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ObjectiveTo evaluate the relative strengths of 3 frailty assessment instruments for predicting mortality and prolonged hospitalization in acute coronary syndrome patients.DesignProspective cohort study.SettingAcute cardiac care units in New Zealand.Participants1174 patients >70 years of age hospitalized with an acute coronary syndrome.InterventionsThe Clinical Frailty Scale (CFS), Edmonton Frail Scale (EFS) and Fried Criteria (Fried), were completed during hospital admission following an acute coronary syndrome when the patient was clinically stable.Primary and secondary outcome measuresAll-cause mortality over the next ~5 years and hospitalization for >10 days in the next year determined from national administrative data.ResultsDuring median follow-up of 5.1 years there were 353 deaths. Harrell's C-statistic for mortality for EFS was 0.663, Fried 0.648 and CFS 0.640 (p10 days (n = 267, 22%) were EFS 0.649, Fried 0.628, and CFS 0.584 (pConclusionIn older patients assessed following an acute coronary syndrome the EFS discriminated the risk of all cause mortality and prolonged hospitalization better than the CFS and Fried tests, and improved risk discrimination when added to clinical risk scores.

Background Short-term improvements in quality of life (QOL) have been reported in adult congenital heart disease patients with systemic right ventricle (sRV) failure after treatment with sacubitril/valsartan. This study aimed to evaluate the medium-term QOL changes in sRV failure patients treated with sacubitril/valsartan.Methods In this single-centre, prospective cohort study, patients with symptomatic sRV failure completed the Netherlands Organisation for Applied Scientific Research/Academic Hospital Leiden Questionnaire for Adult’s Health-Related Quality of Life (TAAQOL) at baseline and after starting treatment with sacubitril/valsartan. The TAAQOL was taken at structured outpatient follow-up moments after 6, 12, 24 and 36 months of treatment. Linear mixed effects models were used to evaluate the medium-term changes in 12 QOL domains.Results Of 40 sRV failure patients initiated on sacubitril/valsartan, 35 completed the titration phase, and 31 filled in a total of 98 TAAQOL questionnaires (response rate 77.5%). Significant improvements in gross motoric functioning (p=0.008), cognitive function (p=0.002), sleep (p=0.041), social functioning (p

Electrical-stimulation fMRI (es-fMRI) combines direct stimulation of the brain via implanted electrodes with simultaneous rapid functional magnetic resonance imaging of the evoked response. Widely used to map effective functional connectivity in animal studies, its application to the human brain has been limited due to safety concerns. In particular, the method requires reliable prediction and minimization of local tissue heating close to the electrodes, which will vary with imaging parameters and hardware configurations. Electrode leads for such experiments typically remain connected to stimulators outside the magnet room and cannot therefore be treated as electrically short at the radio frequencies employed for 1.5 T and 3 T fMRI. The potential for significant absorption and scattering of radiofrequency energy from excitation pulses during imaging is therefore a major concern. We report a series of temperature measurements conducted in human brain phantoms at two independent imaging centers to characterize factors effecting RF heating of electrically long leads with body coil transmission at 3 Tesla for temporal RMS RF transmit fields (B1+rms) up to 3.5 µT including multiband echo planar imaging and 3D T2w turbo spin echo imaging. Under all conditions tested, with one exception, the temperature rise measured immediately adjacent to electrode contacts in a head-torso phantom with body coil RF transmission was less than 0.75 °C. We provide detailed quantification across a range of configurations and conclude with specific recommendations for cable routing that will help ensure the safety of es-fMRI in humans and provide essential data to institutional review boards.

Abstract Secreted phosphosprotein 1 (SPP1)High tumor‐associated macrophages (TAM) are abundant tumor myeloid cells that are immunosuppressive, pro‐tumorigenic, and have a highly negative prognostic factor. Despite this, there is a lack of efficient TAM‐specific therapeutics capable of reducing SPP1 expression. Here, on a phenotypic screen is reported to identify small molecule SPP1 modulators in macrophages. Several hits and incorporated them into a TAM‐avid systemic nanoformulation are identified. It is shown that the lead compound (CANDI460) can down‐regulate SPP1 in vitro and in vivo and lead to tumor remissions in different murine models. These findings are important as they offer a promising avenue for developing novel therapeutic strategies targeting TAM.

