UV Irradiation Induces a Non-coding RNA that Functionally Opposes the Protein Encoded by the Same Gene.

The transcription-related DNA damage response was analyzed on a genome-wide scale with great spatial and temporal resolution. Upon UV irradiation, a slowdown of transcript elongation and restriction of gene activity to the promoter-proximal ∼25 kb is observed. This is associated with a shift from expression of long mRNAs to shorter isoforms, incorporating alternative last exons (ALEs) that are more proximal to the transcription start site. Notably, this includes a shift from a protein-coding ASCC3 mRNA to a shorter ALE isoform of which the RNA, rather than an encoded protein, is critical for the eventual recovery of transcription. The non-coding ASCC3 isoform counteracts the function of the protein-coding isoform, indicating crosstalk between them. Thus, the ASCC3 gene expresses both coding and non-coding transcript isoforms with opposite effects on transcription recovery after UV-induced DNA damage.

Genomic Features and Classification of Homologous Recombination Deficient Pancreatic Ductal Adenocarcinoma.

BACKGROUND AND AIMS: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2. METHODS: We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status. RESULTS: Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance. CONCLUSIONS: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.

COVID-19 Incidence and Mortality Among American Indian/Alaska Native and White Persons - Montana, March 13-November 30, 2020.

Geographic differences in infectious disease mortality rates have been observed among American Indian or Alaska Native (AI/AN) persons in the United States (1), and aggregate analyses of data from selected U.S. states indicate that COVID-19 incidence and mortality are higher among AI/AN persons than they are among White persons (2,3). State-level data could be used to identify disparities and guide local efforts to reduce COVID-19-associated incidence and mortality; however, such data are limited. Reports of laboratory-confirmed COVID-19 cases and COVID-19-associated deaths reported to the Montana Department of Public Health and Human Services (MDPHHS) were analyzed to describe COVID-19 incidence, mortality, and case-fatality rates among AI/AN persons compared with those among White persons. During March-November 2020 in Montana, the estimated cumulative COVID-19 incidence among AI/AN persons (9,064 cases per 100,000) was 2.2 times that among White persons (4,033 cases per 100,000).* During the same period, the cumulative COVID-19 mortality rate among AI/AN persons (267 deaths per 100,000) was 3.8 times that among White persons (71 deaths per 100,000). The AI/AN COVID-19 case-fatality rate (29.4 deaths per 1,000 COVID-19 cases) was 1.7 times the rate in White persons (17.0 deaths per 1,000). State-level surveillance findings can help in developing state and tribal COVID-19 vaccine allocation strategies and assist in local implementation of culturally appropriate public health measures that might help reduce COVID-19 incidence and mortality in AI/AN communities.

First report of Colletotrichum fructicola, C. perseae, and C. siamense causing anthracnose disease of avocado (Persea americana) in New Zealand.

