Continent-wide declines in shallow reef life over a decade of ocean warming.

Human society is dependent on nature1,2, but whether our ecological foundations are at risk remains unknown in the absence of systematic monitoring of species' populations3. Knowledge of species fluctuations is particularly inadequate in the marine realm4. Here we assess the population trends of 1,057 common shallow reef species from multiple phyla at 1,636 sites around Australia over the past decade. Most populations decreased over this period, including many tropical fishes, temperate invertebrates (particularly echinoderms) and southwestern Australian macroalgae, whereas coral populations remained relatively stable. Population declines typically followed heatwave years, when local water temperatures were more than 0.5 °C above temperatures in 2008. Following heatwaves5,6, species abundances generally tended to decline near warm range edges, and increase near cool range edges. More than 30% of shallow invertebrate species in cool latitudes exhibited high extinction risk, with rapidly declining populations trapped by deep ocean barriers, preventing poleward retreat as temperatures rise. Greater conservation effort is needed to safeguard temperate marine ecosystems, which are disproportionately threatened and include species with deep evolutionary roots. Fundamental among such efforts, and broader societal needs to efficiently adapt to interacting anthropogenic and natural pressures, is greatly expanded monitoring of species' population trends7,8.

COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study.

BACKGROUND: Patients with cancer are purported to have poor COVID-19 outcomes. However, cancer is a heterogeneous group of diseases, encompassing a spectrum of tumour subtypes. The aim of this study was to investigate COVID-19 risk according to tumour subtype and patient demographics in patients with cancer in the UK. METHODS: We compared adult patients with cancer enrolled in the UK Coronavirus Cancer Monitoring Project (UKCCMP) cohort between March 18 and May 8, 2020, with a parallel non-COVID-19 UK cancer control population from the UK Office for National Statistics (2017 data). The primary outcome of the study was the effect of primary tumour subtype, age, and sex and on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and the case-fatality rate during hospital admission. We analysed the effect of tumour subtype and patient demographics (age and sex) on prevalence and mortality from COVID-19 using univariable and multivariable models. FINDINGS: 319 (30·6%) of 1044 patients in the UKCCMP cohort died, 295 (92·5%) of whom had a cause of death recorded as due to COVID-19. The all-cause case-fatality rate in patients with cancer after SARS-CoV-2 infection was significantly associated with increasing age, rising from 0·10 in patients aged 40-49 years to 0·48 in those aged 80 years and older. Patients with haematological malignancies (leukaemia, lymphoma, and myeloma) had a more severe COVID-19 trajectory compared with patients with solid organ tumours (odds ratio [OR] 1·57, 95% CI 1·15-2·15; p<0·0043). Compared with the rest of the UKCCMP cohort, patients with leukaemia showed a significantly increased case-fatality rate (2·25, 1·13-4·57; p=0·023). After correction for age and sex, patients with haematological malignancies who had recent chemotherapy had an increased risk of death during COVID-19-associated hospital admission (OR 2·09, 95% CI 1·09-4·08; p=0·028). INTERPRETATION: Patients with cancer with different tumour types have differing susceptibility to SARS-CoV-2 infection and COVID-19 phenotypes. We generated individualised risk tables for patients with cancer, considering age, sex, and tumour subtype. Our results could be useful to assist physicians in informed risk-benefit discussions to explain COVID-19 risk and enable an evidenced-based approach to national social isolation policies. FUNDING: University of Birmingham and University of Oxford.

Mobile Stroke Unit in the UK Healthcare System: Avoidance of Unnecessary Accident and Emergency Admissions.

