Entrectinib-related myocarditis in a young female patient with metastatic non-small cell lung cancer

A 51-year-old woman presented with a 2-week history of off balance, left lower limb weakness and neglect and neck pain radiating down the right arm. Investigations revealed a metastatic, ROS1 fusion-positive, non-small cell lung cancer, and treatment with entrectinib, a recently approved multikinase inhibitor, was started. Two weeks after, she was admitted to the emergency department with new-onset pressure-like chest pain and dyspnoea. Laboratory evaluation showed elevated troponin and mild left ventricular systolic dysfunction with reduced global longitudinal strain on transthoracic echocardiogram. Cardiac magnetic resonance revealed mild oedema and non-ischaemic fibrosis. A diagnosis of drug-induced myocarditis was made. Cardioprotective medication with an angiotensin-converting enzyme inhibitor and a beta-blocker was started. Entrectinib was temporarily discontinued and restarted at a reduced dose after a multidisciplinary team meeting involving both the oncology and cardio-oncology teams. This is the second described case of entrectinib-induced myocarditis and the first one without eosinophilia

Age at death estimation from bone histology in Malaysian males.

Estimation of age from microscopic examination of human bone utilizes bone remodeling. This allows 2 regression equation to be determined in a specific population based on the variation in osteon turnover in different populations. The aim of this study was to provide age estimation for Malaysian males. Ground undecalcified cross sections were prepared from long limb bones of 50 deceased males aged between 21 and 78 years. Ten microstructural parameters were measured and subjected to multivariate regression analysis. Results showed that osteon count had the highest correlation with age (R = 0.43), and age was estimated to be within 10.94 years of the true value in 98% of males. Cross validation of the equation on 50 individuals showed close correspondence of true ages with estimated ages. Further studies are needed to validate and expand these results

Lymph node hemophagocytosis in rickettsial diseases: a pathogenetic role for CD8 T lymphocytes in human monocytic ehrlichiosis (HME)?

BACKGROUND: Human monocytic ehrlichiosis (HME) and Rocky Mountain spotted fever (RMSF) are caused by Ehrlichia chaffeensis and Rickettsia rickettsii, respectively. The pathogenesis of RMSF relates to rickettsia-mediated vascular injury, but it is unclear in HME. METHODS: To study histopathologic responses in the lymphatic system for correlates of immune injury, lymph nodes from patients with HME (n = 6) and RMSF (n = 5) were examined. H&E-stained lymph node tissues were examined for five histopathologic features, including hemophagocytosis, cellularity, necrosis, and vascular congestion and edema. The relative proportions of CD68 macrophages, CD8 and CD4 T lymphocytes, and CD20 B lymphocytes were evaluated by immunohistochemical staining. RESULTS: Hemophagocytosis was similar in HME and RMSF, and was greater than in control cases (p = .015). Cellularity in HME was not different from controls, whereas RMSF lymph nodes were markedly less cellular (p < 0.002). E. chaffeensis-infected mononuclear phagocytes were infrequent compared to R. rickettsii-infected endothelial cells. More CD8 cells in lymph nodes were observed with HME (p < .001), but no quantitative differences in CD4 lymphocytes, macrophages, or B lymphocytes were identified. CONCLUSION: Hemophagocytosis, CD8 T cell expansion, and the paucity of infected cells in HME, suggest that E. chaffeensis infection leads to macrophage activation and immune-mediated injury

Neural Responses to Novel and Existing Words in Children with Autism Spectrum and Developmental Language Disorder