Thrips are one of the most challenging pests in agricultural crops, including Chrysanthemum. In this study we tested via two plant assays whether solutions containing sticky rice germ oil (RGO) droplets could effectively trap thrips and lower thrips damage on Chrysanthemum. In the first assay, we additionally assessed the metabolomic effects of these RGO droplet sprays and thrips presence on plant chemistry via 1H NMR and headspace GC-MS on multiple timepoints to investigate which plant metabolites were affected by spraying and their potential relation to plant resistance against thrips. In the second assay, we tested the individual RGO solution constituents against thrips. Our results suggested that the adhesive RGO droplets were not effective as a physical trap as only three out of 600 adult thrips were caught at the achieved coverage. However, average thrips damage was still reduced up to 50% and no negative effects on plant growth were observed up to 25 days. Results from the second plant assay indicated that the individual constituents of the solution containing RGO droplets may have direct effects against thrips. Metabolomics analysis of sprayed leaves via headspace GC-MS and 1H NMR indicated that fatty acids and several volatile compounds such as 4(10)-thujene (sabinene), eucalyptol, cis-4-thujanol, and isocaryophyllene were highest on day 10, while sucrose, malic acid, o-Cymene, and 3-Methyl-2-butenoic acid were highest on day 25. Plants with thrips showed higher flavonoid, carbohydrate and glutamine acetic acid levels, and lower fatty acids and malic acid levels. RGO application increased the levels of fatty acids and alcohols present on top of and inside the Chrysanthemum leaves, while decreasing the concentrations of volatile compounds such as eucalyptol, chrysanthenone and eugenol in the Chrysanthemum leaves. Most interestingly, the thrips effect on the plant metabolome was no longer visible in RGO treated plants at the later harvesttime, suggesting that RGO application may overrule or prevent the metabolomic effects of thrips infestation. In conclusion, our study provides new information on how the application of a new plant-based plant protection product affects insect herbivores and alters crop phytochemistry for improved herbivore resistance.

BackgroundHeart failure (HF) is a chronic, progressive condition where the heart cannot pump enough blood to meet the body’s needs. In addition to the daily challenges that HF poses, acute exacerbations can lead to costly hospitalizations and increased mortality. High health care costs and the burden of HF have led to the emerging application of new technologies to support people living with HF to stay well while living in the community. However, many digital solutions have not involved consumers and health care professionals in their design, leading to poor adoption. The SmartHeart project aimed to codevelop a smart health ecosystem to support the early detection of HF deterioration and encourage self-care, potentially preventing hospitalizations. ObjectiveThis study aims to provide an overview of the SmartHeart project by describing our approach to designing the SmartHeart system, outlining its features, and describing the planned pilot study to determine the feasibility of the system. MethodsWe used the Integrate, Design, Assess, and Share (IDEAS) framework to guide the development of the SmartHeart system, involving users (people with HF and their caregivers) and stakeholders (health care providers involved in the management of HF) in its design. SmartHeart is a complete remote heart health monitoring and automated feedback delivery system. It includes 2 user interfaces for patients: an Amazon Alexa conversational agent and a smartphone app. The system collects physiological, symptom, and behavioral data through wireless sensors and self-reports from users. These data are processed and analyzed to provide personalized health insights, self-care support, and alerts in case of health deterioration. The system also includes a web-based user interface for health care professionals, allowing them to access data, send messages to users, and receive notifications about potential health deterioration. A single-arm, multicenter pilot trial (N=20) is planned to determine the feasibility and acceptability of SmartHeart before evaluation through a randomized controlled trial. The primary outcome will be a description of the study's feasibility (recruitment, attrition, engagement, and changes in self-care). ResultsThe SmartHeart study started in January 2021 on procurement of funding. Recruitment for the pilot trial started in August 2024 and will be completed by March 2025. We have currently enrolled 12 participants. Follow-up of all participants will be completed by the end of May 2025. ConclusionsWe have co-designed and developed a complete remote heart health monitoring and automated feedback delivery system for the early detection of HF deterioration and prevention of HF-related hospitalizations. The next step is a pilot study, which will provide valuable information on feasibility and preliminary effects to inform a larger evaluation trial. SmartHeart has the potential to augment existing health services and help people with HF stay well while living in the community. International Registered Report Identifier (IRRID)DERR1-10.2196/62964

