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Sequential adaptive trial designs can help accomplish the goals of personalized medicine, optimizing outcomes and avoiding unnecessary toxicity. Here we describe the results of incorporating a promising antibody-drug conjugate, datopotamab-deruxtecan (Dato-DXd) in combination with programmed cell death-ligand 1 inhibitor, durvalumab, as the first sequence of therapy in the I-SPY2.2 phase 2 neoadjuvant sequential multiple assignment randomization trial for high-risk stage 2/3 breast cancer. The trial includes three blocks of treatment, with initial randomization to different experimental agent(s) (block A), followed by a taxane-based regimen tailored to tumor subtype (block B), followed by doxorubicin-cyclophosphamide (block C). Subtype-specific algorithms based on magnetic resonance imaging volume change and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathologic complete response, which is the primary endpoint assessed when resection occurs. There are two primary efficacy analyses: after block A and across all blocks for six prespecified HER2-negative subtypes (defined by hormone receptor status and/or response-predictive subtypes). In total, 106 patients were treated with Dato-DXd/durvalumab in block A. In the immune-positive subtype, Dato-DXd/durvalumab exceeded the prespecified threshold for success (graduated) after block A; and across all blocks, pathologic complete response rates were equivalent to the rate expected for the standard of care (79%), but 54% achieved that result after Dato-DXd/durvalumab alone (block A) and 92% without doxorubicin-cyclophosphamide (after blocks A + B). The treatment strategy across all blocks graduated in the hormone-negative/immune-negative subtype. No new toxicities were observed. Stomatitis was the most common side effect in block A. No patients receiving block A treatment alone had adrenal insufficiency. Dato-DXd/durvalumab is a promising therapy combination that can eliminate standard chemotherapy in many patients, particularly the immune-positive subtype.ClinicalTrials.gov registration: NCT01042379 .

Since emergence of the highly pathogenic avian influenza virus (HPAIV) H5 A/Goose/Guangdong/1/1996 (gs/GD) lineage in 1996, successors continue to circulate in waves around the world, leading to massive losses in [...]

For years, there has been an increasing interest in natural alternatives to the conventional coccidiostats applied as feed additives, which have been used for decades to prevent coccidiosis in poultry and fattening rabbits. This study aimed to compare the possible anticoccidial effects of oregano oil to the established substance diclazuril in growing rabbits. The control group (CG) received a non-supplemented basal compound feed, to which either diclazuril (1 mg/kg; DG) or oregano oil (75 mg/kg; OG) was added. In each of the three trials, subgroups of 50 rabbits each were assigned to one of the three experimental groups (CG, DG and OG). Natural Eimeria infection was monitored weekly by fecal oocyst counts and Eimeria species identification following sporulation. Additionally, the performance parameters were determined at the middle and the end of the trials, and the deceased rabbits were subjected to necropsy. Neither oocyst excretion nor the performance parameters differed significantly between the three experimental groups. Eimeria media, Eimeria magna, Eimeria perforans and Eimeria exigua were identified as the occurring species. The highest animal losses (16.0%) occurred in the OG, while the losses were 12.7% in the DG and 12.0% in the CG. However, these differences were not statistically significant. Overall, neither diclazuril nor oregano oil was superior to the non-supplemented feed. This underlines the importance of diagnostics, as this study’s results indicate that in the absence of the highly pathogenic Eimeria species, economic rabbit rearing and fattening is achievable without the use of coccidiostats.

In a 1-year survey of wild terrestrial predators in northern Germany, we found that 5 of 110 foxes were infected with contemporary avian influenza A(H5N1) viruses, forming a temporal cluster during January‒March 2023. Encephalitis and strong cerebral virus replication but only sporadic mammalian-adaptive viral polymerase basic 2 protein E627K mutations were seen.

Indiana television broadcaster and film historian David L. Smith has this entry in his Indiana Historical Society Press book Hoosiers in Hollywood: 'Winning (1969): Shot at the Indianapolis Motor Speedway. [...]

