The switch between acute and persistent paramyxovirus infection caused by single amino acid substitutions in the RNA polymerase P subunit

Paramyxoviruses can establish persistent infections both in vitro and in vivo, some of which lead to chronic disease. However, little is known about the molecular events that contribute to the establishment of persistent infections by RNA viruses. Using parainfluenza virus type 5 (PIV5) as a model we show that phosphorylation of the P protein, which is a key component of the viral RNA polymerase complex, determines whether or not viral transcription and replication becomes repressed at late times after infection. If the virus becomes repressed, persistence is established, but if not, the infected cells die. We found that single amino acid changes at various positions within the P protein switched the infection phenotype from lytic to persistent. Lytic variants replicated to higher titres in mice than persistent variants and caused greater infiltration of immune cells into infected lungs but were cleared more rapidly. We propose that during the acute phases of viral infection in vivo, lytic variants of PIV5 will be selected but, as the adaptive immune response develops, variants in which viral replication can be repressed will be selected, leading to the establishment of prolonged, persistent infections. We suggest that similar selection processes may operate for other RNA viruses

Epidemiology and natural history of central venous access device use and infusion pump function in the NO16966 trial

Background: Central venous access devices in fluoropyrimidine therapy are associated with complications; however, reliable data are lacking regarding their natural history, associated complications and infusion pump performance in patients with metastatic colorectal cancer.<p></p> Methods: We assessed device placement, use during treatment, associated clinical outcomes and infusion pump perfomance in the NO16966 trial.<p></p> Results: Device replacement was more common with FOLFOX-4 (5-fluorouracil (5-FU)+oxaliplatin) than XELOX (capecitabine+oxaliplatin) (14.1% vs 5.1%). Baseline device-associated events and post-baseline removal-/placement-related events occurred more frequently with FOLFOX-4 than XELOX (11.5% vs 2.4% and 8.5% vs 2.1%). Pump malfunctions, primarily infusion accelerations in 16% of patients, occurred within 1.6–4.3% of cycles. Fluoropyrimidine-associated grade 3/4 toxicity was increased in FOLFOX-4-treated patients experiencing a malfunction compared with those who did not (97 out of 155 vs 452 out of 825 patients), predominantly with increased grade 3/4 neutropenia (53.5% vs 39.8%). Febrile neutropenia rates were comparable between patient cohorts±malfunction. Efficacy outcomes were similar in patient cohorts±malfunction.<p></p> Conclusions: Central venous access device removal or replacement was common and more frequent in patients receiving FOLFOX-4. Pump malfunctions were also common and were associated with increased rates of grade 3/4 haematological adverse events. Oral fluoropyrimidine-based regimens may be preferable to infusional 5-FU based on these findings

Enhancing automated analysis of marine soundscapes using ecoacoustic indices and machine learning

This is the final version. Available on open access from Elsevier via the DOI in this record. Historically, ecological monitoring of marine habitats has primarily relied on labour-intensive, non-automated survey methods. The field of passive acoustic monitoring (PAM) has demonstrated the potential of this practice to automate surveying in marine habitats. This has primarily been through the use of ‘ecoacoustic indices’ to quantify attributes from natural soundscapes. However, investigations using individual indices have had mixed success. Using PAM recordings collected at one of the world’s largest coral reef restoration programmes, we instead apply a machine-learning approach across a suite of ecoacoustic indices to improve predictive power of ecosystem health. Healthy and degraded reef sites were identified through live coral cover surveys, with 90–95% and 0–20% cover respectively. A library of one-minute recordings were extracted from each. Twelve ecoacoustic indices were calculated for each recording, in up to three different frequency bandwidths (low: 0.05–0.8 kHz, medium: 2–7 kHz and broad: 0.05–20 kHz). Twelve of these 33 index-frequency combinations differed significantly between healthy and degraded habitats. However, the best performing single index could only correctly classify 47% of recordings, requiring extensive sampling from each site to be useful. We therefore trained a regularised discriminant analysis machine-learning algorithm to discriminate between healthy and degraded sites using an optimised combination of ecoacoustic indices. This multi-index approach discriminated between these two habitat classes with improved accuracy compared to any single index in isolation. The pooled classification rate of 1000 cross-validated iterations of the model had a 91.7% 0.8, mean SE) success rate at correctly classifying individual recordings. The model was subsequently used to classify recordings from two actively restored sites, established >24 months prior to recordings, with coral cover values of 79.1% (±3.9) and 66.5% (±3.8). Of these recordings, 37/38 and 33/39 received a classification as healthy respectively. The model was also used to classify recordings from a newly restored site established <12 months prior with a coral cover of 25.6% (±2.6), from which 27/33 recordings were classified as degraded. This investigation highlights the value of combining PAM recordings with machine-learning analysis for ecological monitoring and demonstrates the potential of PAM to monitor reef recovery over time, reducing the reliance on labour-intensive in-water surveys by experts. As access to PAM recorders continues to rapidly advance, effective automated analysis will be needed to keep pace with these expanding acoustic datasets.Natural Environment Research CouncilSwiss National Science FoundationNatural Environment Research Council (NERC)University of ExeterMars Sustainable Solution