BACKGROUND: Acute stroke patients are usually transported to the nearest hospital regardless of their required level of care. This can lead to increased pressure on emergency departments and treatment delay. OBJECTIVE: The aim of the study was to explore the benefit of a mobile stroke unit (MSU) in the UK National Health Service (NHS) for reduction of hospital admissions. METHODS: Prospective cohort audit observation with dispatch of the MSU in the East of England Ambulance Service area in Southend-on-Sea was conducted. Emergency patients categorized as code stroke and headache were included from June 5, 2018, to December 18, 2018. Rate of avoided admission to the accident and emergency (A&E) department, rate of admission directly to target ward, and stroke management metrics were assessed. RESULTS: In 116 MSU-treated patients, the following diagnoses were made: acute stroke, n = 33 (28.4%); transient ischaemic attacks, n = 13 (11.2%); stroke mimics, n = 32 (27.6%); and other conditions, n = 38 (32.8%). Pre-hospital thrombolysis was administered to 8 of 28 (28.6%) ischaemic stroke patients. Pre-hospital diagnosis avoided hospital admission for 29 (25.0%) patients. As hospital treatment was indicated, 35 (30.2%) patients were directly triaged to the stroke unit, 1 patient (0.9%) even directly to the catheter laboratory. Thus, only 50 (43.1%) patients required transfer to the A&E department. Moreover, the MSU enabled thrombolysis with a median dispatch-to-needle time of 42 min (interquartile range, 40-60). CONCLUSION: This first deployment of an MSU in the UK NHS demonstrated improved triage decision-making for or against hospital admission and admission to the appropriate target ward, thereby reducing pressure on strained A&E departments.

Corrigendum: Assessing National Biodiversity Trends for Rocky and Coral Reefs through the Integration of Citizen Science and Scientific Monitoring Programs.

[This corrects the article DOI: 10.1093/biosci/biw180.].

Assessing National Biodiversity Trends for Rocky and Coral Reefs through the Integration of Citizen Science and Scientific Monitoring Programs.

Reporting progress against targets for international biodiversity agreements is hindered by a shortage of suitable biodiversity data. We describe a cost-effective system involving Reef Life Survey citizen scientists in the systematic collection of quantitative data covering multiple phyla that can underpin numerous marine biodiversity indicators at high spatial and temporal resolution. We then summarize the findings of a continental- and decadal-scale State of the Environment assessment for rocky and coral reefs based on indicators of ecosystem state relating to fishing, ocean warming, and invasive species and describing the distribution of threatened species. Fishing impacts are widespread, whereas substantial warming-related change affected some regions between 2005 and 2015. Invasive species are concentrated near harbors in southeastern Australia, and the threatened-species index is highest for the Great Australian Bight and Tasman Sea. Our approach can be applied globally to improve reporting against biodiversity targets and enhance public and policymakers' understanding of marine biodiversity trends.

Evaluation of the effectiveness of care groups in expanding population coverage of Key child survival interventions and reducing under-5 mortality: a comparative analysis using the lives saved tool (LiST).

BACKGROUND: Globally, less than half of Countdown Countries will achieve the Millennium Development Goal of reducing the under-5 mortality rate (U5MR) by two-thirds by 2015. There is growing interest in community-based delivery mechanisms to help accelerate progress. One promising approach is the use of a form of participatory mothers' groups, called Care Groups, for expanding coverage of key child survival interventions, an essential feature for achieving mortality impact. METHODS: In this study we evaluate the effectiveness of Care Group projects conducted in 5 countries in Africa and Asia in comparison to other United States Agency for International Development-funded child survival projects in terms of increasing coverage of key child survival interventions and reducing U5MR (estimated using the Lives Saved Tool, or LiST). Ten Care Group and nine non-Care Group projects were matched by country and year of program implementation. RESULTS: In Care Group project areas, coverage increases were more than double those in non-Care Group project areas for key child survival interventions (p = 0.0007). The mean annual percent change in U5MR modelled in LiST for the Care Group and non-Care Group projects was -4.80% and -3.14%, respectively (p = 0.09). CONCLUSIONS: Our findings suggest that Care Groups may provide a promising approach to significantly increase key child survival interventions and increase reductions in U5MR. Evaluations of child survival programs should be a top priority in global health to build a greater evidence base for effective approaches for program delivery.

Plasma Microbial Cell-Free DNA Sequencing for Pathogen Detection and Quantification in Children With Musculoskeletal Infections.