Abstract Background Unlike other domestic mammals, in which metaphase-II oocytes are ovulated, canine ovulation is characterized by the release of primary oocytes, which may take 12 to up to 36 hours. Further 60 hours are needed for maturation to secondary oocytes which then remain fertile for about 48 hours. Oestrus takes 7 to 10 days on average and may start as early as a week before ovulation. This together with the prolonged process of post-ovulatory oocyte maturation requires an according longevity of spermatozoa in the female genital tract in order to provide a population of fertile sperm when oocytes have matured to fertilizability. Therefore the distribution and viability of spermatozoa in the bitch genital tract was examined during post-ovulatory oocyte maturation. Methods Thirteen beagle bitches were inseminated on the day of sonographically verified ovulation with pooled semen of two beagle dogs containing one billion progressively motile spermatozoa. Ovariohysterectomy was performed two days later (group 1, n = 6) and four days later (group 2, n = 7). The oviduct and uterine horn of one side were flushed separately and the flushing’s were checked for the presence of gametes. The oviducts including the utero-tubal junction and the uterine horns, both the flushed and unflushed, were histologically examined for sperm distribution. Results The total number of spermatozoa recovered by flushing was low and evaluation of viability was limited. Prophase-I oocytes were collected from oviduct flushing in group 1, whereas unfertilized metaphase-II oocytes were detected in group 2. From day 2 to day 4 after ovulation a significant decrease in the percentage of glands containing sperm (P Conclusions Oocyte maturation to metaphase-II stage is accompanied by a continuous sperm detachment and elimination in the uterine horns. Entrance of spermatozoa into the caudal oviduct seems to be steadily controlled by the utero-tubal junction thus providing a selected sperm population to be shifted towards the site of fertilization when oocyte maturation is completed.

Abstract COVID-19 survivors often suffer from post-acute sequelae of SARS-CoV-2 infection (PASC). Current evidence suggests dysregulated alveolar regeneration as a possible explanation for respiratory PASC, which deserves further investigation in a suitable animal model. This study investigates morphological, phenotypical and transcriptomic features of alveolar regeneration in SARS-CoV-2 infected Syrian golden hamsters. We demonstrate that CK8+ alveolar differentiation intermediate (ADI) cells occur following SARS-CoV-2-induced diffuse alveolar damage. A subset of ADI cells shows nuclear accumulation of TP53 at 6- and 14-days post infection (dpi), indicating a prolonged arrest in the ADI state. Transcriptome data show high module scores for pathways involved in cell senescence, epithelial-mesenchymal transition, and angiogenesis in cell clusters with high ADI gene expression. Moreover, we show that multipotent CK14+ airway basal cell progenitors migrate out of terminal bronchioles, aiding alveolar regeneration. At 14 dpi, ADI cells, peribronchiolar proliferates, M2-macrophages, and sub-pleural fibrosis are observed, indicating incomplete alveolar restoration. The results demonstrate that the hamster model reliably phenocopies indicators of a dysregulated alveolar regeneration of COVID-19 patients. The results provide important information on a translational COVID-19 model, which is crucial for its application in future research addressing pathomechanisms of PASC and in testing of prophylactic and therapeutic approaches for this syndrome.

Media Highlights are short, approximately one-half to three-quarters of a page, reviews intended to help CMJ readers monitor a broad spectrum of publications, web materials, professional activities, and instructional resources. Readers are encouraged to submit items that will be of interest to colleagues in the mathematical community. Media Highlights should be sent to Lowell Beineke at . [ABSTRACT FROM AUTHOR]