In January and March 2019, an inspection of 11 commercial 'Hass' avocado orchards in mid-North and Tauranga (New Zealand) was conducted by NZ Avocado Growers Association Inc. (NZAGA) and the samples were sent to Plant Diagnostics Limited for investigation of a newly observed fruit staining symptom termed "tannin stain". Fruit symptoms consisted of areas of minute small spots which coalesced into areas of tear staining associated with water movement over the fruit's surface (Supplementary Fig. 1). Up to seven trees per orchard were sampled targeting symptomatic fruit with the aim of determining the cause of the problem. Fruit was surface disinfected for 4 minutes in 1% sodium hypochlorite solution and sections from lesions were plated on agar medium (prune extract agar) to isolate any plant pathogens. The predominant fungi isolated, represented species in the Colletotrichum acutatum, C. gloeosporioides, and C. boninense species complexes. Since the morphological characters within these complexes overlap (see Supplementary Fig. 2 for examples), the isolates were differentiated by amplification and sequencing of the glyceraldehyde-3-phosphate dehydrogenase (GPDH) gene and, where necessary, the calmodulin (CAL) gene and/or the Apn2-Mat1-2 intergenic spacer region (ApMat) locus (Weir et al., 2012; Rojas et al., 2010). The sequence analysis revealed eight Colletotrichum species comprising C. alienum, C. aotearoa, C. cigarro, C. fioriniae, C. fructicola, C. karstii, C. perseae, and C. siamense. This range included three species that have not previously been recorded in New Zealand: C. fructicola (Cf), C. perseae (Cp), and C. siamense (Cs). Colonies for all these three fungi were white to grey with salmon-coloured and black acervuli. Conidia were aseptate, hyaline, straight, cylindrical, with broadly rounded ends, forming on cylindrical conidiogenous cells. The respective GPDH, CAL, and/or ApMat sequences of the Cf, Cp, and Cs isolates were identical to reference sequences of representative isolates in GenBank (e.g. ApMat: Cf - KX620181, Cp - KX620177, Cs - KP703788). An isolate for each species is stored in the International Collection of Microorganisms from Plants (Cf - ICMP22409, Cp - ICMP22431, Cs - ICMP22411) and sequences are deposited in GenBank (accession numbers MT522858-MT522865). Pathogenicity of each of the newly recorded species was confirmed on freshly picked 'Hass' avocado fruit. After surface disinfection with 1% sodium hypochlorite solution for 5 minutes, fruit was triple washed with sterile water and air dried. Five fruits per species were pin-pricked and inoculated with 10µL of conidial suspension (7 x 106 to 1 x 107 conidia/mL) prepared with sterile water containing Tween 20 (1µL/mL H2O) from 6-day-old cultures grown on PDA. Control fruit was pin-pricked and mock-inoculated with sterile water containing Tween 20 (1µL/mL H2O). All fruit was incubated in moist chambers at 25°C for 7 days. The three Colletotrichum species produced anthracnose symptoms on inoculated fruit whereas no symptoms were observed on control fruit (Supplementary Fig. 3). Each one of the species was successfully re-isolated from symptomatic tissue and identified using the methods described above, fulfilling Koch's postulates. While Cf and Cs have been reported from several hosts and countries to date (Weir et al. 2012), Cp has only been found from avocado in Israel (Sharma et al. 2017) and grape in Japan (Yokosawa et al. 2020). Although a number of species from the C. gloeosporioides species complex, i.e. C. alienum, C. aotearoa, C. cigarro, and C. gloeosporioides have been previously associated with avocado diseases in New Zealand, the detections of Cf, Cp, and Cs represent first records. In this study, eight Colletotrichum species were associated with the "tannin stain" fruit symptoms in New Zealand avocado orchards. The individual contribution of the newly recorded pathogens Cf, Cp, and Cs to the observed disease symptoms was not determined, but their detection highlights the importance of sequence-based identification of Colletotrichum species, as morphology is insufficiently robust to separate cryptic species. Accurate identification of pathogens provides knowledge of species biodiversity that may be useful in biosecurity decision making. Since it has been reported that fungicide treatment efficiencies differ for some closely related Colletotrichum species on grape (Yokosawa et al. 2020), accurate identification might also contribute to establishing effective management strategies.

Creating an ethical culture to support recovery from substance use disorders.

There is a long-standing failure to create an ethical culture around substance use disorders (SUDs) or dependence that actively supports people's recovery efforts. Issues which impede the development of prorecovery environments are complex, but include the far-reaching effects of the social stigma that surrounds SUDs; and the failure to harness relational and social support that allows debates to transcend blaming individual substance users. As part of efforts to create prorecovery environments, it is important to acknowledge that bioethics debate on SUDs is narrow in scope, prioritising topics related to its traditional interests in individual autonomy and novel technologies. As a result, it has not played a significant role in helping to transform the ethical cultures in which substance use recovery takes place. For example, it largely neglects the ethical challenges of developing an empathic, person-centred approach to substance use problems that listens and responds to the voices of clients. It has also participated little in efforts to develop a positive response to reducing the toxic effects of stigma. Indeed, some contributions from the field fan stigma, rather than alleviate it. The aim of this paper is to seed broader ethical debate, in academic literature and lay/professional communities, on how societies should respond to SUDs: steering a course between the critical, but narrow approach of bioethics and the empowerment discourse of evidence-based treatments.

