PITRI Trial).

Background: The administration of intravenous cangrelor at reperfusion achieves faster onset of platelet P2Y12 inhibition than oral ticagrelor and has been shown to reduce myocardial infarct (MI) size in the pre-clinical setting. We hypothesized that the administration of cangrelor at reperfusion will reduce MI size and prevent microvascular obstruction (MVO) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Methods: This was a Phase 2, multi-center, randomized, double-blind, placebo controlled clinical trial conducted between November 2017 to November 2021 in six cardiac centers in Singapore (NCT03102723). Patients were randomized to receive either cangrelor or placeboinitiated prior to the PPCI procedure on top of oral ticagrelor. The key exclusion criteria included: presenting <6 hours of symptom onset, prior MI and stroke or transient ischemic attack; on concomitant oral anticoagulants; and a contraindication for cardiovascular magnetic resonance (CMR). The primary efficacy endpoint was acute MI size by CMR within the first week expressed as percentage of the left ventricle mass ( %LVmass). MVO was identified as areas of dark core of hypoenhancement within areas of late gadolinium enhancement. The primary safety endpoint was Bleeding Academic Research Consortium (BARC)-defined major bleeding in the first 48 hours. Continuous variables were compared by Mann-Whitney U test [reported as median (1st quartile- 3rd quartile)] and categorical variables were compared by Fisher's exact test. A 2-sided P<0.05 was considered statistically significant. Results: Of 209 recruited patients, 164 patients (78% ) completed the acute CMR scan. There were no significant differences in acute MI size [placebo: 14.9 (7.3 - 22.6) %LVmass versus cangrelor: 16.3 (9.9 - 24.4)%LVmass, P=0.40] or the incidence [placebo: 48% versus cangrelor: 47%, P=0.99] and extent of MVO [placebo:1.63 (0.60 - 4.65)%LVmass versus cangrelor: 1.18 (0.53 - 3.37)%LVmass, P=0.46] between placebo and cangrelor despite a two-fold decrease in platelet reactivity with cangrelor. There were no BARC-defined major bleeding events in either group in the first 48 hours. Conclusions: Cangrelor administered at time of PPCI did not reduce acute MI size or prevent MVO in STEMI patients given oral ticagrelor despite a significant reduction of platelet reactivity during the PCI procedure.

Intravenous iron for heart failure, iron deficiency definitions, and clinical response: the IRONMAN trial.

BACKGROUND AND AIMS: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure? METHODS: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin < 100 µg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death. RESULTS: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction < .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT < 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant. CONCLUSIONS: This hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation.

A Rapid Human Lung Tissue Dissociation Protocol Maximizing Cell Yield and Minimizing Cellular Stress.

The human lung is a complex organ comprised of diverse populations of epithelial, mesenchymal, vascular and immune cells, which gains even greater complexity during disease states. To effectively study the lung at a single cell level, a dissociation protocol that achieves the highest yield of viable cells of interest with minimal dissociation-associated protein or transcription changes key. Here, we detail a rapid collagenase-based dissociation protocol (Col-Short), which provides a high-yield single cell suspension suitable for a variety of downstream applications. Diseased human lung explants were obtained and dissociated through the Col-Short protocol and compared to four other dissociation protocols. Resulting single cell suspensions were then assessed with flow cytometry, differential staining, and quantitative real-time PCR to identify major hematopoietic and non-hematopoietic cell populations, as well as their activation states. We observed that the Col-Short protocol provides the greatest number of cells per gram of lung tissue with no reduction in viability when compared to previously described dissociation protocols. Col-Short had no observable surface protein marker cleavage as well as lower expression of protein activation markers and stress-related transcripts compared to four other protocols. The Col-Short dissociation protocol can be used as a rapid strategy to generate single cells for respiratory cell biology research.

Diffusion Tensor MRI is sensitive to fibrotic injury in a mouse model of oxalate induced chronic kidney disease.

