Using CombiCells, a platform for titration and combinatorial display of cell surface ligands, to study T-cell antigen sensitivity modulation by accessory receptors.

Understanding cellular decisions due to receptor-ligand interactions at cell-cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands-called CombiCells-to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor-ligand interactions at cell-cell interfaces.

Unstructured linker regions play a role in the differential splicing activities of paralogous RNA binding proteins PTBP1 and PTBP2.

RNA Binding Proteins regulate, in part, alternative pre-mRNA splicing and, in turn, gene expression patterns. Polypyrimidine tract binding proteins PTBP1 and PTBP2 are paralogous RNA binding proteins sharing 74% amino acid sequence identity. Both proteins contain four structured RNA-recognition motifs (RRMs) connected by linker regions and an N-terminal region. Despite their similarities, the paralogs have distinct tissue-specific expression patterns and can regulate discrete sets of target exons. How two highly structurally similar proteins can exert different splicing outcomes is not well understood. Previous studies revealed that PTBP2 is post-translationally phosphorylated in the unstructured N-terminal, Linker 1, and Linker 2 regions that share less sequence identity with PTBP1 signifying a role for these regions in dictating the paralog's distinct splicing activities. To this end, we conducted bioinformatics analysis to determine the evolutionary conservation of RRMs versus linker regions in PTBP1 and PTBP2 across species. To determine the role of PTBP2 unstructured regions in splicing activity, we created hybrid PTBP1-PTBP2 constructs that had counterpart PTBP1 regions swapped to an otherwise PTBP2 protein and assayed on differentially regulated exons. We also conducted molecular dynamics studies to investigate how negative charges introduced by phosphorylation in PTBP2 unstructured regions can alter their physical properties. Collectively, results from our studies reveal an important role for PTBP2 unstructured regions and suggest a role for phosphorylation in the differential splicing activities of the paralogs on certain regulated exons.

Global application of National Comprehensive Cancer Network resource-stratified guidelines for systemic treatment of colon cancer: a population-based, customisable model for cost, demand, and procurement.

BACKGROUND: Resource-stratified guidelines (RSGs) can inform systemic treatment decisions in the face of limited resources. The objective of this study was to develop a customisable modelling tool to predict the demand, cost, and drug procurement needs of delivering National Comprehensive Cancer Network (NCCN) RSG-based systemic treatment for colon cancer. METHODS: We developed decision trees for first-course systemic therapy for colon cancer based on the NCCN RSGs. Decision trees were merged with data from the Surveillance, Epidemiology, and End Results programme, the International Agency for Research on Cancer's GLOBOCAN 2020 national estimates for colon cancer incidence, country-level income data, and data on drug costs from Redbook (USA), the Pharmaceutical Benefits Scheme (Australia), and the Management Sciences for Health 2015 International Medical Products price guide to estimate global treatment needs and costs, and forecast drug procurement. Simulations and sensitivity analyses were used to explore the effect of scaling up services globally and the effect of alternative stage distributions on treatment demand and cost. We generated a customisable model, in which estimates can be tailored to local incidence, epidemiological, and costing data. FINDINGS: First-course systemic therapy is indicated in 608 314 (53·6%) of 1 135 864 colon cancer diagnoses in 2020. Indications for first-course systemic therapy are projected to rise to 926 653 in 2040; the indications in 2020 might be as high as 826 123 (72·7%), depending on stage distribution assumptions. Adhering to NCCN RSGs, patients with colon cancer in low-income and middle income countries (LMICs) would constitute 329 098 (54·1%) of 608 314 global systemic therapy demands, but only 10% of global expenditure on systemic therapies. The total cost of NCCN RSG-based first-course systemic therapy for colon cancer in 2020 would be between about US$4·2 and about $4·6 billion, depending on stage distribution. If all patients with colon cancer in 2020 were treated according to maximal resources, global expenditure on systemic therapy for colon cancer would rise to around $8·3 billion. INTERPRETATION: We have developed a customisable model that can be applied at global, national, and subnational levels to estimate systemic treatment needs, forecast drug procurement, and calculate expected drug costs on the basis of local data. This tool can be used to plan resource allocation for colon cancer globally. FUNDING: None.