ABSTRACT Genomics is an invaluable tool for conservation, particularly for endangered species impacted by wildlife trafficking. This study uses genomic data to provide new insights to aid conservation and management of endangered species, using as a case study the Yellow cardinal (Gubernatrix cristata), a bird endemic to southern South America severely affected by illegal trade and the transformation of its natural habitat. We explore population structure within the Yellow cardinal, delimiting management units and describing connectivity among them. Additionally, we develop and assess the accuracy of a panel of 189 informative SNPs, and demonstrate how these can reliably assign confiscated individuals to one of the management units established. Lastly, we assess hybridization between the Yellow cardinal and the Diuca finch (Diuca diuca), which is reported to occur in regions of sympatry. We confirm that hybridization occurs, although it is not as common as previously thought, and that hybrids might be fertile, as we found evidence of backcrossing with Yellow cardinals. We discuss the implications of this introgression for the evolution and conservation of Yellow cardinals. Our study provides new, valuable information that can guide conservation efforts, comprising a test case for the use of genomics in combating illegal trafficking, with potential application beyond the case of the Yellow cardinal.

ABSTRACT In recent years, DNA metabarcoding has been used for a more efficient assessment of bulk samples. However, there remains a paucity of studies examining potential disparities in species identification methodologies. Here, we explore the outcomes of diverse clustering and filtering techniques on data from a non‐destructive metabarcoding approach, compared to species‐level morphological identification of Brachycera (Diptera) and Hymenoptera of two bulk samples collected with Malaise traps. The study evaluated four distinct approaches, namely clustering to Amplicon Sequence Variants (ASVs) or ASVs clustered to Operational Taxonomic Units (OTUs) coupled with subsequent filtering using the LULU algorithm at 84% and 96% minimum match. In total, 114 species of Brachycera (35 families) and 85 species of Hymenoptera (27 families) were identified morphologically. Depending on the selected approach, DNA metabarcoding results strongly varied in terms of detected molecular units blasted to brachyceran and hymenopteran species. For Brachycera, ASVs clustered into OTUs followed by LULU using a 96% minimum match (OTU96) inferred the number of molecular units closest to the number of morphologically identified species. Using Syrphidae as an exemplary family, we found an overlap ranging from 9% to 81% between the morphological identification and the different clustering and filtering approaches, OTU96 being also here the closest one. For Hymenoptera, while OTU96 also yielded the highest number of molecular units, it was still considerably low compared to the number of morphologically identified species. Our results show that metabarcoding methodology needs to be significantly improved to be applied to Hymenoptera. Conversely, for Brachycera, we acknowledge the promise of employing a non‐destructive metabarcoding approach, incorporating ASV clustering into OTUs and filtering with LULU, to derive dependable species lists. Such lists hold significant potential for applications in biomonitoring, conservation efforts, and other related fields.

Abstract A dataset of multi‐tagged sea surface roughness synthetic aperture radar (SAR) satellite images was established near Barbados from January to June 2016 to 2019. It is an advancement of the Sentinel‐1 Wave Mode TenGeoP‐SARwv (a labelled SAR imagery dataset of 10 geophysical phenomena from Sentinel‐1 wave mode) dataset that targets SAR marine atmospheric boundary layer (MABL) coherent structures. Twelve tags define roll vortices, convective cells, mixed rolls and convective cells, fronts, rain cells, cold pools and low winds. Examples are provided for each signature. The final dataset is comprised of 2100 Sentinel‐1 wave mode SAR images acquired at 36 incidence angle over an 8° × 8°region centered at 51° W, 15° N. Each image is tagged with one or multiple phenomena by five experts. This strategy extends the TenGeoP‐SARwv by identifying coexisting phenomena within a single SAR image and by the addition of mixed roll/cell states and cold pools. The dataset includes PNG‐formatted SAR image files along with two text files containing the file name, the central latitude/longitude, expert tags for each image, and all dataset metadata. There is a high degree of consensus among expert tags. The dataset complements existing hand‐labelled ocean SAR image datasets and offers the potential for new deep‐learning SAR image classification model developments. Future use is also expected to yield new insights into the tradewind MABL processes such as structure transitions and their relation to the stratification.