Proximate underwater soundscape of a North Sea offshore petroleum exploration jack-up drilling rig in the Dogger Bank.

Little is known about localized, near-field soundscapes during offshore hydrocarbon drilling campaigns. In the Dogger Bank, North Sea, underwater noise recordings were made 41-60 m from the drill stem of the Noble Kolskaya jack-up exploration drilling rig. The aims were to document noise received levels (RLs) and frequency characteristics of rig-associated near-field noise. The rig produced sound pressure levels (SPLs) of 120 dB re 1 µPa in the frequency range of 2-1400 Hz. Over transient periods, RLs varied by 15-20 dB between softest (holding) and noisiest (drilling) operations. Tonal components at different frequencies varied with depth. Support vessel noise was significantly louder than the jack-up rig at frequencies <1 kHz, even in its noisiest "boulder-drilling" phase, though radiated noise levels were higher above 2 kHz. Rig SPLs fell rapidly above 8 kHz. Marine mammals, such as harbor porpoise (Phocoena phocoena) forage regularly near offshore oil and gas rigs and platforms, and it is predicted that animals experience different noise regimes while traversing the water column and can potentially detect the higher-frequency components of drilling noise to a distance of 70 m from the source; however, while levels were unlikely to cause auditory injury, effects on echolocation behavior are still unknown.

The development and psychometric testing of three instruments that measure person-centred caring as three concepts - Personalization, participation and responsiveness.

AIM: To develop and test the psychometric properties of three instruments that measure Person-centred Caring: as Personalization, Participation and Responsiveness. DESIGN: A three-phase mixed methods design used two frameworks: content validity determination and quantification; consensus-based standards for selection of health measurement instruments. METHODS: A narrative literature review identified the domain definition. A systematic review of instruments provided the basis for item pools, which were refined by focus groups (N = 4) of multidisciplinary staff and service users (N = 25) and cognitive interviews (N = 11) with service users. Scale content validity indexes were calculated. Three cross-sectional surveys were conducted between April 2015 and June 2016. The instruments' psychometric properties tested included factor structure, internal consistency and construct validity. Convergent validity was tested, hypothesizing that: Personalization related to relational empathy; Participation related to empowerment; and Responsiveness related to trust. RESULTS: Scale content validity indexes were ≥0.96 in all instruments. Response rates were 24% (N = 191), 15% (N = 108) and 19% (N = 124). Two factors were revealed for the Personalization and Responsiveness instruments and one factor for the Participation instrument. All had acceptable: reliability (Cronbach's Alpha >0.7); construct validity (>50%); and convergent validity (Spearman's correlation coefficient >0.25, p < 0.05). CONCLUSION: This study composed definitions and instruments that reflect the multidisciplinary teams' caring behaviours, which have acceptable reliability and validity in the community population. Further psychometric testing of Participation and Responsiveness instruments should be undertaken with a larger sample. IMPACT: The instruments can be used to monitor the variability of multidisciplinary teams' caring behaviours; research effective interventions to improve caring behaviours; and increase understanding of the impact of caring on health outcomes.

Redox-Dependent Metastability of the Nitrogenase P-Cluster.