Missense variants in human ACE2 strongly affect binding to SARS-CoV-2 Spike providing a mechanism for ACE2 mediated genetic risk in Covid-19: A case study in affinity predictions of interface variants.

SARS-CoV-2 Spike (Spike) binds to human angiotensin-converting enzyme 2 (ACE2) and the strength of this interaction could influence parameters relating to virulence. To explore whether population variants in ACE2 influence Spike binding and hence infection, we selected 10 ACE2 variants based on affinity predictions and prevalence in gnomAD and measured their affinities and kinetics for Spike receptor binding domain through surface plasmon resonance (SPR) at 37°C. We discovered variants that reduce and enhance binding, including three ACE2 variants that strongly inhibited (p.Glu37Lys, ΔΔG = -1.33 ± 0.15 kcal mol-1 and p.Gly352Val, predicted ΔΔG = -1.17 kcal mol-1) or abolished (p.Asp355Asn) binding. We also identified two variants with distinct population distributions that enhanced affinity for Spike. ACE2 p.Ser19Pro (ΔΔG = 0.59 ± 0.08 kcal mol-1) is predominant in the gnomAD African cohort (AF = 0.003) whilst p.Lys26Arg (ΔΔG = 0.26 ± 0.09 kcal mol-1) is predominant in the Ashkenazi Jewish (AF = 0.01) and European non-Finnish (AF = 0.006) cohorts. We compared ACE2 variant affinities to published SARS-CoV-2 pseudotype infectivity data and confirmed that ACE2 variants with reduced affinity for Spike can protect cells from infection. The effect of variants with enhanced Spike affinity remains unclear, but we propose a mechanism whereby these alleles could cause greater viral spreading across tissues and cell types, as is consistent with emerging understanding regarding the interplay between receptor affinity and cell-surface abundance. Finally, we compared mCSM-PPI2 ΔΔG predictions against our SPR data to assess the utility of predictions in this system. We found that predictions of decreased binding were well-correlated with experiment and could be improved by calibration, but disappointingly, predictions of highly enhanced binding were unreliable. Recalibrated predictions for all possible ACE2 missense variants at the Spike interface were calculated and used to estimate the overall burden of ACE2 variants on Covid-19.

Novel techniques in performing extraoral ultrasound in diagnosing dental abscesses.

INTRODUCTION: Dental abscesses are a common reason patients present to the emergency department (ED). Facial and dental imaging are sometimes necessary to support the clinical diagnosis. While radiographs and computed tomography scans are frequently used, point-of-care ultrasound (US) offers several advantages, including decreased radiation exposure, reduced costs, and shorter patient length of stay. This report outlines the use of US in evaluating patients with suspected dental abscesses in the ED. DISCUSSION: The typical orofacial US techniques include examining the affected area for cobblestoning or fluid collections. To improve the accuracy of diagnoses, novel techniques such as the Oral Hydroscan (OHS) and the Tongue Pointing Techniques (TPT) may be employed in specific cases. The OHS utilizes a water-filled oral cavity to enhance the spatial resolution of ultrasound images, providing improved visualization of near-field structures and preventing air accumulation between the gingiva and the buccal mucosa. The TPT involves asking the patient to extend their tongue towards the affected area, pointing to the painful location, and serving as a visual reference for an extraoral US. CONCLUSION: US presents several advantages as an alternative imaging method for patients with suspected dental abscesses in the ED. Using innovative techniques such as the OHS and the TPT can further increase the visibility of tissue planes and help define the area of interest in these cases.

POCUS-first for nephrolithiasis: A Monte Carlo simulation illustrating cost savings, LOS reduction, and preventable radiation.