Chronic kidney disease (CKD) is characterized by inflammation and fibrosis in the kidney. Renal biopsies and estimated glomerular filtration rate (eGFR) remain the standard of care, but these endpoints have limitations in detecting the stage, progression, and spatial distribution of fibrotic pathology in the kidney. MRI diffusion tensor imaging (DTI) has emerged as a promising non-invasive technology to evaluate renal fibrosis in vivo both in clinical and preclinical studies. However, these imaging studies have not systematically identified fibrosis particularly deeper in the kidney where biopsy sampling is limited, or completed an extensive analysis of whole organ histology, blood biomarkers, and gene expression to evaluate the relative strengths and weaknesses of MRI for evaluating renal fibrosis. In this study, we performed DTI in the sodium oxalate mouse model of CKD. The DTI parameters fractional anisotropy, apparent diffusion coefficient, and axial diffusivity were compared between the control and oxalate groups with region-of-interest (ROI) analysis to determine changes in the cortex and medulla. Additionally, voxel-based analysis (VBA) was implemented to systematically identify local regions of injury over the whole kidney. DTI parameters were found to be significantly different in the medulla by both ROI analysis and VBA, which also spatially matched with collagen III IHC. The DTI parameters in this medullary region exhibited moderate to strong correlations with histology, blood biomarkers, hydroxyproline and gene expression. Our results thus highlight the sensitivity of DTI to the heterogeneity of renal fibrosis and importance of whole kidney non-invasive imaging.

Modeling transcriptional regulation of model species with deep learning.

To enable large-scale analyses of transcription regulation in model species, we developed DeepArk, a set of deep learning models of the cis-regulatory activities for four widely studied species: Caenorhabditis elegans, Danio rerio, Drosophila melanogaster, and Mus musculus DeepArk accurately predicts the presence of thousands of different context-specific regulatory features, including chromatin states, histone marks, and transcription factors. In vivo studies show that DeepArk can predict the regulatory impact of any genomic variant (including rare or not previously observed) and enables the regulatory annotation of understudied model species.

Thyroid hormone protects human lung epithelial cells from cold preservation and warm reperfusion-induced injury.

BACKGROUND: Cellular stress associated with static-cold storage (SCS) and warm reperfusion of donor lungs can contribute to ischemia-reperfusion (IR) injury during transplantation. Adding cytoprotective agents to the preservation solution may be conducive to reducing graft deterioration and improving post-transplant outcomes. METHODS: SCS and warm reperfusion were simulated in human lung epithelial cells (BEAS-2B) by exposing cells to low potassium dextran glucose solution at 4 °C for different periods and then switching back to serum-containing culture medium at 37 °C. Transcriptomic analysis was used to explore potential cytoprotective agents. Based on its results, cell viability, caspase activity, cell morphology, mitochondrial function, and inflammatory gene expression were examined under simulated IR conditions with or without thyroid hormones (THs). RESULTS: After 18 h SCS followed by 2 h warm reperfusion, genes related to inflammation and cell death were upregulated, and genes related to protein synthesis and metabolism were downregulated in BEAS-2B cells, which closely mirrored gene profiles found in thyroid glands of mice with congenital hypothyroidism. The addition of THs (T3 or T4) to the preservation solution increases cell viability, inhibits activation of caspase 3, 8 and 9, preserves cell morphology, enhances mitochondrial membrane potential, reduces mitochondrial superoxide production, and suppresses inflammatory gene expression. CONCLUSION: Adding THs to lung preservation solutions may protect lung cells during SCS by promoting mitochondrial function, reducing apoptosis, and inhibiting pro-inflammatory pathways. Further in vivo testing is warranted to determine the potential clinical application of adding THs as therapeutics in lung preservation solutions.

Interactive Big Data Resource to Elucidate Human Immune Pathways and Diseases.

Many functionally important interactions between genes and proteins involved in immunological diseases and processes are unknown. The exponential growth in public high-throughput data offers an opportunity to expand this knowledge. To unlock human-immunology-relevant insight contained in the global biomedical research effort, including all public high-throughput datasets, we performed immunological-pathway-focused Bayesian integration of a comprehensive, heterogeneous compendium comprising 38,088 genome-scale experiments. The distillation of this knowledge into immunological networks of functional relationships between molecular entities (ImmuNet), and tools to mine this resource, are accessible to the public at http://immunet.princeton.edu. The predictive capacity of ImmuNet, established by rigorous statistical validation, is easily accessed by experimentalists to generate data-driven hypotheses. We demonstrate the power of this approach through the identification of unique host-virus interaction responses, and we show how ImmuNet complements genetic studies by predicting disease-associated genes. ImmuNet should be widely beneficial for investigating the mechanisms of the human immune system and immunological diseases.