Molybdenum nitrogenase catalyzes the reduction of dinitrogen into ammonia, which requires the coordinated transfer of eight electrons to the active site cofactor (FeMoco) through the intermediacy of an [8Fe-7S] cluster (P-cluster), both housed in the molybdenum-iron protein (MoFeP). Previous studies on MoFeP from two different organisms, Azotobacter vinelandii ( Av) and Gluconacetobacter diazotrophicus ( Gd), have established that the P-cluster is conformationally flexible and can undergo substantial structural changes upon two-electron oxidation to the POX state, whereby a backbone amidate and an oxygenic residue (Ser or Tyr) ligate to two of the cluster's Fe centers. This redox-dependent change in coordination has been implicated in the conformationally gated electron transfer in nitrogenase. Here, we have investigated the role of the oxygenic ligand in Av MoFeP, which natively contains a Ser ligand (ßSer188) to the P-cluster. Three variants were generated in which (1) the oxygenic ligand was eliminated (ßSer188Ala), (2) the P-cluster environment was converted to the one in Gd MoFeP (ßPhe99Tyr/ßSer188Ala), and (3) two oxygenic ligands were simultaneously included (ßPhe99Tyr). Our studies have revealed that the P-cluster can become compositionally labile upon oxidation and reversibly lose one or two Fe centers in the absence of the oxygenic ligand, while still retaining wild-type-like dinitrogen reduction activity. Our findings also suggest that Av and Gd MoFePs evolved with specific preferences for Ser and Tyr ligands, respectively, and that the structural control of these ligands must extend beyond the primary and secondary coordination spheres of the P-cluster. The P-cluster adds to the increasing number of examples of inherently labile Fe-S clusters whose compositional instability may be an obligatory feature to enable redox-linked conformational changes to facilitate multielectron redox reactions.

Determining the Structural and Energetic Basis of Allostery in a De Novo Designed Metalloprotein Assembly.

Despite significant progress in protein design, the construction of protein assemblies that display complex functions (e.g., catalysis or allostery) remains a significant challenge. We recently reported the de novo construction of an allosteric supramolecular protein assembly (Zn-C38/C81/C96R14) in which the dissociation and binding of ZnII ions were coupled over a distance of 15 Å to the selective hydrolytic breakage and formation of a single disulfide bond. Zn-C38/C81/C96R14 was constructed by ZnII-templated assembly of a monomeric protein (R1, a derivative of cytochrome cb562) into a tetramer, followed by progressive incorporation of noncovalent and disulfide bonding interactions into the protein-protein interfaces to create a strained quaternary architecture. The interfacial strain thus built allowed mechanical coupling between the binding/dissociation of ZnII and formation/hydrolysis of a single disulfide bond (C38-C38) out of a possible six. While the earlier study provided structural evidence for the two end-states of allosteric coupling, the energetic basis for allosteric coupling and the minimal structural requirements for building this allosteric system were not understood. Toward this end, we have characterized the structures and Zn-binding properties of two related protein constructs (C38/C96R1 and C38R1) which also possess C38-C38 disulfide bonds. In addition, we have carried out extensive molecular dynamics simulations of C38/C81/C96R14 to understand the energetic basis for the selective cleavage of the C38-C38 disulfide bond upon ZnII dissociation. Our analyses reveal that the local interfacial environment around the C38-C38 bond is key to its selective cleavage, but this cleavage is only possible within the context of a stable quaternary architecture which enables structural coupling between ZnII coordination and the protein-protein interfaces.

Addressing vaccine hesitancy requires an ethically consistent health strategy.

BACKGROUND: Vaccine hesitancy is a growing threat to public health. The reasons are complex but linked inextricably to a lack of trust in vaccines, expertise and traditional sources of authority. Efforts to increase immunization uptake in children in many countries that have seen a fall in vaccination rates are two-fold: addressing hesitancy by improving healthcare professional-parent exchange and information provision in the clinic; and, secondly, public health strategies that can override parental concerns and values with coercive measures such as mandatory and presumptive vaccination. MAIN TEXT: It is argued that such conflicting, parallel approaches seriously risk undermining trust that is crucial for sustaining herd immunity. Although public health strategies can be ethically justified in limiting freedoms, a parent-centered approach seldom acknowledges how it is impacted by contemporaneous coercive measures. In addition, the clinical encounter is not well suited to helping parents consider the public dimensions of vaccination, despite these being important for trust formation and informed decision-making. Efforts to address vaccine hesitancy require more consistent engagement of parental and citizen views. Along with evidence-based information, debates need to be informed by ethical support that equips parents and professionals to respond to the private and public dimensions of vaccination in a more even-handed, transparent manner. CONCLUSION: Efforts to address vaccine hesitancy need to avoid simple reliance on either parental values or coercive public policies. To do this effectively requires increasing citizen engagement on vaccination to help inform a parent-centered approach and legitimize public policy measures. In addition, cultivating a more ethically consistent strategy means moving beyond the current silos of health ethics - clinical and public health ethics.