OBJECTIVES: Non-contrast computed tomography (NCCT) is the gold standard for nephrolithiasis evaluation in the emergency department (ED). However, Choosing Wisely guidelines recommend against ordering NCCT for patients with suspected nephrolithiasis who are <50 years old with a history of kidney stones. Our primary objective was to estimate the national annual cost savings from using a point-of-care ultrasound (POCUS)-first approach for patients with suspected nephrolithiasis meeting Choosing Wisely criteria. Our secondary objectives were to estimate reductions in ED length of stay (LOS) and preventable radiation exposure. METHODS: We created a Monte Carlo simulation using available estimates for the frequency of ED visits for nephrolithiasis and eligibility for a POCUS-first approach. The study population included all ED patients diagnosed with nephrolithiasis. Based on 1000 trials of our simulation, we estimated national cost savings in averted advanced imaging from this strategy. We applied the same model to estimate the reduction in ED LOS and preventable radiation exposure. RESULTS: Using this model, we estimate a POCUS-first approach for evaluating nephrolithiasis meeting Choosing Wisely guidelines to save a mean (±SD) of $16.5 million (±$2.1 million) by avoiding 159,000 (±18,000) NCCT scans annually. This resulted in a national cumulative decrease of 166,000 (±165,000) annual bed-hours in ED LOS. Additionally, this resulted in a national cumulative reduction in radiation exposure of 1.9 million person-mSv, which could potentially prevent 232 (±81) excess cancer cases and 118 (±43) excess cancer deaths annually. CONCLUSION: If adopted widely, a POCUS-first approach for suspected nephrolithiasis in patients meeting Choosing Wisely criteria could yield significant national cost savings and a reduction in ED LOS and preventable radiation exposure. Further research is needed to explore the barriers to widespread adoption of this clinical workflow as well as the benefits of a POCUS-first approach in other patient populations.

Integrating participant feedback and concerns to improve community and individual level chemical exposure assessment reports.

BACKGROUND: As exposure assessment has shifted towards community-engaged research there has been an increasing trend towards reporting results to participants. Reports aim to increase environmental health literacy, but this can be challenging due to the many unknowns regarding chemical exposure and human health effects. This includes when reports encompass a wide-range of chemicals, limited reference or health standards exist for those chemicals, and/or incompatibility of data generated from exposure assessment tools with published reference values (e.g., comparing a wristband concentration to an oral reference dose). METHODS: Houston Hurricane Harvey Health (Houston-3H) participants wore silicone wristbands that were analyzed for 1,530 organic compounds at two time-points surrounding Hurricane Harvey. Three focus groups were conducted in separate neighborhoods in the Houston metropolitan area to evaluate response to prototype community and individual level report-backs. Participants (n = 31) evaluated prototype drafts using Likert scales and discussion prompts. Focus groups were audio-recorded, and transcripts were analyzed using a qualitative data analysis program for common themes, and quantitative data (ranking, Likert scales) were statistically analyzed. RESULTS: Four main themes emerged from analysis of the transcripts: (1) views on the report layout; (2) expression of concern over how chemicals might impact their individual or community health; (3) participants emotional response towards the researchers; and (4) participants ability to comprehend and evaluate environmental health information. Evaluation of the report and key concerns differed across the three focus groups. However, there was agreement amongst the focus groups about the desire to obtain personal exposure results despite the uncertainty of what the participant results meant. CONCLUSIONS: The report-back of research results (RBRR) for community and individual level exposure assessment data should keep the following key principles in mind: materials should be accessible (language level, data visualization options, graph literacy), identify known information vs unknown (e.g., provide context for what exposure assessment data means, acknowledge lack of current health standards or guidelines), recognize and respect community knowledge and history, and set participant expectations for what they can expect from the report.

Resource stratified guidelines for cancer: Are they all the same? Interguideline concordance for systemic treatment recommendations.