Abstract Background In dogs, data on reference intervals (RIs) for cobalamin, markers of metabolism (markersB12met), age and sex effects are limited. Hypothesis/Objectives Establish RI for serum cobalamin, homocysteine, and methylmalonic acid (sMMA) concentrations, urinary methylmalonic acid‐to‐creatinine ratio (uMMA:crea), and determine effects of sex and age. Methods Prospective study using healthy dogs (1‐10 years). Cobalamin and markersB12met were determined using chemiluminescence immunoassay (cobalamin) and liquid chromatography/tandem mass spectrometry (homocysteine, sMMA, uMMA:crea). In dogs with outlying data, changes in health, markersB12met, and onset of gastrointestinal signs were reevaluated after 9‐15 months. Results Twelve of 120 healthy dogs had abnormal uMMA:crea ratios. No other cobalamin analyte outliers were found. Outlying data re‐examination (odRE) was performed in 10/12 dogs. Chronic gastrointestinal signs occurred in 64% of odRE‐dogs, whereas 36% remained healthy. In total, 112 dogs (67 females, 45 males; median ages, 3.5 and 3.75 years, respectively) were included in RI analyses. Reference intervals were 178.5‐851 pmol/L (cobalamin), 5.8‐29.0 μmol/L (homocysteine), 45.3‐159.5 μg/L (sMMA), and ≤22.4 mg/g (uMMA:crea). Only age affected cobalamin concentrations (significant decrease). Compared by sex and neuter status, intact male dogs had significantly higher uMMA:crea ratios (median, 13.5; range, 1.9‐83.6 mg/g) than the other groups (median, 2.5; range, 0.7‐9.7 mg/g; P

Background Carotid intima‐media thickness (IMT) is a measure of atherosclerosis and a predictor of vascular diseases. Traditional vascular risk factors and genetic variants do not completely explain the variation in carotid IMT. We sought to identify epigenetic factors that may contribute to the remaining carotid IMT variability. Methods and Results An epigenome‐wide association study was performed in 61 Dominican families with 769 individuals. A cytosine nucleotide that precedes a guanine nucleotide methylation in blood‐derived DNA was measured using the Human MethylationEPIC BeadChip. Linear mixed model analyses were performed regressing bifurcation carotid IMT (bIMT) on beta values for cytosine nucleotide that precedes a guanine nucleotide sites, adjusting for covariates, followed by differentially methylated region (DMR) analysis. One‐sample Mendelian randomization analysis was conducted to investigate causal associations between DMRs and bIMT. Twenty‐five DMRs were associated with bIMT (Sidak P

Wheat production is threatened by multiple fungal pathogens, such as the wheat powdery mildew fungus (Blumeria graminis f. sp. tritici, Bgt). Wheat resistance breeding frequently relies on the use of resistance (R) genes that encode diverse immune receptors which detect specific avirulence (AVR) effectors and subsequently induce an immune response. While R gene cloning has accelerated recently, AVR identification in many pathogens including Bgt lags behind, preventing pathogen-informed deployment of resistance sources. Here we describe a new "avirulence depletion (AD) assay" for rapid identification of AVR genes in Bgt. This assay relies on the selection of a segregating, haploid F1 progeny population on a resistant host, followed by bulk sequencing, thereby allowing rapid avirulence candidate gene identification with high mapping resolution. In a proof-of-concept experiment we mapped the AVR component of the wheat immune receptor Pm3a to a 25 kb genomic interval in Bgt harboring a single effector, the previously described AvrPm3a2/f2. Subsequently, we applied the AD assay to map the unknown AVR effector recognized by the Pm60 immune receptor. We show that AvrPm60 is encoded by three tandemly arrayed, nearly identical effector genes that trigger an immune response upon co-expression with Pm60 and its alleles Pm60a and Pm60b. We furthermore provide evidence that Pm60 outperforms Pm60a and Pm60b through more efficient recognition of AvrPm60 effectors, suggesting it should be prioritized for wheat breeding. Finally, we show that virulence towards Pm60 is caused by simultaneous deletion of all AvrPm60 gene paralogs and that isolates lacking AvrPm60 are especially prevalent in the US thereby limiting the potential of Pm60 in this region. The AD assay is a powerful new tool for rapid and inexpensive AVR identification in Bgt with the potential to contribute to pathogen-informed breeding decisions for the use of novel R genes and regionally tailored gene deployment.