The sound of recovery: coral reef restoration success is detectable in the soundscape (article)

This is the final version. Available on open access from Wiley via the DOI in this recordThe dataset associated with this article is available in ORE at https://doi.org/10.24378/exe.37031. Pantropical degradation of coral reefs is prompting considerable investment in their active restoration. However, current measures of restoration success are based largely on coral cover, which does not fully reflect ecosystem function or reef health. 2. Soundscapes are an important aspect of reef health; loud and diverse soundscapes guide the recruitment of reef organisms, but this process is compromised when degradation denudes soundscapes. As such, acoustic recovery is a functionally important component of ecosystem recovery. 3. Here, we use acoustic recordings taken at one of the world’s largest coral reef restoration projects to test whether successful restoration of benthic and fish communities is accompanied by a restored soundscape. We analyse recordings taken simultaneously on healthy, degraded (extensive historic blast fishing) and restored reefs (restoration carried out for 1–3 years on previously-degraded reefs). We compare soundscapes using manual counts of biotic sounds (phonic richness), and two commonly used computational analyses (acoustic complexity index [ACI] and sound-pressure level [SPL]). 4. Healthy and restored reef soundscapes exhibited a similar diversity of biotic sounds (phonic richness), which was significantly higher than degraded reef soundscapes. This pattern was replicated in some automated analyses but not others; the ACI exhibited the same qualitative result as phonic richness in a low-frequency, but not a high-frequency bandwidth, and there was no significant difference between SPL values in either frequency bandwidth. Further, the low-frequency ACI and phonic richness scores were only weakly correlated despite showing a qualitatively equivalent overall result, suggesting that these metrics are likely to be driven by different aspects of the reef soundscape. 5. Synthesis and applications: These data show that coral restoration can lead to soundscape recovery, demonstrating the return of an important ecosystem function. They also suggest that passive acoustic monitoring (PAM) might provide functionally important measures of ecosystemlevel recovery – but only some PAM metrics reflect ecological status, and those that did are likely to be driven by different communities of soniferous animals. Recording soundscapes represents a potentially valuable tool for evaluating restoration success across ecosystems, but caution must be exercised when choosing metrics and interpreting results.Natural Environment Research Council (NERC)Swiss National Science FoundationUniversity of ExeterMARS Sustainable Solution

Oral cancer treatment: developments in chemotherapy and beyond

Oncology is one of the few areas of medicine where most patients are treated intravenously rather than receiving oral drugs. Recently, several oral anti-cancer drugs have been approved and there are many more in development. Oral chemotherapy is attractive because of its convenience and ease of administration, particularly in the palliative setting. With an increasing number of oral agents emerging, we can expect to see a rapid rise in the use of oral chemotherapy in years to come. This article reviews recent developments in oral chemotherapy, both of traditional cytotoxics and novel, targeted agents, from the viewpoint of patients, physicians, drug developers and health-care providers

Disarming the guarded prognosis: predicting survival in newly referred patients with incurable cancer

