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The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54-0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07-1.91; extensive disease: HR 2.02, 95%CI 1.07-3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.

BackgroundRadiotherapy is an essential component of cancer treatment, yet many countries do not have adequate capacity to serve all patients who would benefit from it. Allocation systems are needed to guide patient prioritization for radiotherapy in resource-limited contexts. These systems should be informed by allocation principles deemed relevant to stakeholders. This study explores the ethical dilemmas and views of decision-makers engaged in real-world prioritization of scarce radiotherapy resources at a cancer center in Rwanda in order to identify relevant principles.MethodsSemi-structured interviews were conducted with a purposive sample of 22 oncology clinicians, program leaders, and clinical advisors. Interviews explored the factors considered by decision-makers when prioritizing patients for radiotherapy. The framework method of thematic analysis was used to characterize these factors. Bioethical analysis was then applied to determine their underlying normative principles.ResultsParticipants considered both clinical and non-clinical factors relevant to patient prioritization for radiotherapy. They widely agreed that disease curability should be the primary overarching driver of prioritization, with the goal of saving the most lives. However, they described tension between curability and competing factors including age, palliative benefit, and waiting time. They were divided about the role that non-clinical factors such as social value should play, and agreed that poverty should not be a barrier.ConclusionsMultiple competing principles create tension with the agreed upon overarching goal of maximizing lives saved, including another utilitarian approach of maximizing life-years saved as well as non-utilitarian principles, such as egalitarianism, prioritarianism, and deontology. Clinical guidelines for patient prioritization for radiotherapy can combine multiple principles into a single allocation system to a significant extent. However, conflicting views about the role that social factors should play, and the dynamic nature of resource availability, highlight the need for ongoing work to evaluate and refine priority setting systems based on stakeholder views.

Abstract The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54–0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07–1.91; extensive disease: HR 2.02, 95%CI 1.07–3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.

Abstract Patients diagnosed with advanced osteosarcoma, often in the form of lung metastases, have abysmal five-year overall survival rates. The complexity of the osteosarcoma immune tumor microenvironment has been implicated in clinical trial failures of various immunotherapies. The purpose of this exploratory study was to spatially characterize the immune tumor microenvironment of metastatic osteosarcoma lung specimens. Knowledge of the coordinating cellular networks within these tissues could then lead to improved outcomes when utilizing immunotherapy for treatment of this disease. Importantly, various cell types, interactions, and cellular neighborhoods were associated with five-year survival status. Of note, increases in cellular interactions between T lymphocytes, positive for programmed cell death protein 1, and myeloid-derived suppressor cells were observed in the 5-year deceased cohort. Additionally, cellular neighborhood analysis identified an Immune-Cold Parenchyma cellular neighborhood, also associated with worse 5-year survival. Finally, the Osteosarcoma Spatial Score, which approximates effector immune activity in the immune tumor microenvironment through the spatial proximity of immune and tumor cells, was increased within 5-year survivors, suggesting improved effector signaling in this patient cohort. Ultimately, these data represent a robust spatial multiplexed immunofluorescence analysis of the metastatic osteosarcoma immune tumor microenvironment. Various communication networks, and their association with survival, were described. In the future, identification of these networks may suggest the use of specific, combinatory immunotherapeutic strategies for improved anti-tumor immune responses and outcomes in osteosarcoma.

Abstract Given the existing uncertainty regarding the effectiveness and safety of switching from low-molecular-weight heparin (LMWH) to direct oral anticoagulants (DOACs) in patients with cancer-associated venous thrombosis (CAT), we conducted a comprehensive population-based cohort study utilizing electronic health database in Hong Kong. A total of 4356 patients with CAT between 2010 and 2022 were included, with 1700 (39.0%) patients switching to DOAC treatment. Compared to continuous LMWH treatment, switching to DOACs was associated with a significantly lower risk of hospitalization due to venous thromboembolism (HR: 0.49 [95% CI = 0.35–0.68]) and all-cause mortality (HR: 0.67 [95% CI = 0.61–0.74]), with no significant difference in major bleeding (HR: 1.04 [95% CI = 0.83–1.31]) within six months. These findings provide reassurance regarding the effectiveness and safety of switching from LMWH to DOACs among patients with CAT, including vulnerable patient groups.