Abstract Background While early intervention in psychosis (EIP) programs have been increasingly implemented across the globe, many initiatives from Africa, Asia and Latin America are not widely known. The aims of the current review are (a) to describe population-based and small-scale, single-site EIP programs in Africa, Asia and Latin America, (b) to examine the variability between programs located in low-and-middle income (LMIC) and high-income countries in similar regions and (c) to outline some of the challenges and provide recommendations to overcome existing obstacles. Methods EIP programs in Africa, Asia and Latin America were identified through experts from the different target regions. We performed a systematic search in Medline, Embase, APA PsycInfo, Web of Science and Scopus up to February 6, 2024. Results Most EIP programs in these continents are small-scale, single-site programs that serve a limited section of the population. Population-based programs with widespread coverage and programs integrated into primary health care are rare. In Africa, EIP programs are virtually absent. Mainland China is one of the only LMICs that has begun to take steps toward developing a population-based EIP program. High-income Asian countries (e.g. Hong Kong and Singapore) have well-developed, comprehensive programs for individuals with early psychosis, while others with similar economies (e.g. South Korea and Japan) do not. In Latin America, Chile is the only country in the process of providing population-based EIP care. Conclusions Financial resources and integration in mental health care, as well as the availability of epidemiological data on psychosis, impact the implementation of EIP programs. Given the major treatment gap of early psychosis in Africa, Latin America and large parts of Asia, publicly funded, locally-led and accessible community-based EIP care provision is urgently needed.

Abstract Inflammation and a metabolic shift from oxidative metabolism to glycolysis are common in the ischemic heart, the latter partly controlled by pyruvate kinase (muscle, PKM). We previously identified alternative splicing promoting the PKM2 isoform after myocardial infarction (MI). We examined the role of PKM2 physiological upregulation after MI, modeled by ligation of the left anterior descending coronary artery, using global PKM2 knockout (PKM2−/−) mice. Echocardiography showed similar cardiac function between PKM2−/− and control mice after MI. However, PKM2−/− infarcted hearts had increased abundances of transcripts associated with oxidative stress and immune responses. Immunohistochemistry revealed greater abundance of macrophages in PKM2−/− hearts prior to MI, with a small increase in CD86+ macrophages in PKM2−/− infarcted hearts. Elevated baseline plasma IL‐6, IL‐1β, and C‐reactive protein, and cardiac IL‐6, 3 days post‐MI, were observed in PKM2−/− mice. Oxidative lipid products were also elevated in baseline PKM2−/− hearts, while antioxidant glutathione peroxidase 4 was reduced. Greater fibrosis was seen in PKM2−/− hearts 28 days after MI. These findings suggest Pkm2 ablation primes the heart for increased oxidative stress, inflammation, and fibrosis post‐MI. The natural upregulation of PKM2 may mitigate fibrosis by reducing oxidative stress and inflammation, highlighting its protective role in the infarcted heart.