People affected by cancer want information about their prognosis but clinicians have trouble estimating and talking about it. We sought to determine the nature and accuracy of medical oncologists' estimates of life expectancy in newly referred patients with incurable cancer. With reference to each patient, medical oncologists estimated how long they thought 90, 50, and 10% of similar patients would live. These proportions were chosen to reflect worst case, predicted, and best case scenarios suitable for discussions. After a median follow-up of 35 months, 86 of the 102 patients had died with an observed median survival of 12 months. Oncologists' estimates of each patient's worst case, predicted and best case scenarios were well-calibrated: 10% of patients lived for fewer months than estimated for the worst 10% of similar patients; 50% lived for at least as long as estimated for 50% of similar patients (predicted survival), and 17% lived for more months than estimated for the best 10% of similar patients. Oncologists' estimates of each patient's predicted survival were imprecise: 29% were within 0.67–1.33 times the patient's actual survival, 35% were too optimistic (>1.33 times the actual survival), and 39% were too pessimistic (<0.67 times the actual survival). The proportions of patients with actual survival times bounded by simple multiples of their predicted survival were as follows: 61% between half to double their predicted, 6% at least three to four times their predicted, and 4% no more than 1/6 of their predicted; similar to the proportions in an exponential distribution (about 50%, 10% and 10% respectively). Ranges based on simple multiples of the predicted survival time appropriately convey prognosis and its uncertainty in newly referred people with incurable cancer

The Impact of Venous Thromboembolism on Risk of Death or Hemorrhage in Older Cancer Patients

BACKGROUND: Among older cancer patients, there is uncertainty about the degree to which venous thromboembolism (VTE) and its treatment increase the risk of death or major hemorrhage. OBJECTIVE: To determine the prevalence of VTE in a cohort of older cancer patients, as well as the degree to which VTE increased the risk of death or major hemorrhage. METHODS: We conducted a retrospective cohort study of linked Surveillance, Epidemiology, and End Results cancer registry and Medicare administrative claims data. Patients with any of ten invasive cancers diagnosed during 1995 through 1999 were included; the independent variable was VTE diagnosed concomitantly with cancer diagnosis. Outcomes included major hemorrhage during the first year after cancer diagnosis and all-cause mortality; RESULTS: Overall, about 1% of patients who were diagnosed with cancer also had a VTE diagnosed concomitantly. After adjusting for sociodemographic factors and cancer stage and grade, concomitant VTE was associated with a relative increase in the risk of death for 8 of the 10 cancer types; the increase in risk tended to range 20–40% across most cancer types. Approximately 16.8% (95% confidence interval [CI] 14.9–18.8%) of patients with a concomitant VTE and 7.9% (95% CI 7.7–8.0%) of patients without a VTE experienced a major hemorrhage during the year after cancer diagnosis (P value <.001). The excess risk of hemorrhage associated with VTE varied substantially across cancer types, ranging from no significant excess (kidney and uterine cancer) to 11.5% (lymphoma). CONCLUSION: Concomitant VTE is not only a marker and potential mediator of increased risk of death among older cancer patients, but patients with a VTE have a marked increased risk of major hemorrhage

Older adults' beliefs about physician-estimated life expectancy: a cross-sectional survey

BACKGROUND: Estimates of life expectancy assist physicians and patients in medical decision-making. The time-delayed benefits for many medical treatments make an older adult's life expectancy estimate particularly important for physicians. The purpose of this study is to assess older adults' beliefs about physician-estimated life expectancy. METHODS: We performed a mixed qualitative-quantitative cross-sectional study in which 116 healthy adults aged 70+ were recruited from two local retirement communities. We interviewed them regarding their beliefs about physician-estimated life expectancy in the context of a larger study on cancer screening beliefs. Semi-structured interviews of 80 minutes average duration were performed in private locations convenient to participants. Demographic characteristics as well as cancer screening beliefs and beliefs about life expectancy were measured. Two independent researchers reviewed the open-ended responses and recorded the most common themes. The research team resolved disagreements by consensus. RESULTS: This article reports the life-expectancy results portion of the larger study. The study group (n = 116) was comprised of healthy, well-educated older adults, with almost a third over 85 years old, and none meeting criteria for dementia. Sixty-four percent (n = 73) felt that their physicians could not correctly estimate their life expectancy. Sixty-six percent (n = 75) wanted their physicians to talk with them about their life expectancy. The themes that emerged from our study indicate that discussions of life expectancy could help older adults plan for the future, maintain open communication with their physicians, and provide them knowledge about their medical conditions. CONCLUSION: The majority of the healthy older adults in this study were open to discussions about life expectancy in the context of discussing cancer screening tests, despite awareness that their physicians' estimates could be inaccurate. Since about a third of participants perceived these discussions as not useful or even harmful, physicians should first ascertain patients' preferences before discussing their life expectancies