BACKGROUND: Nearly half of all pediatric musculoskeletal infections (MSKIs) are culture negative. Plasma microbial cell-free DNA (mcfDNA) sequencing is noninvasive and not prone to the barriers of culture. We evaluated the performance of plasma mcfDNA sequencing in identifying a pathogen, and examined the duration of pathogen detection in children with MSKIs. METHODS: We conducted a prospective study of children, aged 6 months to 18 years, hospitalized from July 2019 to May 2022 with MSKIs, in whom we obtained serial plasma mcfDNA sequencing samples and compared the results with cultures. RESULTS: A pathogen was recovered by culture in 23 of 34 (68%) participants, and by initial mcfDNA sequencing in 25 of 31 (81%) participants. Multiple pathogens were detected in the majority (56%) of positive initial samples. Complete concordance with culture (all organisms accounted for by both methods) was 32%, partial concordance (at least one of the same organism(s) identified by both methods) was 36%, and discordance was 32%. mcfDNA sequencing was more likely to show concordance (complete or partial) if obtained prior to a surgical procedure (82%), compared with after (20%), (RR 4.12 [95% CI 1.25, 22.93], p = .02). There was no difference in concordance based on timing of antibiotics (presample antibiotics 60% vs no antibiotics 75%, RR 0.8 [95% CI 0.40, 1.46], p = .65]). mcfDNA sequencing was positive in 67% of culture-negative infections and detected a pathogen for a longer interval than blood culture (median 2 days [IQR 1, 6 days] vs 1 day [1, 1 day], p < .01). CONCLUSIONS: Plasma mcfDNA sequencing may be useful in culture-negative pediatric MSKIs if the sample is obtained prior to surgery. However, results must be interpreted in the appropriate clinical context as multiple pathogens are frequently detected supporting the need for diagnostic stewardship.

Validated machine learning tools to distinguish immune checkpoint inhibitor, radiotherapy, COVID-19 and other infective pneumonitis.

BACKGROUND: Pneumonitis is a well-described, potentially disabling, or fatal adverse effect associated with both immune checkpoint inhibitors (ICI) and thoracic radiotherapy. Accurate differentiation between checkpoint inhibitor pneumonitis (CIP) radiation pneumonitis (RP), and infective pneumonitis (IP) is crucial for swift, appropriate, and tailored management to achieve optimal patient outcomes. However, correct diagnosis is often challenging, owing to overlapping clinical presentations and radiological patterns. METHODS: In this multi-centre study of 455 patients, we used machine learning with radiomic features extracted from chest CT imaging to develop and validate five models to distinguish CIP and RP from COVID-19, non-COVID-19 infective pneumonitis, and each other. Model performance was compared to that of two radiologists. RESULTS: Models to distinguish RP from COVID-19, CIP from COVID-19 and CIP from non-COVID-19 IP out-performed radiologists (test set AUCs of 0.92 vs 0.8 and 0.8; 0.68 vs 0.43 and 0.4; 0.71 vs 0.55 and 0.63 respectively). Models to distinguish RP from non-COVID-19 IP and CIP from RP were not superior to radiologists but demonstrated modest performance, with test set AUCs of 0.81 and 0.8 respectively. The CIP vs RP model performed less well on patients with prior exposure to both ICI and radiotherapy (AUC 0.54), though the radiologists also had difficulty distinguishing this test cohort (AUC values 0.6 and 0.6). CONCLUSION: Our results demonstrate the potential utility of such tools as a second or concurrent reader to support oncologists, radiologists, and chest physicians in cases of diagnostic uncertainty. Further research is required for patients with exposure to both ICI and thoracic radiotherapy.

Plasma HHV8 DNA predicts relapse in individuals with HIV-associated multicentric Castleman disease.