BackgroundThe large-scale proteomic platform known as the SomaScan® assay is capable of simultaneously measuring thousands of proteins in patient specimens through next-generation aptamer-based multiplexed technology. While previous studies have utilized patient peripheral blood to suggest serum biomarkers of prognostic or diagnostic value in osteosarcoma (OSA), the most common primary pediatric bone cancer, they have ultimately been limited in the robustness of their analyses. We propose utilizing this aptamer-based technology to describe the systemic proteomic milieu in patients diagnosed with this disease.MethodsTo determine novel biomarkers associated with overall survival in OSA, we deployed the SomaLogic SomaScan® 7k assay to investigate the plasma proteomic profile of naive primary, recurrent, and metastatic OSA patients. Following identification of differentially expressed proteins (DEPs) between 2-year deceased and survivor cohorts, publicly available databases including Survival Genie, TIGER, and KM Plotter Immunotherapy, among others, were utilized to investigate the significance of our proteomic findings.ResultsApo-transcobalamin-II (APO-TCN2) was identified as the most DEP between 2-year deceased and survivor cohorts (Log2 fold change = 6.8, P-value = 0.0017). Survival analysis using the Survival Genie web-based platform indicated that increased intratumoral TCN2 expression was associated with better overall survival in both OSA (TARGET-OS) and sarcoma (TCGA-SARC) datasets. Cell-cell communication analysis using the TIGER database suggested that TCN2+ Myeloid cells likely interact with marginal zone and immunoglobin-producing B lymphocytes expressing the TCN2 receptor (CD320) to promote their proliferation and survival in both non-small cell lung cancer and melanoma tumors. Analysis of publicly available OSA scRNA-sequencing datasets identified similar populations in naive primary tumors. Furthermore, circulating APO-TCN2 levels in OSA were then associated with a plasma proteomic profile likely necessary for robust B lymphocyte proliferation, infiltration, and formation of intratumoral tertiary lymphoid structures for improved anti-tumor immunity.ConclusionsOverall, APO-TCN2, a circulatory protein previously described in various lymphoproliferative disorders, was associated with 2-year survival status in patients diagnosed with OSA. The relevance of this protein and apparent immunological function (anti-tumor B lymphocyte responses) was suggested using publicly available solid tumor RNA-sequencing datasets. Further studies characterizing the biological function of APO-TCN2 and its relevance in these diseases is warranted.

Introduction: Characteristics of long-term survivors in EGFR-mutant (EGFRm) NSCLC are not fully understood. This retrospective analysis evaluated a multi-institution cohort of patients with EGFRm NSCLC treated in the pre-osimertinib era and sought to describe characteristics of long-term survivors. Methods: Clinical characteristics and outcomes were abstracted from the electronic medical records of patients with EGFRm metastatic NSCLC who started first-line therapy before 2015. Demographics and comutations were compared between greater than or equal to 5-year survivors and less than 5-year survivors. Multivariable Cox proportional hazard and logistic regression models were used to evaluate factors associated with survival and the odds of death within 5 years, respectively. Results: Overall, 133 patients were greater than or equal to 5-year survivors; 127 were less than 5-year survivors. Burden of pathogenic comutations including TP53 and PIK3CA was similar between greater than or equal to 5-year survivors and less than 5-year survivors. Receipt of first-line chemotherapy rather than EGFR tyrosine kinase inhibitor was similar between the groups (22% of

Abstract Soluble angiotensin‐converting enzyme 2 (ACE2) can act as a decoy molecule that neutralizes severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) by blocking spike (S) proteins on virions from binding ACE2 on host cells. Based on structural insights of ACE2 and S proteins, we designed a “muco‐trapping” ACE2‐Fc conjugate, termed ACE2‐(G4S)6‐Fc, comprised of the extracellular segment of ACE2 (lacking the C‐terminal collectrin domain) that is linked to mucin‐binding IgG1‐Fc via an extended glycine‐serine flexible linker. ACE2‐(G4S)6‐Fc exhibits substantially greater binding affinity and neutralization potency than conventional full length ACE2‐Fc decoys or similar truncated ACE2‐Fc decoys without flexible linkers, possessing picomolar binding affinity and strong neutralization potency against pseudovirus and live virus. ACE2‐(G4S)6‐Fc effectively trapped fluorescent SARS‐CoV‐2 virus like particles in fresh human airway mucus and was stably nebulized using a commercial vibrating mesh nebulizer. Intranasal dosing of ACE2‐(G4S)6‐Fc in hamsters as late as 2 days postinfection provided a 10‐fold reduction in viral load in the nasal turbinate tissues by Day 4. These results strongly support further development of ACE2‐(G4S)6‐Fc as an inhaled immunotherapy for COVID‐19, as well as other emerging viruses that bind ACE2 for cellular entry.

