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Background Leptospira are shed into the environment via urine of infected animals. Rivers are thought to be an important risk factor for transmission to humans, though much is unknown about the types of environment or characteristics that favor survival. To address this, we screened for Leptospira DNA in two rivers in rural Ecuador where Leptospirosis is endemic. Results We collected 112 longitudinal samples and recorded pH, temperature, river depth, precipitation, and dissolved oxygen. We also performed a series of three experiments designed to provide insight into Leptospira presence in the soil. In the first soil experiment, we characterized prevalence and co-occurrence of Leptospira with other bacterial taxa in the soil at dispersed sites along the rivers ( n  = 64). In the second soil experiment, we collected 24 river samples and 48 soil samples at three points along eight transects to compare the likelihood of finding Leptospira in the river and on the shore at different distances from the river. In a third experiment, we tested whether Leptospira presence is associated with soil moisture by collecting 25 soil samples from two different sites. In our river experiment, we found pathogenic Leptospira in only 4 (3.7%) of samples. In contrast, pathogenic Leptospira species were found in 22% of shore soil at dispersed sites, 16.7% of soil samples (compared to 4.2% of river samples) in the transects, and 40% of soil samples to test for associations with soil moisture. Conclusions Our data are limited to two sites in a highly endemic area, but the scarcity of Leptospira DNA in the river is not consistent with the widespread contention of the importance of river water for leptospirosis transmission. While Leptospira may be shed directly into the river, onto the shores, or washed into the river from more remote sites, massive dilution and limited persistence in rivers may reduce the environmental load and therefore, the epidemiological significance of such sources. It is also possible that transmission may occur more frequently on shores where people are liable to be barefoot. Molecular studies that further explore the role of rivers and water bodies in the epidemiology of leptospirosis are needed.

BackgroundPatients with advanced head and neck squamous cell carcinoma (HNSCC) have poor prognosis in part due to insufficient anti-tumor immune responses. Unfortunately, immune checkpoint inhibitors (ICIs) have poor or no efficacy for the majority of advanced HNSCC patients. Radiation therapy (RT) as an adjuvant treatment is a promising combination partner for ICI due to its inflammatory properties and has been shown to enhance response to ICI in the clinic. Thus far, the mechanisms by which RT improves anti-tumor immunity and mechanisms leading to treatment resistance are only partially understood.MethodsTo investigate which pre-treatment tumor characteristics contribute to a successful immune response to RT, we investigated The Cancer Genome Atlas (TCGA) HNSC database for gene expression biomarkers of response. Given the relevance of natural killer (NK) cells in that analysis, we employed two immune-competent mouse models of HNSCC to study NK cell responses with and without RT treatment: one which responds to RT with increased survival (responder), and one which does not (non-responder). We conducted in vitro experiments where cell lines from both models were treated +/- 10 Gray RT and rested for 48 hours prior to either single cell RNA sequencing (scRNAseq) or co-culture with syngeneic healthy mouse splenocytes followed by flow cytometry.ResultsTCGA analysis revealed that pre-treatment expression of a signature gene for NK cell maturation positively correlated with overall survival in RT-treated patients but not untreated patients, suggesting that the presence of mature NK cells is crucial to response to RT. In our preclinical mouse models of HNSCC, scRNAseq revealed that RT increased the expression of ligands for the NK cell activating receptor NKG2D in the responder cells. This was correlated with Irf3 transcription factor activity, which is downstream of cGAS-STING signaling. These changes were not observed in the non-responder model, suggesting a cancer cell-intrinsic mechanism of resistance to RT in that model. Co-culture experiments revealed that RT induced NK cell activation against responder cells as determined by CD107A surface expression on NK cells.ConclusionsThese studies support the prognostic value of mature NK cell tumor infiltration in HNSCC patients to be treated with RT, providing a potential clinical biomarker to predict response to RT/ICI combination therapy. These findings also show that RT impacts cancer cell immunogenicity, which may underly the prognostic value of NK cells. These findings will inform the design of new NK cell-focused combination therapies including RT.

Leptospira are shed into the environment via urine of infected animals. Rivers are thought to be an important risk factor for transmission to humans, though much is unknown about the types of environment or characteristics that favor survival. To address this, we screened for Leptospira DNA in two rivers in rural Ecuador where Leptospirosis is endemic. We collected 112 longitudinal samples and recorded pH, temperature, river depth, precipitation, and dissolved oxygen. We also performed a series of three experiments designed to provide insight into Leptospira presence in the soil. In the first soil experiment, we characterized prevalence and co-occurrence of Leptospira with other bacterial taxa in the soil at dispersed sites along the rivers (n = 64). In the second soil experiment, we collected 24 river samples and 48 soil samples at three points along eight transects to compare the likelihood of finding Leptospira in the river and on the shore at different distances from the river. In a third experiment, we tested whether Leptospira presence is associated with soil moisture by collecting 25 soil samples from two different sites. Our data are limited to two sites in a highly endemic area, but the scarcity of Leptospira DNA in the river is not consistent with the widespread contention of the importance of river water for leptospirosis transmission. While Leptospira may be shed directly into the river, onto the shores, or washed into the river from more remote sites, massive dilution and limited persistence in rivers may reduce the environmental load and therefore, the epidemiological significance of such sources. It is also possible that transmission may occur more frequently on shores where people are liable to be barefoot. Molecular studies that further explore the role of rivers and water bodies in the epidemiology of leptospirosis are needed.