Webcam-based eye tracking to detect mind wandering and comprehension errors.

Recent advances in computer vision have opened the door for scalable eye tracking using only a webcam. Such solutions are particularly useful for online educational technologies, in which a goal is to respond adaptively to students' ongoing experiences. We used WebGazer, a webcam-based eye-tracker, to automatically detect covert cognitive states during an online reading-comprehension task related to task-unrelated thought and comprehension. We present data from two studies using different populations: (1) a relatively homogenous sample of university students (N = 105), and (2) a more diverse sample from Prolific (N = 173, with < 20% White participants). Across both studies, the webcam-based eye-tracker provided sufficiently accurate and precise gaze measurements to predict both task-unrelated thought and reading comprehension from a single calibration. We also present initial evidence of predictive validity, including a positive correlation between predicted rates of task-unrelated thought and comprehension scores. Finally, we present slicing analyses to determine how performance changed under certain conditions (lighting, glasses, etc.) and generalizability of the results across the two datasets (e.g., training on the data Study 1 and testing on data from Study 2, and vice versa). We conclude by discussing results in the context of remote research and learning technologies.

Neuronal responses in mouse inferior colliculus correlate with behavioral detection of amplitude-modulated sound.

Amplitude modulation (AM) is a common feature of natural sounds, including speech and animal vocalizations. Here, we used operant conditioning and in vivo electrophysiology to determine the AM detection threshold of mice as well as its underlying neuronal encoding. Mice were trained in a Go-NoGo task to detect the transition to AM within a noise stimulus designed to prevent the use of spectral side-bands or a change in intensity as alternative cues. Our results indicate that mice, compared with other species, detect high modulation frequencies up to 512 Hz well, but show much poorer performance at low frequencies. Our in vivo multielectrode recordings in the inferior colliculus (IC) of both anesthetized and awake mice revealed a few single units with remarkable phase-locking ability to 512 Hz modulation, but not sufficient to explain the good behavioral detection at that frequency. Using a model of the population response that combined dimensionality reduction with threshold detection, we reproduced the general band-pass characteristics of behavioral detection based on a subset of neurons showing the largest firing rate change (both increase and decrease) in response to AM, suggesting that these neurons are instrumental in the behavioral detection of AM stimuli by the mice.NEW & NOTEWORTHY The amplitude of natural sounds, including speech and animal vocalizations, often shows characteristic modulations. We examined the relationship between neuronal responses in the mouse inferior colliculus and the behavioral detection of amplitude modulation (AM) in sound and modeled how the former can give rise to the latter. Our model suggests that behavioral detection can be well explained by the activity of a subset of neurons showing the largest firing rate changes in response to AM.

Acellular ex vivo lung perfusate silences pro-inflammatory signaling in human lung endothelial and epithelial cells.

BACKGROUND: Ischemia-reperfusion injury is a key complication following lung transplantation. The clinical application of ex vivo lung perfusion (EVLP) to assess donor lung function has significantly increased the utilization of "marginal" donor lungs with good clinical outcomes. The potential of EVLP on improving organ quality and ameliorating ischemia-reperfusion injury has been suggested. METHODS: To determine the effects of ischemia-reperfusion and EVLP on gene expression in human pulmonary microvascular endothelial cells and epithelial cells, cell culture models were used to simulate cold ischemia (4 °C for 18 h) followed by either warm reperfusion (DMEM + 10% FBS) or EVLP (acellular Steen solution) at 37 °C for 4 h. RNA samples were extracted for bulk RNA sequencing, and data were analyzed for significant differentially expressed genes and pathways. RESULTS: Endothelial and epithelial cells showed significant changes in gene expressions after ischemia-reperfusion or EVLP. Ischemia-reperfusion models of both cell types showed upregulated pro-inflammatory and downregulated cell metabolism pathways. EVLP models, on the other hand, exhibited downregulation of cell metabolism, without any inflammatory signals. CONCLUSION: The commonly used acellular EVLP perfusate, Steen solution, silenced the activation of pro-inflammatory signaling in both human lung endothelial and epithelial cells, potentially through the lack of serum components. This finding could establish the basic groundwork of studying the benefits of EVLP perfusate as seen from current clinical practice.

Defining research priorities and needs in cancer symptoms for adults diagnosed with cancer: an Australian/New Zealand modified Delphi study.