A number of organizations are producing resource stratified guidelines (RSGs) for cancer. Despite using similar definitions of resource levels, systemic treatment recommendations often differ between organizations. We systematically searched for RSGs focusing on solid tumors. We qualitatively compared the methods used to generate guidelines using the AGREE-II appraisal tool. We extracted systemic treatment recommendations and assessed interguideline concordance using the Gwet AC1 coefficient, stratified by resource level, treatment setting and cancer type. We identified 69 RSGs cancer covering 15 solid tumors produced by four organizations. Despite using common resource-level definitions (Basic, Core/Limited, Enhanced and Maximal), recommendations differed between organizations. Concordance for chemotherapy recommendations was poor in Basic (58.3%, Gwet 0.20), fair in Core (58.3%, Gwet 0.32) and excellent in Enhanced (92.4%, Gwet 0.92) and Maximal settings (95.4%, Gwet 0.95). Concordance rates for endocrine therapy were good in Basic (80% Gwet 0.61), and excellent in Core (90%, Gwet 0.87), Enhanced (90%, Gwet 0.89) and Maximal settings (90%, Gwet 0.89). There was moderate to excellent concordance in targeted therapy recommendations across all resource levels. Differences in recommendations appeared driven by different opinions among the chosen panel of experts regarding what is resource appropriate. Overall, we found that countries looking to base treatment and health-policy on RSGs will find conflicting information depending on which guidelines are used, particularly for chemotherapy in Basic and Core settings. Improved transparency regarding the methods used to determine the value of a therapy for a given resource level is needed.

A generic cell surface ligand system for studying cell-cell recognition.

Dose-response experiments are a mainstay of receptor biology studies and can reveal valuable insights into receptor function. Such studies of receptors that bind cell surface ligands are currently limited by the difficulty in manipulating the surface density of ligands at a cell-cell interface. Here, we describe a generic cell surface ligand system that allows precise manipulation of cell surface ligand densities over several orders of magnitude. These densities are robustly quantifiable, a major advance over previous studies. We validate the system for a range of immunoreceptors, including the T-cell receptor (TCR), and show that this generic ligand stimulates via the TCR at a similar surface density as its native ligand. We also extend our work to the activation of chimeric antigen receptors. This novel system allows the effect of varying the surface density, valency, dimensions, and affinity of the ligand to be investigated. It can be readily broadened to other receptor-cell surface ligand interactions and will facilitate investigation into the activation of, and signal integration between, cell surface receptors.

Regional Variations in Clinical Trial Outcomes in Oncology.

BACKGROUND: It is unknown how often regional differences in oncology trials are observed. Based on our study findings, we quantified regional variation in registration studies in oncology and developed a question guide to help clinicians evaluate regional differences. METHODS: Using FDA archives, we identified registration studies in solid tumor malignancies from 2010 to 2020. We extracted the baseline study characteristics and participating countries and determined whether the primary publication reported a regional subgroup analysis. For studies presenting outcomes stratified by region, we extracted the stratified hazard ratios (HRs) and extracted or calculated the test for heterogeneity. We performed a random effects meta-analysis and a pairwise comparison to determine whether outcomes differed between high-income versus mixed-income regions. RESULTS: We included 147 studies in our final analysis. Studies supporting FDA drug approval have become increasingly multinational over time (ß = 0.5; P=.04). The median proportion of countries from high-income groups was 81.2% (range, 44%-100%), with no participation from low-income countries in our cohort. Regional subgroup analysis was presented for 78 studies (53%). Regional heterogeneity was found in 17.8% (8/45) and 18% (8/44) of studies presenting an overall survival (OS) and progression-free survival endpoint, respectively. After grouping regions by income level, we found no difference in OS outcomes in high-income regions compared with mixed-income regions (n=20; HR, 0.95; 95% CI, 0.84-1.07). To determine whether regional variation is genuine, clinicians should evaluate the data according to the following 5 questions: (1) Are the regional groupings logical? (2) Is the regional difference on an absolute or relative scale? (3) Is the regional difference consistent and plausible? (4) Is the regional difference statistically significant? (5) Is there a clinical explanation? CONCLUSIONS: As registration studies in oncology become increasingly international, regional variations in trial outcomes may be detected. The question guide herein will help clinicians determine whether regional variations are likely to be clinically meaningful or statistical anomalies.

Evidence-based benchmarks for use of cancer surgery in high-income countries: a population-based analysis.