ABSTRACT Acinetobacter baumannii is associated with multidrug-resistant infections in healthcare settings, with fluoroquinolones such as ciprofloxacin being currently ineffective. Clinical isolates largely harbor mutations in the GyrA and TopoIV fluoroquinolone targets, as well as mutations that increase expression of drug resistance-nodulation-division (RND) efflux pumps. Factors critical for maintaining fitness levels of pump overproducers are uncharacterized despite their prevalence in clinical isolates. We, here, identify proteins that contribute to the fitness of fluoroquinolone-resistant (FQR) strains overexpressing three known RND systems using high-density insertion mutagenesis. Overexpression of the AdeFGH efflux pump caused hypersensitization to defects in outer membrane homeostatic regulation, including lesions that reduced lipooligosaccharide (LOS) biosynthesis and blocked production of the major A. baumannii porin. In contrast, AdeAB pump hyperexpression, in the absence of elevated adeC expression (the outer membrane component of the pump), was relatively tolerant to loss of these functions, consistent with the outer membrane protein being the primary disruptive component. Surprisingly, overexpression of proton-transporting efflux pumps had little impact on cytosolic pH, consistent with a compensatory response to pump activity. The most striking transcriptional changes were associated with AdeFGH pump overexpression, including the activation of the phenylacetate (PAA) degradation regulon. Disruption of the PAA pathway resulted in cytosolic acidification and defective expression of genes involved in protection from oxidative stress. These results indicate that RND efflux pump overproduction is compensated by maintenance of outer membrane integrity in A. baumannii to facilitate fitness of FQR isolates.IMPORTANCEAcinetobacter baumannii is a pathogen that often causes multidrug-resistant infections in healthcare settings, presenting a threat to the efficacy of known therapeutic interventions. Fluoroquinolones such as ciprofloxacin are currently ineffective against a majority of clinical A. baumannii isolates, many of which express pumps that remove this antibiotic class from within the bacterium. Three of these pumps can be found in most clinical isolates, with one of the three often hyperproduced at all times. In this study, we identify proteins that are necessary for the fitness of pump hyperproducers. The identified proteins are necessary to stabilize the outer membrane and allow the cytoplasm to tolerate the accumulation of ions as a consequence of excess pump activity. These results point to strategies for developing therapies that combine known antibiotics with drugs that target proteins important for survival of strains hyper-expressing efflux pumps.

IntroductionThe gut microbiota plays a pivotal role in influencing host health, through the production of metabolites and other key signalling molecules. While the impact of specific metabolites or taxa on host cells is well-documented, the broader impact of a disrupted microbiota on immune homeostasis is less understood, which is particularly important in the context of the increasing overuse of antibiotics.MethodsFemale C57BL/6 mice were gavaged twice daily for four weeks with Vancomycin, Polymyxin B, or PBS (control). Caecal microbiota composition was assessed via 16S rRNA sequencing and caecal metabolites were quantified with NMR spectroscopy. Immune profiles of spleen and mesenteric lymph nodes (MLNs) were assessed by flow cytometry, and splenocytes assessed for ex vivo cytokine production. A generalised additive model approach was used to examine the relationship between global antibiotic consumption and IBD incidence.ResultsAntibiotics significantly altered gut microbiota composition, reducing alpha-diversity. Acetate and butyrate were significantly reduced in antibiotic groups, while propionate and succinate increased in Vancomycin and PmB-treated mice, respectively. The MLNs and spleen showed changes only to DC numbers. Splenocytes from antibiotic-treated mice stimulated ex vivo exhibited increased production of TNF. Epidemiological analysis revealed a positive correlation between global antibiotic consumption and IBD incidence.DiscussionOur findings demonstrate that antibiotic-mediated dysbiosis results in significantly altered short-chain fatty acid levels but immune homeostasis in spleen and MLNs at steady state is mostly preserved. Non-specific activation of splenocytes ex vivo, however, revealed mice with perturbed microbiota had significantly elevated production of TNF. Thus, this highlights antibiotic-mediated disruption of the gut microbiota may program the host towards dysregulated immune responses, predisposing to the development of TNF-associated autoimmune or chronic inflammatory disease.