Despite efforts to reduce the incidence of second cancer, the risk was not lower among 5-year survivors of Hodgkin's lymphoma in the Netherlands treated between 1989 and 2000, a period when more limited radiation fields and doses were used, than in earlier periods. Since the late 1960s, when combination chemotherapy and high-energy radiation therapy were introduced for the treatment of Hodgkin’s lymphoma, survival has increased dramatically. Cure has come at a price, however, because the treatment of Hodgkin’s lymphoma has been shown to increase the risk of subsequent malignant neoplasms and other late effects considerably. 1 – 22 Although very high relative risks have been observed for leukemia (especially among patients who were treated with alkylating agents) and non-Hodgkin’s lymphoma (which was not previously associated with a particular type of therapy), second solid cancers, the occurrence of which is related primarily to radiation therapy, contribute . . .

Bastin et al .’s estimate (Reports, 5 July 2019, p. 76) that tree planting for climate change mitigation could sequester 205 gigatonnes of carbon is approximately five times too large. Their analysis inflated soil organic carbon gains, failed to safeguard against warming from trees at high latitudes and elevations, and considered afforestation of savannas, grasslands, and shrublands to be restoration.

B-cell maturation antigen (BCMA) is a prominent tumor-associated target for chimeric antigen receptor (CAR)-T cell therapy in multiple myeloma (MM). Here, we describe the case of a patient with MM who was enrolled in the CARTITUDE-1 trial ( NCT03548207 ) and who developed a progressive movement disorder with features of parkinsonism approximately 3 months after ciltacabtagene autoleucel BCMA-targeted CAR-T cell infusion, associated with CAR-T cell persistence in the blood and cerebrospinal fluid, and basal ganglia lymphocytic infiltration. We show BCMA expression on neurons and astrocytes in the patient’s basal ganglia. Public transcriptomic datasets further confirm BCMA RNA expression in the caudate of normal human brains, suggesting that this might be an on-target effect of anti-BCMA therapy. Given reports of three patients with grade 3 or higher parkinsonism on the phase 2 ciltacabtagene autoleucel trial and of grade 3 parkinsonism in the idecabtagene vicleucel package insert, our findings support close neurological monitoring of patients on BCMA-targeted T cell therapies. A progressive movement disorder in a patient with multiple myeloma treated with anti-BCMA CAR-T cells that might have been related to on-target activity in the brain supports prospective neurologic monitoring after BCMA-targeting therapies.

Millions of people are suffering from Long COVID or post-acute sequelae of COVID-19 (PASC). Several biological factors have emerged as potential drivers of PASC pathology. Some individuals with PASC may not fully clear the coronavirus SARS-CoV-2 after acute infection. Instead, replicating virus and/or viral RNA—potentially capable of being translated to produce viral proteins—persist in tissue as a ‘reservoir’. This reservoir could modulate host immune responses or release viral proteins into the circulation. Here we review studies that have identified SARS-CoV-2 RNA/protein or immune responses indicative of a SARS-CoV-2 reservoir in PASC samples. Mechanisms by which a SARS-CoV-2 reservoir may contribute to PASC pathology, including coagulation, microbiome and neuroimmune abnormalities, are delineated. We identify research priorities to guide the further study of a SARS-CoV-2 reservoir in PASC, with the goal that clinical trials of antivirals or other therapeutics with potential to clear a SARS-CoV-2 reservoir are accelerated. Proal and colleagues review the evidence for long-term persistence of coronavirus SARS-CoV-2 in tissues of infected individuals and discuss how this viral reservoir may contribute to the pathogenesis of post-acute sequelae of COVID-19 (PASC).

In a randomized trial, 48 weeks of treatment with bulevirtide, which inhibits hepatitis D virus entry into hepatocytes, reduced HDV RNA and alanine aminotransferase levels in patients with chronic hepatitis D.

There are no approved treatments for post-COVID-19 condition (also known as long COVID), a debilitating disease state following SARS-CoV-2 infection that is estimated to affect tens of millions of people. A growing body of evidence shows that SARS-CoV-2 can persist for months or years following COVID-19 in a subset of individuals, with this reservoir potentially driving long-COVID symptoms or sequelae. There is, therefore, an urgent need for clinical trials targeting persistent SARS-CoV-2, and several trials of antivirals or monoclonal antibodies for long COVID are underway. However, because mechanisms of SARS-CoV-2 persistence are not yet fully understood, such studies require important considerations related to the mechanism of action of candidate therapeutics, participant selection, duration of treatment, standardisation of reservoir-associated biomarkers and measurables, optimal outcome assessments, and potential combination approaches. In addition, patient subgroups might respond to some interventions or combinations of interventions, making post-hoc analyses crucial. Here, we outline these and other key considerations, with the goal of informing the design, implementation, and interpretation of trials in this rapidly growing field. Our recommendations are informed by knowledge gained from trials targeting the HIV reservoir, hepatitis C, and other RNA viruses, as well as precision oncology, which share many of the same hurdles facing long-COVID trials.

Many drugs have progressed through preclinical and clinical trials and have been available – for years in some cases – before being recalled by the FDA for unanticipated toxicity in humans. One reason for such poor translation from drug candidate to successful use is a lack of model systems that accurately recapitulate normal tissue function of human organs and their response to drug compounds. Moreover, tissues in the body do not exist in isolation, but reside in a highly integrated and dynamically interactive environment, in which actions in one tissue can affect other downstream tissues. Few engineered model systems, including the growing variety of organoid and organ-on-a-chip platforms, have so far reflected the interactive nature of the human body. To address this challenge, we have developed an assortment of bioengineered tissue organoids and tissue constructs that are integrated in a closed circulatory perfusion system, facilitating inter-organ responses. We describe a three-tissue organ-on-a-chip system, comprised of liver, heart, and lung, and highlight examples of inter-organ responses to drug administration. We observe drug responses that depend on inter-tissue interaction, illustrating the value of multiple tissue integration for in vitro study of both the efficacy of and side effects associated with candidate drugs.