PURPOSE: This study asked consumers (patients, carers) and healthcare professionals (HCPs) to identify the most important symptoms for adults with cancer and potential treatment interventions. METHODS: A modified Delphi study was conducted involving two rounds of electronic surveys based on prevalent cancer symptoms identified from the literature. Round 1 gathered information on participant demographics, opinions and/or experience on cancer symptom frequency and impact, and suggestions for interventions and/or service delivery models for further research to improve management of cancer symptoms. In Round 2, respondents ranked the importance of the top ten interventions identified in Round 1. In Round 3, separate expert panels of consumers and healthcare professionals (HCPs) attempted to reach consensus on the symptoms and interventions previously identified. RESULTS: Consensus was reached for six symptoms across both groups: fatigue, constipation, diarrhoea, incontinence, and difficulty with urination. Notably, fatigue was the only symptom to reach consensus across both groups in Round 1. Similarly, consensus was reached for six interventions across both groups. These were the following: medicinal cannabis, physical activity, psychological therapies, non-opioid interventions for pain, opioids for breathlessness and cough, and other pharmacological interventions. CONCLUSIONS: Consumers and HCPs prioritise differently; however, the symptoms and interventions that reached consensus provide a basis for future research. Fatigue should be considered a high priority given its prevalence and its influence on other symptoms. The lack of consumer consensus indicates the uniqueness of their experience and the need for a patient-centred approach. Understanding individual consumer experience is important when planning research into better symptom management.

Site of care and factors associated with mortality in unvaccinated Australian aged care residents during COVID-19 outbreaks.

BACKGROUND: Residential InReach presents an alternative to hospital admission for aged care residents swabbed for coronavirus disease 2019 (COVID-19), although relative outcomes remain unknown. AIMS: To compare rates and predictors of 28-day mortality for aged care residents seen by InReach with COVID-19, or 'suspected COVID-19' (sCOVID), including hospital versus InReach-based care. METHODS: Prospective observational study of consecutive patients referred to a Victorian InReach service meeting COVID-19 testing criteria between April and October 2020 (prevaccine availability). COVID-19 was determined by positive polymerase chain reaction testing on nasopharyngeal swab. sCOVID-19 was defined as meeting symptomatic Victorian Government testing criteria but persistently swab negative. RESULTS: There were no significant differences in age, sex, Clinical Frailty Score (CFS) or Charlson Comorbidity Index (CCI) between 152 patients with COVID-19 and 118 patients with sCOVID. Similar results were found for 28-day mortality between patients with COVID-19 (35/152, 23%) and sCOVID (32/118, 27%) (P = 0.4). For the combined cohort, 28-day mortality was associated with initial oxygen saturation (P < 0.001), delirium (P < 0.001), hospital transfer for acuity (P = 0.02; but not public health/facility reasons), CFS (P = 0.04), prior ischaemic heart disease (P = 0.01) and dementia (P = 0.02). For patients with COVID-19, 28-day mortality was associated with initial oxygen saturation (P = 0.02), delirium (P < 0.001) and hospital transfer for acuity (P = 0.01), but not public health/facility reasons. CONCLUSION: Unvaccinated aged care residents meeting COVID-19 testing criteria seen by InReach during a pandemic experience high mortality rates, including with negative swab result. Residents remaining within-facility (with InReach) experienced similar adjusted mortality odds to residents transferred to hospital for public health/facility-based reasons, and lower than those transferred for clinical acuity.

Molecular Characterization of Membranous Nephropathy.