The prairies and savannahs historically found in the Mixedwood Plains Ecozone have been largely converted into farmland, the dominant present-day land cover. Consequently, many species native to these grasslands have shifted to inhabiting suitable agricultural lands. More recently, agricultural intensification has led to the conversion of pastures and hay fields to annual crops, further removing habitat suitable for the persistence of grassland species. We quantified the shift from pasture and forage to annual crops as well as the dynamics among agricultural lands and other land covers in the Mixedwood Plains Ecozone, predicting biodiversity implications by providing a case study on Eastern Meadowlark (Sturnella magna (Linnaeus, 1758)). The total agricultural land area changed little over the study period, but area of pasture and forage decreased while row crop area increased. The loss of agricultural lands to urbanization was partly offset by the conversion of forests and wetlands; however, the farmland gained was of lesser agricultural quality than the farmland lost. Declines in Eastern Meadowlark abundance correlated significantly with carrying capacity loss, suggesting that habitat availability is a limiting factor for this species. We highlight the importance of land management policies to minimize the impacts of land conversion on biodiversity and agricultural production.

Abstract Background Approximately 32 million pregnant women are at risk of malaria with up to 10,000 maternal deaths and 200,000 neonates at risk annually. Intermittent Preventive Treatment (IPT) with sulfadoxine-pyrimethamine (SP) is recommended by the World Health Organization (WHO) to reduce disease in pregnancy and adverse maternal and newborn outcomes. At least three doses of SP should be taken by pregnant women during antenatal consultation (ANC) beginning from the thirteenth week of pregnancy till parturition. The aim of this study was to assess uptake of IPT during pregnancy and risk factors for maternal anaemia and infant birth weight in Dschang, West region of Cameroon. Methods A total of 380 consenting pregnant women at delivery were recruited in a cross- sectional prospective survey between January to December 2021. Data on ANC attendance, total dose of IPT and history of malaria were abstracted from hospital ANC records while socio-demographic characteristics, bed net use and obstetrics history of each participant were also recorded through an interview. Further, blood samples were collected from the intervillous space for assessment of maternal anaemia and microscopic parasitology. Nested PCR based on amplification of the Plasmodium 18S sRNA was carried out to detect submicroscopic infection. IPTp coverage was calculated per WHO recommendation and the prevalence of anaemia and low birth weight were estimated as proportions in the total sample of pregnant women and live births, respectively. Crude and adjusted odds ratios and their 95% confidence intervals were used to estimate associations between pregnancy outcomes considered and risk factors in specific and general models. A p

Background Radiotherapy is an essential component of cancer treatment, yet many countries do not have adequate capacity to serve all patients who would benefit from it. Allocation systems are needed to guide patient prioritization for radiotherapy in resource-limited contexts. These systems should be informed by allocation principles deemed relevant to stakeholders. This study explores the ethical dilemmas and views of decision-makers engaged in real-world prioritization of scarce radiotherapy resources at a cancer center in Rwanda in order to identify relevant principles. Methods Semi-structured interviews were conducted with a purposive sample of 22 oncology clinicians, program leaders, and clinical advisors. Interviews explored the factors considered by decision-makers when prioritizing patients for radiotherapy. The framework method of thematic analysis was used to characterize these factors. Bioethical analysis was then applied to determine their underlying normative principles. Results Participants considered both clinical and non-clinical factors relevant to patient prioritization for radiotherapy. They widely agreed that disease curability should be the primary overarching driver of prioritization, with the goal of saving the most lives. However, they described tension between curability and competing factors including age, palliative benefit, and waiting time. They were divided about the role that non-clinical factors such as social value should play, and agreed that poverty should not be a barrier. Conclusions Multiple competing principles create tension with the agreed upon overarching goal of maximizing lives saved, including another utilitarian approach of maximizing life-years saved as well as non-utilitarian principles, such as egalitarianism, prioritarianism, and deontology. Clinical guidelines for patient prioritization for radiotherapy can combine multiple principles into a single allocation system to a significant extent. However, conflicting views about the role that social factors should play, and the dynamic nature of resource availability, highlight the need for ongoing work to evaluate and refine priority setting systems based on stakeholder views.