Intestinal epithelial cell interactions with enteric pathogens have been incompletely elucidated owing to the lack of model systems that recapitulate the cellular diversity, architecture and functionality of the intestine. To analyze rotavirus (RV) infection and the subsequent innate immune response, we established cultures of differentiated porcine intestinal epithelial cells in three different variations: basolateral-out enteroids, apical-out enteroids and two-dimensional (2D) filter-grown intestinal epithelial cells. Application of specific antibodies for fluorescent staining indicated that enteroids and enteroid-derived cell cultures contain multiple intestinal epithelial cell types. Infection studies indicated that both apical-out enteroids and 2D intestinal epithelial cells are susceptible to porcine RV infection. However, 2D intestinal epithelial cells are more useful for a detailed characterization and comparison of apical and basolateral infection than apical-out enteroids. Virus-induced apoptosis was observed in apical-out enteroids at 24 h post infection but not at earlier time points after infection. RV infected not only enterocytes but also goblet cells and Paneth cells in apical-out enteroids and 2D intestinal epithelial cells. Interestingly, despite the lack of significant differences in the efficiency of infection after apical and basolateral infection of 2D intestinal epithelial cells, stronger innate immune and inflammatory responses were observed after basolateral infection as compared to infection via the apical route. Therefore, apical-out enteroids and 2D intestinal epithelial cells provide useful primary cell culture models that can be extended to analyze invasion and replication strategies of agents implicated in enteric diseases or to study immune and inflammatory responses of the host induced by enteric pathogens.

Abstract Background Theiler’s murine encephalomyelitis virus (TMEV) is a single-stranded RNA virus that causes encephalitis followed by chronic demyelination in SJL mice and spontaneous seizures in C57BL/6 mice. Since earlier studies indicated a critical role of type I interferon (IFN-I) signaling in the control of viral replication in the central nervous system (CNS), mouse strain-specific differences in pathways induced by the IFN-I receptor (IFNAR) might determine the outcome of TMEV infection. Methods Data of RNA-seq analysis and immunohistochemistry were used to compare the gene and protein expression of IFN-I signaling pathway members between mock- and TMEV-infected SJL and C57BL/6 mice at 4, 7 and 14 days post-infection (dpi). To address the impact of IFNAR signaling in selected brain-resident cell types, conditional knockout mice with an IFNAR deficiency in cells of the neuroectodermal lineage (NesCre±IFNARfl/fl), neurons (Syn1Cre±IFNARfl/fl), astrocytes (GFAPCre±IFNARfl/fl), and microglia (Sall1CreER±IFNARfl/fl) on a C57BL/6 background were tested. PCR and an immunoassay were used to quantify TMEV RNA and cytokine and chemokine expression in their brain at 4 dpi. Results RNA-seq analysis revealed upregulation of most ISGs in SJL and C57BL/6 mice, but Ifi202b mRNA transcripts were only increased in SJL and Trim12a only in C57BL/6 mice. Immunohistochemistry showed minor differences in ISG expression (ISG15, OAS, PKR) between both mouse strains. While all immunocompetent Cre-negative control mice and the majority of mice with IFNAR deficiency in neurons or microglia survived until 14 dpi, lack of IFNAR expression in all cells (IFNAR−/−), neuroectodermal cells, or astrocytes induced lethal disease in most of the analyzed mice, which was associated with unrestricted viral replication. NesCre±IFNARfl/fl mice showed more Ifnb1, Tnfa, Il6, Il10, Il12b and Ifng mRNA transcripts than Cre−/−IFNARfl/fl mice. IFNAR−/− mice also demonstrated increased IFN-α, IFN-β, IL1-β, IL-6, and CXCL-1 protein levels, which highly correlated with viral load. Conclusions Ifi202b and Trim12a expression levels likely contribute to mouse strain-specific susceptibility to TMEV-induced CNS lesions. Restriction of viral replication is strongly dependent on IFNAR signaling of neuroectodermal cells, which also controls the expression of key pro- and anti-inflammatory cytokines during viral brain infection.

Idiopathic multicentric Castleman disease (iMCD) is a life-threatening inflammatory disease requiring immediate intervention, for which the recommended first-line therapy is the Interleukin-6 pathway inhibitor siltuximab. Authors here show that the change in levels of the chemokine CXCL13 shortly following the start of siltuximab treatment is predictive of response.