Functional analysis of FOXE3 mutations causing dominant and recessive ocular anterior segment disease.

Mutations in FOXE3 are associated with both recessive and dominant inheritance of severe anterior ocular malformations and glaucoma. However, functional analyses of putative pathogenic mutations have not been performed. We tested the hypothesis that variations in FOXE3 activity underlie the different modes of inheritance and disease phenotype. In band shift assays, three recessive mutants showed loss-of-function, one retained DNA binding activity, whereas two dominant mutants showed altered activity. All six mutants showed reduced transactivation function compared with wild-type, and modeling the heterozygous state resulted in an intermediate level of activity providing no evidence for dominant negative action. Our in vitro data are consistent with loss-of-function below a dosage sensitive threshold as a mechanism of action for recessive mutations, but indicate an altered mutant protein function rather than a haploinsufficient mechanism for dominant mutations. This study provides the first functional evidence demonstrating that FOXE3 mutations identified in patients impair protein function with differential effects.

Extending life for people with a terminal illness: a moral right and an expensive death? Exploring societal perspectives.

BACKGROUND: Many publicly-funded health systems apply cost-benefit frameworks in response to the moral dilemma of how best to allocate scarce healthcare resources. However, implementation of recommendations based on costs and benefit calculations and subsequent challenges have led to 'special cases' with certain types of health benefits considered more valuable than others. Recent debate and research has focused on the relative value of life extensions for people with terminal illnesses. This research investigates societal perspectives in relation to this issue, in the UK. METHODS: Q methodology was used to elicit societal perspectives from a purposively selected sample of data-rich respondents. Participants ranked 49 statements of opinion (developed for this study), onto a grid, according to level of agreement. These 'Q sorts' were followed by brief interviews. Factor analysis was used to identify shared points of view (patterns of similarity between individuals' Q sorts). RESULTS: Analysis produced a three factor solution. These rich, shared accounts can be broadly summarised as: i) 'A population perspective - value for money, no special cases', ii) 'Life is precious - valuing life-extension and patient choice', iii) 'Valuing wider benefits and opportunity cost - the quality of life and death'. From the factor descriptions it is clear that the main philosophical positions that have long dominated debates on the just allocation of resources have a basis in public opinion. CONCLUSIONS: The existence of certain moral positions in the views of society does not ethically imply, and pragmatically cannot mean, that all are translated into policy. Our findings highlight normative tensions and the importance of critically engaging with these normative issues (in addition to the current focus on a procedural justice approach to health policy). Future research should focus on i) the extent to which these perspectives are supported in society, ii) how respondents' perspectives relate to specific resource allocation questions, and iii) the characteristics of respondents associated with each perspective.

Patient and citizen participation in health: the need for improved ethical support.

Patient and citizen participation is now regarded as central to the promotion of sustainable health and health care. Involvement efforts create and encounter many diverse ethical challenges that have the potential to enhance or undermine their success. This article examines different expressions of patient and citizen participation and the support health ethics offers. It is contended that despite its prominence and the link between patient empowerment and autonomy, traditional bioethics is insufficient to guide participation efforts. In addition, the turn to a "social paradigm" of ethics in examinations of biotechnologies and public health does not provide an account of values that is commensurable with the pervasive autonomy paradigm. This exacerbates rather than eases tensions for patients and citizens endeavoring to engage with health. Citizen and patient participation must have a significant influence on the way we do health ethics if its potential is to be fulfilled.