BACKGROUND: Estimating a population-level benchmark rate for use of surgery in the management of cancer helps to identify treatment gaps, estimate the survival impact of such gaps, and benchmark the workforce and other resources, including budgets, required to meet service needs. A population-based benchmark for use of surgery in high-income settings to inform policy makers and service provision has not been developed but was recommended by the Lancet Oncology Commission on Global Cancer Surgery. We aimed to develop and validate a cancer surgery benchmarking model. METHODS: We examined the latest clinical guidelines from high-income countries (Australia, the UK, the EU, the USA, and Canada) and mapped surgical treatment pathways for 30 malignant cancer sites (19 individual sites and 11 grouped as other cancers) that were notifiable in Australia in 2014, broadly reflecting contemporary high-income models of care. The optimal use of surgery was considered as an indication for surgery where surgery is the treatment of choice for a given clinical scenario. Population-based epidemiological data, such as cancer stage, tumour characteristics, and fitness for surgery, were derived from Australia and other similar high-income settings for 2017. The probabilities across the clinical pathways of each cancer were multiplied and added together to estimate the population-level benchmark rates of cancer surgery, and further validated with the comparisons of observed rates of cancer surgery in the South Western Sydney Local Health District in 2006-12. Univariable and multivariable sensitivity analyses were done to explore uncertainty around model inputs, with mean (95% CI) benchmark surgery rates estimated on the basis of 10 000 Monte Carlo simulations. FINDINGS: Surgical treatment was indicated in 58% (95% CI 57-59) of newly diagnosed patients with cancer in Australia in 2014 at least once during the course of their treatment, but varied by site from 23% (17-27) for prostate cancer to 99% (96-99) for testicular cancer. Observed cancer surgery rates in South Western Sydney were comparable to the benchmarks for most cancers, but were higher for some cancers, such as prostate (absolute increase of 29%) and lower for others, such as lung (-14%). INTERPRETATION: The model provides a new template for high-income and emerging economies to rationally plan and assess their cancer surgery provision. There are differences in modelled versus observed surgery rates for some cancers, requiring more in-depth analysis of the observed differences. FUNDING: University of New South Wales Scientia Scholarship, UK Research and Innovation-Global Challenges Research Fund.

Global demand for cancer surgery and an estimate of the optimal surgical and anaesthesia workforce between 2018 and 2040: a population-based modelling study.

BACKGROUND: The growing demand for cancer surgery has placed a global strain on health systems. In-depth analyses of the global demand for cancer surgery and optimal workforce requirements are needed to plan service provision. We estimated the global demand for cancer surgery and the requirements for an optimal surgical and anaesthesia workforce, using benchmarks based on clinical guidelines. METHODS: Using models of benchmark surgical use based on clinical guidelines, we estimated the proportion of cancer cases with an indication for surgery across 183 countries, stratified by income group. These proportions were multiplied by age-adjusted national estimates of new cancer cases using GLOBOCAN 2018 data and then aggregated to obtain the estimated number of surgical procedures required globally. The numbers of cancer surgical procedures in 44 high-income countries were divided by the actual number of surgeons and anaesthetists in the respective countries to calculate cancer procedures per surgeon and anaesthetist ratios. Using the median (IQR) of these ratios as benchmarks, we developed a three-tiered optimal surgical and anaesthesia workforce matrix, and the predictions were extrapolated up to 2040. FINDINGS: Our model estimates that the number of cancer cases globally with an indication for surgery will increase by 5 million procedures (52%) between 2018 (9 065 000) and 2040 (13 821 000). The greatest relative increase in surgical demand will occur in 34 low-income countries, where we also observed the largest gaps in workforce requirements. To match the median benchmark for high-income countries, the surgical workforce in these countries would need to increase by almost four times and the anaesthesia workforce by nearly 5·5 times. The greatest increase in optimal workforce requirements from 2018 to 2040 will occur in low-income countries (from 28 000 surgeons to 58 000 surgeons; 107% increase), followed by lower-middle-income countries (from 166 000 surgeons to 277 000 surgeons; 67% increase). INTERPRETATION: The global demand for cancer surgery and the optimal workforce are predicted to increase over the next two decades and disproportionately affect low-income countries. These estimates provide an appropriate framework for planning the provision of surgical services for cancer worldwide. FUNDING: University of New South Wales Scientia Scholarship and UK Research and Innovation Global Challenges Research Fund.