Introduction: The management of de novo non-specific spinal infections (spondylodiscitis - SD) remains inconsistent due to varying clinical practices and a lack of high-level evidence, particularly regarding the indications for surgery. Research question: This study aims to develop consensus recommendations for the diagnosis and management of SD, addressing diagnostic modalities, surgical indications, and treatment strategies. Material and methods: A Delphi process was conducted with 26 experts from the European Association of Neurosurgical Societies (EANS). Sixtytwo statements were developed on diagnostic workup, management decisions, surgical techniques, non-surgical treatment, and follow-up and submitted to the panel of experts. Results: Consensus was reached on 38 of 62 statements. MRI was confirmed as the gold standard for diagnosis. Regarding surgical indications, the panel agreed that any new neurological deficit, even subtle, warrants surgical consideration. Motor deficits with a motor score (MRC) below 4 and bladder or bowel dysfunction were unanimously considered clear indications for surgery. For spinal deformity and instability, thresholds such as kyphosis >20°, scoliosis >10°, and vertebral body collapse >50% were established to guide surgical decision-making. Minimally invasive surgery (MIS) was endorsed whenever feasible, and a 12 week antibiotic treatment regimen was favored in cases of complicated infections. Discussion and conclusion: This EANS consensus provides updated recommendations for SD management, incorporating recent evidence on improved outcomes with surgical therapy. While these guidelines offer a more structured approach to clinical decision-making, further research is required to optimize surgical timing and validate the long-term impact of these treatment strategies.

Summary: Background: Dual inhibition of cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1) has been shown to be an effective treatment strategy in many cancers. We sought to determine the objective response rate of combination durvalumab (D) plus tremelimumab (TM) in parallel cohorts of patients with carefully selected rare cancer types in which these agents had not previously been evaluated in phase II trials and for which there was clinical or biological rationale for dual immune checkpoint inhibitor therapy to be active. Methods: We designed a multi-centre, non-blinded, open-label phase II basket trial with each of the following 8 rare cancers considered a separate phase II trial: salivary carcinoma, carcinoma of unknown primary (CUP) with tumour infiltrating lymphocytes and/or expressing PD-L1, mucosal melanoma, acral melanoma, osteosarcoma, undifferentiated pleomorphic sarcoma, clear cell carcinoma of the ovary (CCCO) or squamous cell carcinoma of the anal canal (SCCA). The primary objective was to evaluate the response rate of the combination of D and TM, and the secondary objectives were to evaluate the tolerability and safety of D and TM combination. Eligible patients had advanced, metastatic or recurrent, or unresectable cancer with no known life-prolonging treatment option, age ≥16 years, ECOG performance status 0 or 1. Patients received D (1500 mg IV) + TM (75 mg IV) on Day 1 q4 weeks for 4 cycles followed by D q4 weeks until disease progression. This trial is registered with ClinicalTrials.gov, NCT02879162. Findings: From December 14th, 2016, to August 14, 2019, 140 patients enrolled into seven cohorts. The rare melanoma cohorts were closed due to lack of accrual. Of the 140 patients enrolled, 138 were eligible, 138 were evaluable for toxicity and 128 (91%) were evaluable for response. Durable responses were noted in all cohorts except for osteosarcoma. The overall response rate for eligible patients was 16% (95% CI: 10–23%). The response rates in each cancer cohort were undifferentiated pleomorphic sarcoma 15% (n = 3/20; 95% CI 3–38%), salivary carcinoma 20% (n = 4/20; 95% CI: 6–44%), CUP 17% (n = 3/18; 95% CI 4–41%), SCCA 10% (n = 2/20; 95% CI 12–32%) and CCCO 21% (n = 8/39; 95% CI 9–37%). Grade 3/4 adverse events were rare, where 4 patients experienced grade 4 related events and39 patients experienced grade 3 events. Interpretation: Durvalumab + tremelimumab treatment resulted in meaningful responses in salivary carcinoma and CCCO and deserves further exploration in front-line studies. Funding: AstraZeneca and Canadian Cancer Society.

A febrile man in Italy who had traveled to Cuba in July 2024 was diagnosed with Oropouche fever. Reverse transcription PCR detected prolonged shedding of Oropouche virus RNA in whole blood, serum, urine, and semen. Sixteen days after symptom onset, replication-competent virus was detected in semen, suggesting risk for sexual transmission.