Using client reminders to increase colorectal cancer screening in Montana, 2012.

BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer death for men and women in the United States. CRC screening can save lives by detecting precancerous polyps that are then removed or by detecting cancer early when treatment is most effective. COMMUNITY CONTEXT: CRC screening participation in Montana is low. To increase screening participation among Montanans with health insurance, the Montana Cancer Control Programs (MCCP) partnered with a small association health organization (AHO). This partnership implemented a postcard campaign to increase CRC screening participation among the AHO's enrollees. METHODS: Postcards were sent to 1,011 people insured through the AHO; 504 people were mailed 1 postcard and 507 people were mailed 2 postcards. Evaluation of the campaign assessed recall of the campaign among people who received 1 postcard versus people who received 2 postcards. OUTCOME: Women were 60% more likely to recall receiving the postcards than were men. People who received 2 postcards were 2.3 times as likely to recall receiving them as were people who received 1 postcard. INTERPRETATION: The MCCP considers this collaborative project with an AHO a promising approach to implementing evidence-based colorectal cancer screening interventions. The MCCP plans to partner with additional AHOs in Montana to evaluate CRC screening participation among their enrollees.

Exploration of Germline Correlates and Risk of Immune-Related Adverse Events in Advanced Cancer Patients Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of many tumor types, and durable responses can be observed in select populations. However, patients may exhibit significant immune-related adverse events (irAEs) that may lead to morbidity. There is limited information on whether the presence of specific germline mutations may highlight those at elevated risk of irAEs. We evaluated 117 patients with metastatic solid tumors or hematologic malignancies who underwent genomic analysis through the ongoing Personalized OncoGenomics (POG) program at BC Cancer and received an ICI during their treatment history. Charts were reviewed for irAEs. Whole genome sequencing of a fresh biopsy and matched normal specimens (blood) was performed at the time of POG enrollment. Notably, we found that MHC class I alleles in the HLA-B27 family, which have been previously associated with autoimmune conditions, were associated with grade 3 hepatitis and pneumonitis (q = 0.007) in patients treated with combination PD-1/PD-L1 and CTLA-4 inhibitors, and PD-1 inhibitors in combination with IDO-1 inhibitors. These data highlight that some patients may have a genetic predisposition to developing irAEs.

Whole genome and transcriptome integrated analyses guide clinical care of pediatric poor prognosis cancers.

The role for routine whole genome and transcriptome analysis (WGTA) for poor prognosis pediatric cancers remains undetermined. Here, we characterize somatic mutations, structural rearrangements, copy number variants, gene expression, immuno-profiles and germline cancer predisposition variants in children and adolescents with relapsed, refractory or poor prognosis malignancies who underwent somatic WGTA and matched germline sequencing. Seventy-nine participants with a median age at enrollment of 8.8 y (range 6 months to 21.2 y) are included. Germline pathogenic/likely pathogenic variants are identified in 12% of participants, of which 60% were not known prior. Therapeutically actionable variants are identified by targeted gene report and whole genome in 32% and 62% of participants, respectively, and increase to 96% after integrating transcriptome analyses. Thirty-two molecularly informed therapies are pursued in 28 participants with 54% achieving a clinical benefit rate; objective response or stable disease ≥6 months. Integrated WGTA identifies therapeutically actionable variants in almost all tumors and are directly translatable to clinical care of children with poor prognosis cancers.

Which Concerns Deserve Consideration in Dietary Counseling of Patients Earning Low Incomes?

This commentary on a case considers when physicians offering health advice on diet has potential to undermine trust. If physicians fail to model behaviors for which they advocate, they could be targeted by media or have disputes with colleagues, which could further undermine trust. To better manage professional obligations to both individual patients and the public, this article proposes prioritizing interprofessional, community-engaged approaches to advocacy.

Supporting One Health for Pandemic Prevention: The Need for Ethical Innovation.