HIV-associated multicentric Castleman disease (HIV-MCD) is a rare lymphoproliferative disorder caused by infection with human herpesvirus-8. The disease follows a relapsing and remitting clinical course, with marked systemic symptoms during an active attack, which can prove fatal. Its incidence is rising, and new data indicate the utility of the anti-CD20 monoclonal antibody rituximab at inducing remissions in both first- and second-line settings, although biomarkers associated with relapse have not been previously identified. In 52 individuals with a histologic diagnosis of HIV-MCD, we performed univariate and multivariate analyses to predict factors associated with an HIV-MCD attack. Although a younger age (< 50 years) was associated with an attack, the strongest association was observed with plasma levels of human herpesvirus-8 DNA. Rising levels predicted an attack (hazard ratio = 2.9; 95% confidence interval, 1.3-6.7), and maintenance therapy with rituximab should be considered in these individuals.

Final results of the Chronic Total Occlusion Crossing With the Ocelot System II (CONNECT II) study.

PURPOSE: To evaluate the safety and effectiveness of the optical coherence tomography-guided Ocelot catheter to cross femoropopliteal chronic total occlusions (CTOs). METHODS: The CONNECT II study was a prospective, multicenter, non-randomized single-arm study of the safety and effectiveness of the Ocelot catheter in CTO crossing. Key inclusion criteria were a 99% to 100% stenosed femoropopliteal segment, lesion length between 1 and 30 cm, and resistance to guidewire crossing. The main exclusion criterion was a severely calcified target vessel. The primary safety endpoint was 30-day major adverse events (MAE), while the primary effectiveness endpoint was successful CTO crossing (i.e., guidewire placement in the distal true lumen) with the Ocelot catheter. Endpoint analysis was based on pre-specified objective performance criteria. Between February and June 2012, 100 patients (55 men; mean age 69 years) were enrolled. Most of the CTOs (94%) were in the superficial femoral artery (SFA); mean lesion length was 16.6±9.3 cm. RESULTS: Through 30 days, 2 patients experienced MAE (significant perforations) related to the Ocelot catheter. The Ocelot catheter successfully crossed 97% of target CTOs either alone (72%), in conjunction with an assist device (18%), or in conjunction with a re-entry device (7%). Both primary safety and effectiveness endpoints were met. CONCLUSION: The Ocelot catheter with optical coherence tomography guidance offers physicians a reliable option for crossing femoral and popliteal chronic total occlusions with low MAE rates.

Effects of a Nurturing Care Group behavior change program on child protection outcomes in Ghana: A controlled before and after trial.

BACKGROUND: As part of an effort to rigorously apply behavioral science to child protection efforts, a behavior change model called Nurturing Care Groups (NCGs) was tested for effectiveness in changing child abuse and corporal punishment behaviors. OBJECTIVE: The primary research question was to what degree NCGs could change child protection knowledge, attitudes, and practices among caregivers in a low-cost program with broad reach, which could feasibly be scaled. PARTICIPANTS AND SETTING: The NCG project was implemented in two distinct ecological zones in Ghana, reaching 73,959 caregivers of children under 5 across 41 communities; while 20 communities were control sites with no NCG intervention. METHODS: Stratified random sampling was used to select intervention area respondents. Cluster sampling was utilized in control areas, using the Probability Proportional to Size method. Standard measures were used to assess changes in practices of violence and abuse, stress experience and management, parenting techniques, and the household environment. Difference-in-difference linear regression was used to compare intervention and control results. RESULTS: Intervention areas demonstrated statistically-significant and substantial changes in reported knowledge, attitudes and behaviors related to physical abuse and corporal punishment. Knowledge of negative impacts of stress on parenting, as well as stress reduction techniques increased in intervention areas, as did positive discipline and parenting practices. CONCLUSIONS: The NCG model demonstrated important promising results for changing child protection behaviors in this descriptive study. Statistically-significant decreases in reported physical and psychological punishment and corresponding increases in reported positive discipline indicate that this may be an effective and low-cost intervention for child protection behavior change.

Climate change threatens unique evolutionary diversity in Australian kelp refugia.