BACKGROUND: Molecular characterization of nephropathies may facilitate pathophysiologic insight, development of targeted therapeutics, and transcriptome-based disease classification. Although membranous nephropathy (MN) is a common cause of adult-onset nephrotic syndrome, the molecular pathways of kidney damage in MN require further definition. METHODS: We applied a machine-learning framework to predict diagnosis on the basis of gene expression from the microdissected kidney tissue of participants in the Nephrotic Syndrome Study Network (NEPTUNE) cohort. We sought to identify differentially expressed genes between participants with MN versus those of other glomerulonephropathies across the NEPTUNE and European Renal cDNA Bank (ERCB) cohorts, to find MN-specific gene modules in a kidney-specific functional network, and to identify cell-type specificity of MN-specific genes using single-cell sequencing data from reference nephrectomy tissue. RESULTS: Glomerular gene expression alone accurately separated participants with MN from those with other nephrotic syndrome etiologies. The top predictive classifier genes from NEPTUNE participants were also differentially expressed in the ERCB participants with MN. We identified a signature of 158 genes that are significantly differentially expressed in MN across both cohorts, finding 120 of these in a validation cohort. This signature is enriched in targets of transcription factor NF-κB. Clustering these MN-specific genes in a kidney-specific functional network uncovered modules with functional enrichments, including in ion transport, cell projection morphogenesis, regulation of adhesion, and wounding response. Expression data from reference nephrectomy tissue indicated 43% of these genes are most highly expressed by podocytes. CONCLUSIONS: These results suggest that, relative to other glomerulonephropathies, MN has a distinctive molecular signature that includes upregulation of many podocyte-expressed genes, provides a molecular snapshot of MN, and facilitates insight into MN's underlying pathophysiology.

The Role of Pharmacogenomics in Opioid Prescribing.

OPINION STATEMENT: Pharmacogenomics is increasingly important to guide objective, safe, and effective individualised prescribing. Personalised prescribing has revolutionised treatments in the past decade, allowing clinicians to maximise drug efficacy and minimise adverse effects based on a person's genetic profile. Opioids, the gold standard for cancer pain relief, are among the commonest medications prescribed in palliative care practice. This narrative review examines the literature surrounding opioid pharmacogenomics and its applicability to the palliative care cancer population. There is currently limited intersection between the fields of palliative care and pharmacogenomics, but growing evidence presents a need to build linkages between the two disciplines. Pharmacogenomic evidence guiding opioid prescribing is currently available for codeine and tramadol, which relates to CYP2D6 gene variants. However, these medications are prescribed less commonly for pain in palliative care. Research is accelerating with other opioids, where oxycodone (CYP2D6) and methadone (CYP2B6, ABCB1) already have moderate evidence of an association in terms of drug metabolism and downstream analgesic response and side effects. OPRM1 and COMT are receiving increasing attention and have implications for all opioids, with changes in opioid dosage requirements observed but they have not yet been studied widely enough to be considered clinically actionable. Current evidence indicates that incorporation of pharmacogenomic testing into opioid prescribing practice should focus on the CYP2D6 gene and its actionable variants. Although opioid pharmacogenomic tests are not widely used in clinical practice, the progressively reducing costs and rapid turnover means greater accessibility and affordability to patients, and thus, clinicians will be increasingly asked to provide guidance in this area. The upsurge in pharmacogenomic research will likely discover more actionable gene variants to expand international guidelines to impact opioid prescribing. This rapidly expanding area requires consideration and monitoring by clinicians in order for key findings with clinical implications to be accessible, meaningfully interpretable and communicated.

Telehealth in outpatient delivery of palliative care: a prospective survey evaluation by patients and clinicians.

BACKGROUND: In Australia during the COVID-19 pandemic new funding models were introduced to support telehealth consultations, resulting in their widescale adoption in palliative care service delivery. Clarity around the clinical circumstances and patient populations that might be most appropriate for telehealth models was required. AIMS: To evaluate patient and physician satisfaction, acceptability and utility of outpatient palliative care provision through telehealth. METHODS: This is a multi-site prospective, cross-sectional, observational study conducted during a time of significant public health restrictions. A survey was used to collect matched patient- and physician-reported perceptions of palliative care telehealth consultations across three metropolitan hospitals in Victoria, Australia. RESULTS: There were 127 matched patient-physician data of telehealth consultations and a further 812 physician-only assessments. Telehealth was generally acceptable and satisfactory, with patients providing greater positive scores than clinicians. Telehealth incorporating both audio and video were more acceptable and satisfactory, particularly with the presence of a carer, and during routine reviews. Physicians were less satisfied using telehealth when there was increasing symptom complexity across all domains (pain, psychological, and other symptoms). CONCLUSIONS: Telehealth has high utility in palliative care practice. A future hybrid model of care comprising both face-to-face and telehealth consultations seems favoured by patients and physicians but must be accompanied by targeted support for specific patient groups to ensure equitable healthcare access. Further evaluation of telehealth during a time of fewer public health emergency measures and lower community anxiety is required to fully understand its ongoing role.

A multi-centre study on patients dying from COVID-19: communication between clinicians, patients and their families.