Patterns of care for men with prostate cancer: the 45 and Up Study.

OBJECTIVES: To describe patterns of care in New South Wales for men with prostate cancer, and to ascertain factors associated with receiving different types of treatment. DESIGN: Individual patient data record linkage study. SETTING, PARTICIPANTS: 4003 New South Wales men aged 45 years or more enrolled in the population-based 45 and Up Study in whom prostate cancer was first diagnosed during 2006-2013. MAIN OUTCOME MEASURES: Prostate cancer treatment type received; factors statistically associated with treatment received; proportions of patients who consulted radiation oncologists prior to treatment. RESULTS: In total, 1619 of 4003 patients underwent radical prostatectomy (40%), 893 external beam radiotherapy (EBRT) (22%), 183 brachytherapy (5%), 87 chemotherapy (2%), 373 androgen deprivation therapy alone (9%), and 848 no active treatment (21%). 205 of 1628 patients who had radical prostatectomies (13%) had radiation oncology consultations prior to surgery. Radical prostatectomy was more likely for patients aged 45-59 years, with regional stage disease, living 100 km or more from the nearest radiotherapy centre, having partners, or having private health insurance, while lower physical functioning, obesity, and living in areas of greater socio-economic disadvantage reduced the likelihood. EBRT was more likely for patients aged 70-79 years, with non-localised or unknown stage disease, living less than 100 km from the nearest radiotherapy centre, or not having private health insurance, while the likelihood was lower for patients aged 45-59 years or more than 80 years and for those who had several comorbid conditions. CONCLUSIONS: Men with prostate cancer were twice as likely to have radical prostatectomy as to receive EBRT, and fewer than one in seven had consulted radiation oncologists prior to prostatectomy. The treatment received was influenced by several socio-demographic factors. Given the treatment-specific side effects and costs, policies that affect access to different treatments for prostate cancer should be reviewed.

Fact versus fiction: bridging contrasting medicinal cannabis information needs.

Regulatory changes now permit the availability and prescribing of medicinal cannabis in Australia. Public awareness and patient interest are high. Using a co-design approach involving cancer patients, carers and oncology and palliative care clinicians, two information resources were developed to provide readily available sources of important information for cancer patients and clinicians who are considering the use of medicinal cannabis. Focus groups and evaluation interviews revealed some areas of dissonance between consumers and clinicians concerning aspects of medicinal cannabis.

The value of first-line chemotherapy and targeted therapy in the treatment of breast cancer.

OBJECTIVE: To investigate the value (survival benefit and cost) of first-line chemotherapy and targeted therapy in breast cancer at a population level. METHODS: Based on guideline recommendations, a model of optimal utilisation was constructed for first-line chemotherapy and targeted therapy in breast cancer, calculating the survival benefit and average cost of all regimens recommended for each treatment indication at 5 years and at 10 years. RESULTS: Survival benefits from chemotherapy and targeted therapy differ markedly depending on the treatment indications. The cost per life-year gained at 5 years is $38,044 for stages I and II, $33,749 for stage III and $ 151,668 for patients presenting with stage IV breast cancer. The cost per life-year gained at 10 years is $ 13,587 for early breast cancer. The most expensive chemotherapy indication in breast cancer is the treatment of metastatic HER2-positive breast cancer costing $330,978 per LYG for a survival benefit of 11% at 5 years falling to zero survival benefit at 10 years. CONCLUSION: There are large differences in value between the different indications for first-course chemotherapy and targeted therapy in the treatment of breast cancer that should be considered when pricing cancer drugs.

SARS/CoV-2: Behavioral Host Manipulation.