Climate change has driven contemporary decline and loss of kelp forests globally with an accompanying loss of their ecological and economic values. Kelp populations at equatorward-range edges are particularly vulnerable to climate change as these locations are undergoing warming at or beyond thermal tolerance thresholds. Concerningly, these range-edge populations may contain unique adaptive or evolutionary genetic diversity that is vulnerable to warming. We explore haplotype diversity by generating a Templeton-Crandall-Sing (TCS) network analysis of 119 Cytochrome C Oxidase (COI) sequences among four major population groupings for extant and putatively extinct populations only known from herbarium specimens of the dominant Laminarian kelp Ecklonia radiata in the south-western Pacific, a region warming at 2-4 times the global average. Six haplotypes occurred across the region with one being widespread across most populations. Three unique haplotypes were found in a deep-water range-edge population off Moreton Island, Queensland, which likely represents both a contemporary and historic refuge during periods of climatic change. Hindcasting E. radiata cover estimates using extant data, we reveal that this region likely supported the highest kelp cover in eastern Australia during the last glacial maximum. The equatorward range edge, deep-water kelp populations off Moreton Island represent a genetically diverse evolutionary refuge that is currently threatened by warming and requires prompt ex-situ conservation measures.

A multicenter experience evaluating chronic total occlusion crossing with the Wildcat catheter (the CONNECT study).

OBJECTIVE: Percutaneous techniques for crossing femoropopliteal chronic total occlusions (CTOs) offer an alternative to bypass surgery in patients deemed to be at increased risk due to advanced age or comorbidities. Recent reports document good success rates in catheters designed to reconstitute peripherally occluded arteries following failed guidewire passage. The Wildcat catheter (Avinger, Redwood City, Calif) is a novel device with a rotating distal tip and deployable wedges fashioned for channeling a passage through arterial occlusions. This report describes the results of a prospective, multicenter, nonrandomized trial evaluating the safety and efficacy of the Wildcat device when crossing de novo or restenotic femoropopliteal CTOs. METHODS: Between August 2010 and April 2011, patients with peripheral arterial disease due to a femoropopliteal CTO>1 cm and ≤35 cm were evaluated for study enrollment at 15 U.S. sites. During treatment, the physician initially attempted to cross the CTO using conventional guidewires per protocol; if the guidewire successfully crossed, the patient was considered a screen failure and the Wildcat was not deployed. At 30 days, patients were reevaluated. The primary efficacy end point was successful crossing of the Wildcat into the distal true lumen as confirmed by angiography. Primary safety end points included no in-hospital or 30-day major adverse events, no clinically significant perforation or embolization, and no grade C or greater dissection. Additional data collected included lesion length, degree of calcification, and location. RESULTS: Eighty-eight patients were enrolled in the trial. Of these, the Wildcat device was used in 84 patients (95%) per protocol. Successful CTO crossing was reported and confirmed by independent review in 89% (75/84) of cases with 5% (4/84) major adverse events as defined in the protocol (predominantly perforations sealed with balloon inflation). There were no clinically relevant events associated with any of the perforations. The mean CTO length was 174±96 mm (range, 15-350 mm). Approximately 57% (n=48) of all lesions were categorized as containing at least moderate calcification. Eighty-nine percent (n=75) of vessels recanalized were superficial femoral arteries. CONCLUSIONS: In this multicenter study, the Wildcat catheter demonstrated an 89% crossing success rate with little associated morbidity. The Wildcat catheter is a viable device for crossing moderately calcified femoropopliteal CTOs.

Behavioral determinants for COVID-19 vaccine acceptance among students, faculty, and staff at a rural public university.