Bioethics is a field in which innovation is required to help prevent and respond to zoonotic diseases with the potential to cause epidemics and pandemics. Some of the developments necessary to fight pandemics, such as COVID-19 vaccines, require public debate on the benefits and risks of individual choice versus responsibility to society. While these debates are necessary, a more fundamental ethical innovation to rebalance human, animal, and environmental interests is also needed. One Health (OH) can be characterized as a strategy that recognizes and promotes the synergy between human, animal, and environmental health. Yet, despite the recognition that these entities are interdependent, there is a pronounced inequality in the power relations between human, non-human animal, and the environmental interests which threatens the well-being of all. Until OH can ensure the moral status of animals and the environment and thereby the equal consideration of these interests, it will struggle to protect non-human interests and, as a result, human health. To create a sustainable health system requires a renewed concept of justice that is ecocentric in nature and an application of OH that is flexible and responsive to different ethical interests (e.g., person-centred care and physician responsibilities). Ultimately, to save themselves, humans must now think beyond themselves. Bioethics must assume a key role in supporting the developments required to create and maintain relationships able to sustain environmental and human health.

Horizon scanning, rapid reviews and living evidence to support decision-making: lessons from the work of the Critical Intelligence Unit in New South Wales, Australia during the COVID-19 pandemic.

The COVID-19 pandemic has seen an increase in rapidly disseminated scientific evidence and highlighted that traditional evidence synthesis methods, such as time and resource intensive systematic reviews, may not be successful in responding to rapidly evolving policy and practice needs. In New South Wales (NSW) Australia, the Critical Intelligence Unit (CIU) was established early in the pandemic and acted as an intermediary organisation. It brought together clinical, analytical, research, organisational and policy experts to provide timely and considered advice to decision-makers. This paper provides an overview of the functions, challenges and future implications of the CIU, particularly the Evidence Integration Team. Outputs from the Evidence Integration Team included a daily evidence digest, rapid evidence checks and living evidence tables. These products have been widely disseminated and used to inform policy decisions in NSW, making valuable impacts. Changes and innovations to evidence generation, synthesis and dissemination in response to the COVID-19 pandemic provide an opportunity to shift the way evidence is used in future. The experience and methods of the CIU have potential to be adapted and applied to the broader health system nationally and internationally.

Chemokine expression predicts T cell-inflammation and improved survival with checkpoint inhibition across solid cancers.

Immune checkpoint inhibitors (ICI) are highly effective in specific cancers where canonical markers of antitumor immunity are used for patient selection. Improved predictors of T cell-inflammation are needed to identify ICI-responsive tumor subsets in additional cancer types. We investigated associations of a 4-chemokine expression signature (c-Score: CCL4, CCL5, CXCL9, CXCL10) with metrics of antitumor immunity across tumor types. Across cancer entities from The Cancer Genome Atlas, subgroups of tumors displayed high expression of the c-Score (c-Scorehi) with increased expression of immune checkpoint (IC) genes and transcriptional hallmarks of the cancer-immunity cycle. There was an incomplete association of the c-Score with high tumor mutation burden (TMB), with only 15% of c-Scorehi tumors displaying ≥10 mutations per megabase. In a heterogeneous pan-cancer cohort of 82 patients, with advanced and previously treated solid cancers, c-Scorehi tumors had a longer median time to progression (103 versus 72 days, P = 0.012) and overall survival (382 versus 196 days, P = 0.038) following ICI therapy initiation, compared to patients with low c-Score expression. We also found c-Score stratification to outperform TMB assignment for overall survival prediction (HR = 0.42 [0.22-0.79], P = 0.008 versus HR = 0.60 [0.29-1.27], P = 0.18, respectively). Assessment of the c-Score using the TIDE and PredictIO databases, which include ICI treatment outcomes from 10 tumor types, provided further support for the c-Score as a predictive ICI therapeutic biomarker. In summary, the c-Score identifies patients with hallmarks of T cell-inflammation and potential response to ICI treatment across cancer types, which is missed by TMB assignment.