INTRODUCTION: Though it has not been extensively studied, host manipulation has been documented for various pathogens. Examples of this phenomenon can be seen in cases of toxoplasmosis, rabies, and the influenza virus. An examination of the possible means by which SARS/CoV-2 alters the behavior of its host to spread among populations is elaborated. Indirect evidence that serves as indicators of this phenomenon is presented. METHODS: This is primarily a theoretical document. Many of the ideas raised are not amenable to direct testing due to ethical concerns. However, several indirect means by which to test the hypothesis are discussed. Primary data from cell phones regarding miles traveled, number of times leaving home, etc., are among the possible indirect measures. RESULTS: The rapid ability of the SARS/CoV-2 virus to spread through society suggests that it may cause behavioral changes of the host to increase its transmission. Numerous cases of super spreader events are noted that have provided meaningful measures of host manipulation. CONCLUSION: In the case of SARS/CoV-2, the largest advantage of the pathogen is likely that between 50% and 70% of those infected are asymptomatic (John's Hopkins Coronavirus Resource Center, John's Hopkins University Corona Virus Resource Center. Available at https://coronavirus.jhu.edu/map.html , 2020). This component is a threat to elderly individuals and those immunocompromised who are more likely to have severe complications from the virus and die. To spread within these groups, a seemingly healthy host is necessary to carry the virus to them. The goal of the virus is not to kill the host, but to survive and reproduce.

Measuring the impact of clinical practice guidelines on infantile hemangioma referrals.

High-risk infantile hemangiomas may be associated with significant patient comorbidity. The American Academy of Pediatrics published clinical practice guidelines with recommendations to refer high-risk hemangiomas early. The results of this study suggest that these guidelines may have resulted in an earlier referral age of patients with high-risk IH to hemangioma specialists.

Critical Assessment of Metagenome Interpretation-a benchmark of metagenomics software.

Methods for assembly, taxonomic profiling and binning are key to interpreting metagenome data, but a lack of consensus about benchmarking complicates performance assessment. The Critical Assessment of Metagenome Interpretation (CAMI) challenge has engaged the global developer community to benchmark their programs on highly complex and realistic data sets, generated from ∼700 newly sequenced microorganisms and ∼600 novel viruses and plasmids and representing common experimental setups. Assembly and genome binning programs performed well for species represented by individual genomes but were substantially affected by the presence of related strains. Taxonomic profiling and binning programs were proficient at high taxonomic ranks, with a notable performance decrease below family level. Parameter settings markedly affected performance, underscoring their importance for program reproducibility. The CAMI results highlight current challenges but also provide a roadmap for software selection to answer specific research questions.

Who is asking about medicinal cannabis in palliative care?

Following legislative changes in the availability and prescribing of medicinal cannabis in Australia, we sought to understand prospectively the nature of information seeking and requests for medicinal cannabis in consultations between palliative care clinicians and patients with cancer. The 104 discussions were overwhelmingly initiated by patients and carers (93%) and were for a variety of symptoms, reflecting high levels of patient interest in the use of medicinal cannabis in cancer.

Red puffy hand syndrome mistaken for inflammatory arthritis.

Red puffy hand syndrome is an uncommon clinical manifestation of intravenous drug abuse, which presents with bilateral, painless and non-pitting erythema and edema of the dorsal hands. The pathophysiology is believed to primarily be the result of lymphatic blockage from either direct toxicity of the injected drug, drainage of impurities, or infection complications. A woman in her 40's with remote intravenous drug use presented with over a decade of fixed, painless erythema and swelling of bilateral dorsal hands. Owing to an elevated rheumatoid factor, which would later be attributed to patient's untreated hepatitis C, these findings were mistaken for rheumatoid arthritis and unnecessarily treated with methotrexate and prednisone. Upon proper recognition of her underlying Red puffy hand syndrome, systemic medications were discontinued and appropriate care was initiated with lymphedema decongestion and occupational therapy. Red puffy hand syndrome, albeit rare, is an important manifestation of intravenous drug abuse; its recognition will spare patients from unnecessary systemic treatments.