Background: Vaccine hesitancy for COVID-19 is a major obstacle to achieving high vaccine coverage. Low vaccine confidence among college students is one factor fueling the COVID-19 pandemic in the U.S. Objective: The purpose of this study was to evaluate COVID-19 vaccine hesitancy and barriers to vaccine uptake among students, faculty, and staff at a rural public university. Method: We used the Barrier Analysis (BA) mixed-methods approach, which explores determinants of the desired behavior using the Health Belief Model and Theory of Reasoned Action. We developed a BA questionnaire and distributed it through Qualtrics to 4,600 randomly selected students (n = 4,000), faculty (n = 300), and staff (n = 300) from March 11 to April 1, 2021. We defined Acceptors as those who were willing to be vaccinated and Non-acceptors as those who were not. Results: Our analysis found that among Non-acceptors, perceived social norms, perceived negative consequences, and trust had the highest association with COVID-19 vaccine hesitancy among students, faculty, and staff. Conclusion: These findings illustrate the need to develop effective behavior change strategies for COVID-19 vaccines uptake that identify sources of trusted information among vaccine-hesitant college students, faculty, and staff, while leveraging enablers to increase COVID-19 vaccination coverage on university campuses.

Association of primary and community care services with emergency visits and hospital admissions at the end of life in people with cancer: a retrospective cohort study.

OBJECTIVE: To examine the association between primary and community care use and measures of acute hospital use in people with cancer at the end of life. DESIGN: Retrospective cohort study. SETTING: We used Discover, a linked administrative and clinical data set from general practices, community and hospital records in North West London (UK). PARTICIPANTS: People registered in general practices, with a diagnosis of cancer who died between 2016 and 2019. PRIMARY AND SECONDARY OUTCOME MEASURES: ≥3 hospital admissions during the last 90 days, ≥1 admissions in the last 30 days and ≥1 emergency department (ED) visit in the last 2 weeks of life. RESULTS: Of 3581 people, 490 (13.7%) had ≥3 admissions in last 90 days, 1640 (45.8%) had ≥1 admission in the last 30 days, 1042 (28.6%) had ≥1 ED visits in the last 2 weeks; 1069 (29.9%) had more than one of these indicators. Contacts with community nurses in the last 3 months (≥13 vs <4) were associated with fewer admissions in the last 30 days (risk ratio (RR) 0.88, 95% CI 0.90 to 0.98) and ED visits in the last 2 weeks of life (RR 0.79, 95% CI 0.68 to 0.92). Contacts with general practitioners in the last 3 months (≥11 vs <4) was associated with higher risk of ≥3 admissions in the last 90 days (RR 1.63, 95% CI 1.33 to 1.99) and ED visits in the last 2 weeks of life (RR 1.27, 95% CI 1.10 to 1.47). CONCLUSIONS: Expanding community nursing could reduce acute hospital use at the end of life and improve quality of care.

Tracking widespread climate-driven change on temperate and tropical reefs.

Warming seas, marine heatwaves, and habitat degradation are increasingly widespread phenomena affecting marine biodiversity, yet our understanding of their broader impacts is largely derived from collective insights from independent localized studies. Insufficient systematic broadscale monitoring limits our understanding of the true extent of these impacts and our capacity to track these at scales relevant to national policies and international agreements. Using an extensive time series of co-located reef fish community structure and habitat data spanning 12 years and the entire Australian continent, we found that reef fish community responses to changing temperatures and habitats are dynamic and widespread but regionally patchy. Shifts in composition and abundance of the fish community often occurred within 2 years of environmental or habitat change, although the relative importance of these two mechanisms of climate impact tended to differ between tropical and temperate zones. The clearest of these changes on temperate and subtropical reefs were temperature related, with responses measured by the reef fish thermal index indicating reshuffling according to the thermal affinities of species present. On low latitude coral reefs, the community generalization index indicated shifting dominance of habitat generalist fishes through time, concurrent with changing coral cover. Our results emphasize the importance of maintaining local ecological detail when scaling up datasets to inform national policies and global biodiversity targets. Scaled-up ecological monitoring is needed to discriminate among increasingly diverse drivers of large-scale biodiversity change and better connect presently disjointed systems of biodiversity observation, indicator research, and governance.

Primary results from TAIL: a global single-arm safety study of atezolizumab monotherapy in a diverse population of patients with previously treated advanced non-small cell lung cancer.