BACKGROUND: COVID-19 has led to challenges in providing effective and timely communication in healthcare. Services have been required to adapt and evolve as successful communication remains core to high-quality patient-centred care. AIM: To describe the communication between admitted patients, their families and clinicians (medical, nursing, allied health) during end-of-life care. METHODS: This retrospective review included all patients (n = 230) who died directly due to COVID-19 at five Melbourne hospitals between 1 January and 31 December 2020. Contacts and modality used (face to face, video, telephone) during the 8 days prior to death were recorded. RESULTS: Patients were predominantly elderly (median age 86 years) and from residential aged care facilities (62%; n = 141). Communication frequency increased the closer the patient was to death, where on day of death, contact between clinicians and patients was 93% (n = 213) clinicians and families 97% (n = 222) and between patients and families 50% (n = 115). Most contact between patients and families was facilitated by a clinician (91.3% (n = 105) day of death) with the most commonly used mode being video call (n = 30 day of death). CONCLUSION: This study is one of the first and largest Australian reports on how communication occurs at the end of life for patients dying of COVID-19. Contact rates were relatively low between patients and families, compared with other cohorts dying from non-COVID-19 related causes. The impact of this difference on bereavement outcomes requires surveillance and attention.

Viability and Cosmesis of Right Angle and Vertical Paramedian Forehead Flaps Are Equivalent: A Retrospective Quantitative Study.

BACKGROUND: Paramedian forehead flaps (PMFFs) are commonly used for reconstruction of nasal defects. The classic PMFF is vertically oriented while the modified PMFF is designed with a 90-degree angle. No study has compared outcomes between these PMFF designs. OBJECTIVE: To compare and quantify viability and cosmesis of 90-degree and vertical PMFF. METHODS: Retrospective chart review of 70 consecutive patients with a vertical or 90-degree PMFF design for nasal repairs after Mohs micrographic surgery (MMS). Cosmetic outcome was assessed on a 10-cm, 100-point, visual analog scale (VAS) by an independent observer using standardized 3-month postoperative photographs. Flap viability was assessed using standardized 3-week postoperative photographs. Descriptive statistics, t -test, and Mann-Whitney test were used for statistical analysis. RESULTS: Forty-eight patients were repaired with a vertical PMFF and 22 using the 90-degree PMFF. The mean defect area of vertical and 90-degree designs was equivalent (7.7 ± 4.0 cm 2 vs 8.1 ± 4.0 cm 2 , p = .70). There was no significant difference in cosmetic outcome (75.9 ± 9.4 vs 72.9 ± 6.8, p = .19) or flap viability (3.8% ± 11.6 vs 2.6% ± 7.9, p = .67) between vertical and 90-degree designs. CONCLUSION: Vertical and 90-degree PMFF designs for nasal repairs after MMS are equivalent in cosmetic outcome and viability.

Telehealth in outpatient delivery of palliative care: A qualitative study of patient and physician views.

OBJECTIVES: The COVID-19 pandemic has widened the funded use of telehealth in Australia to support telehealth delivery to all patients in any setting. Increasing the use and experience of telehealth brings to light unique insights into the advantages and challenges of this new model of healthcare delivery This study aimed to qualitatively explore the experiences of both palliative care physicians and patients setting, including their views on its future role in healthcare. METHODS: This qualitative study was conducted across three metropolitan tertiary palliative care centers in Victoria, Australia between November 2020 and March 2021. Purposive sampling identified 23 participants (12 physicians and 11 patients). Semi-structured interviews focused on the last telehealth consultation, thoughts and impressions of telehealth, and the possibility of telehealth remaining in palliative care. A thematic approach was adopted to code and analyze the data. RESULTS: Telehealth transformed the ways physicians and patients in this study perceived and engaged with outpatient palliative care across the entire continuum of care. Four key themes were identified: (1) access to care; (2) delivery of care; (3) engagement with care; and (4) the future. SIGNIFICANCE OF RESULTS: This study provides novel data bringing together the perspective of patients and physicians, which confirms the utility of telehealth in palliative care. Its convenience enables more frequent review, enables reviews to occur in response to lower levels of concern, and adds toward enhancing the continuity of care across and between settings. Moving forward, support seemed strongest for a hybrid model of telehealth and face-to-face consultations guided by key parameters relating to the level of anticipated complexity.