AbstractGiven a graph G with at least one edge, the line graph L(G) is that graph whose vertices are the edges of G, with two of these vertices being adjacent if the corresponding edges are adjacent in G. The line graph transformation is one of the most extensively studied, and the concept extends naturally to digraphs. The authors have recently published a book Line Graphs and Line Digraphs that covers many properties and generalizations of both types of structure. In this paper we discuss some recent progress in this area. We include a discussion of several recognition algorithms related to line graphs, and some new results on the line completion numbers. We also present some open problems and directions for further research.

Abstract In the last fifteen years, an epidemic of canine distemper virus (CDV) with marked neurotropism has occurred in Europe after a longer period of endemic transmission. Many wildlife species have been infected, with red foxes (Vulpes vulpes) being particularly affected. Given that this species is assumed to mediate cross-species CDV infections to domestic and wild animals, tissue samples from foxes with confirmed CDV infection in North-Western Germany were investigated to better understand the neurotropic aspects of the disease. This analysis included histopathology, virus distribution and cell tropism, phenotyping of inflammatory responses and determination of the genotype of the viruses based on the phylogeny of the hemagglutinin (H) gene. The predominant lesion type is gliosis in both gray and white matter areas associated with an accumulation of Iba1+ macrophages/microglia and upregulation of major histocompatibility complex class II molecules in the brain, while sequestration of CD3+ T and Pax5+ B cell in CDV-infected foxes is limited. Demyelination is found in few foxes, characterized by reduced myelin staining with loss of CNPase+ oligodendrocytes in the cerebellar white matter and brainstem. In addition, axonal damage, characterized by β-amyloid precursor protein expression, is found mainly in these brain regions. In situ hybridization reveals a primary infection of the cerebral and cerebellar gray matter and brain stem. Iba1+ cells and NeuN+ neurons represent the main CDV targets. Sequencing of the CDV H open reading frame from fox tissues reveals that the virus strains belongs to three different sub-lineages of the Europe-1/South America-1 genotype, suggesting independent transmission lines.

During his career as an author, Harold M. Sherman of Mountain View, Arkansas, wrote dozens of books, a few Broadway plays, and the screenplay for the 1944 Frederic March film [...]

Abstract Background Specialized neurons in the diencephalon detect blood hypernatremia in dehydrated animals. These neurons are connected with the pituitary gland, subsequently producing antidiuretic hormone to reabsorb water from urine in the kidneys, and to the forebrain to generate thirst and trigger drinking behavior. Case presentation This is the first case report describing clinical findings, magnetic resonance imaging (MRI) and necropsy results of a Belted Galloway heifer with severe clinical signs of dehydration and hypernatremia, but concurrent adipsia and isosthenuria. Due to insufficient recovery with symptomatic treatment, owners elected euthanasia. Postmortem MRI and necropsy revealed a complex forebrain malformation: mild abnormal gyrification of the forebrain cortex, lobar holoprosencephaly, and corpus callosum hypoplasia. The affected brain structures are well known to be involved in osmoregulation and generation of thirst in dogs, humans and rodents. Conclusions Complex forebrain malformation can be involved in the pathogenesis of hypernatremia and adipsia in bovines.

BackgroundThe emergence of novel SARS-CoV-2 variants that resist neutralizing antibodies drew the attention to cellular immunity and calls for the development of alternative vaccination strategies to combat the pandemic. Here, we have assessed the kinetics of T cell responses and protective efficacy against severe COVID-19 in pre- and post-exposure settings, elicited by PolyPEPI-SCoV-2, a peptide based T cell vaccine.Methods75 Syrian hamsters were immunized subcutaneously with PolyPEPI-SCoV-2 on D0 and D14. On D42, hamsters were intranasally challenged with 102 TCID50 of the virus. To analyze immunogenicity by IFN-γ ELISPOT and antibody secretion, lymphoid tissues were collected both before (D0, D14, D28, D42) and after challenge (D44, D46, D49). To measure vaccine efficacy, lung tissue, throat swabs and nasal turbinate samples were assessed for viral load and histopathological changes. Further, body weight was monitored on D0, D28, D42 and every day after challenge.ResultsThe vaccine induced robust activation of T cells against all SARS-CoV-2 structural proteins that were rapidly boosted after virus challenge compared to control animals (~4-fold, p