BACKGROUND: Atezolizumab treatment improves survival, with manageable safety, in patients with previously treated advanced/metastatic non-small cell lung cancer. The global phase III/IV study TAIL (NCT03285763) was conducted to evaluate the safety and efficacy of atezolizumab monotherapy in a clinically diverse population of patients with previously treated non-small cell lung cancer, including those not eligible for pivotal trials. METHODS: Patients with stage IIIB/IV non-small cell lung cancer whose disease progressed after 1-2 lines of chemotherapy were eligible for this open-label, single-arm, multicenter study, including those with severe renal impairment, an Eastern Cooperative Oncology Group performance status of 2, prior anti-programmed death 1 (PD-1) therapy, and autoimmune disease. Atezolizumab was administered intravenously (1200 mg every 3 weeks). Coprimary endpoints were treatment-related serious adverse events and immune-related adverse events. RESULTS: 619 patients enrolled and 615 received atezolizumab. At data cutoff, the median follow-up was 12.6 months (95% CI 11.9 to 13.1). Treatment-related serious adverse events occurred in 7.8% and immune-related adverse events in 8.3% of all patients and as follows, respectively, in these subgroups: renal impairment (n=78), 11.5% and 12.8%; Eastern Cooperative Oncology Group performance status of 2 (n=61), 14.8% and 8.2%; prior anti-PD-1 therapy (n=39), 5.1% and 7.7%; and autoimmune disease (n=30), 6.7% and 10.0%. No new safety signals were reported. In the overall population, the median overall survival was 11.1 months (95% CI 8.9 to 12.9), the median progression-free survival was 2.7 months (95% CI 2.1 to 2.8) and the objective response rate was 11%. CONCLUSIONS: This study confirmed the benefit-risk profile of atezolizumab monotherapy in a clinically diverse population of patients with previously treated non-small cell lung cancer. These safety and efficacy outcomes may inform treatment decisions for patients generally excluded from checkpoint inhibitor trials.

Systemic pro-inflammatory response identifies patients with cancer with adverse outcomes from SARS-CoV-2 infection: the OnCovid Inflammatory Score.

BACKGROUND: Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study. METHODS: In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets. RESULTS: We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p<0.01), recovering in survivors to pre-COVID-19 levels. Patients in poorer risk categories for each index except the PLR exhibited higher mortality rates (p<0.001) and shorter median overall survival in the training and validation sets (p<0.01). Multivariable analyses revealed the OIS to be most independently predictive of survival (validation set HR 2.48, 95% CI 1.47 to 4.20, p=0.001; adjusted concordance index score 0.611). CONCLUSIONS: Systemic inflammation is a validated prognostic domain in SARS-CoV-2-infected patients with cancer and can be used as a bedside predictor of adverse outcome. Lymphocytopenia and hypoalbuminemia as computed by the OIS are independently predictive of severe COVID-19, supporting their use for risk stratification. Reversal of the COVID-19-induced proinflammatory state is a putative therapeutic strategy in patients with cancer.

Generation of tumour-rejecting anti-carbohydrate monoclonal antibodies using melanoma modified with Fas ligand.

Carbohydrate antigens such as glycolipids and glycoproteins are over-expressed in a variety of cancers and have therefore been identified as ideal candidates for tumour vaccines. Detection of anti-carbohydrate antibodies is associated with a good prognosis in cancer patients. However, generation of an efficient adaptive immune response has been hampered by the low immunogenicity of carbohydrates due to tolerance. Here, we describe a method by which tumour-rejecting antibodies directed against carbohydrates can be elicited in two different melanoma mouse models. Thus, using the murine melanoma B16F10 over-expressing Fas ligand (FasL), we have generated mAbs against cancer carbohydrate antigens expressed by the melanoma. Importantly, passive transfer of mAbs resulted in rejection of melanoma in vivo. Their protective effect in vivo was dependent on FcR and in vitro antibody-dependent cellular phagocytosis. They were also able to delay tumour growth when injected after the tumour was established. FasL-expressing tumours as an adjuvant are a novel way to generate anti-carbohydrate antibodies able to reject tumours in vivo.