\ua9 2021, the Authors.The formation of new phonological representations is key in establishing items in the mental lexicon. Phonological forms become stable with repetition, time and sleep. Atypicality in the establishment of new word forms is characteristic of children with developmental language disorder (DLD) and autism spectrum disorder (ASD), yet neural changes in response to novel word forms over time have not yet been directly compared in these groups. This study measured habituation of event-related-potentials (ERPs) to novel and known words within and between two sessions spaced 24 hours apart in typically developing (TD) children, and their peers with DLD or ASD. We hypothesised that modulation of the auditory N400 amplitude would mark real-time changes in lexical processing with habituation evident within and across sessions in the TD group, while the DLD group would show attenuated habituation within sessions, and the ASD group attenuated habituation between sessions. Twenty-one typically developing children, 19 children with ASD, and 16 children with DLD listened passively to known and novel words on two consecutive days, while ERPs were recorded using dry electrodes. Counter to our hypotheses, no habituation effect emerged within sessions. However, responses did habituate between sessions, with this effect being reduced in the DLD group, indicating less pre-activation of lexical representations in response to words encountered the previous day. No differences in change over time were observed between the TD and ASD groups. These data are in keeping with theories stressing the importance of sleep-related consolidation in word learning

Orientia tsutsugamushi in Human Scrub Typhus Eschars Shows Tropism for Dendritic Cells and Monocytes Rather than Endothelium

Scrub typhus is a common and underdiagnosed cause of febrile illness in Southeast Asia, caused by infection with Orientia tsutsugamushi. Inoculation of the organism at a cutaneous mite bite site commonly results in formation of a localized pathological skin reaction termed an eschar. The site of development of the obligate intracellular bacteria within the eschar and the mechanisms of dissemination to cause systemic infection are unclear. Previous postmortem and in vitro reports demonstrated infection of endothelial cells, but recent pathophysiological investigations of typhus patients using surrogate markers of endothelial cell and leucocyte activation indicated a more prevalent host leucocyte than endothelial cell response in vivo. We therefore examined eschar skin biopsies from patients with scrub typhus to determine and characterize the phenotypes of host cells in vivo with intracellular infection by O. tsutsugamushi, using histology, immunohistochemistry, double immunofluorescence confocal laser scanning microscopy and electron microscopy. Immunophenotyping of host leucocytes infected with O. tsutsugamushi showed a tropism for host monocytes and dendritic cells, which were spatially related to different histological zones of the eschar. Infected leucocyte subsets were characterized by expression of HLADR+, with an “inflammatory” monocyte phenotype of CD14/LSP-1/CD68 positive or dendritic cell phenotype of CD1a/DCSIGN/S100/FXIIIa and CD163 positive staining, or occasional CD3 positive T-cells. Endothelial cell infection was rare, and histology did not indicate a widespread inflammatory vasculitis as the cause of the eschar. Infection of dendritic cells and activated inflammatory monocytes offers a potential route for dissemination of O. tsutsugamushi from the initial eschar site. This newly described cellular tropism for O. tsutsugamushi may influence its interaction with local host immune responses

Dose-response model of murine typhus (Rickettsia typhi): time post inoculation and host age dependency analysis

<p>Abstract</p> <p>Background</p> <p><it>Rickettsia typhi (R. mooseri) </it>is the causative agent of murine typhus. It is one of the most widely distributed flea-borne diseases with a relatively mild febrile initial illness with six to 14 days of incubation period. The bacterium is gram negative and an obligate intracellular pathogen. The disease is transmitted to humans and vertebrate host through fleabites or via contact with infected feces. This paper develops dose-response models of different routes of exposure for typhus in rodents.</p> <p>Methods</p> <p>Data from published articles were analyzed using parametric dose-response relationship models. Dose-response relationships were fit to data using the method of maximum likelihood estimation (MLE).</p> <p>Results</p> <p>Dose-response models quantifying the effects of different ages of rats and time post inoculation in BALB/c mice were analyzed in the study. Both the adult rats (inoculated intradermally) and newborn rats (inoculated subcutaneously) were best fit by exponential models and both distributions could be described by a single dose-response relationship. The BALB/C mice inoculated subcutaneously were best fit by Beta-Poisson models. The time post inoculation analysis showed that there was a definite time and response relationship existed in this case.</p> <p>Conclusions</p> <p>Intradermally or subcutaneously inoculated rats (adult and newborn) models suggest that less than 1 plaque-forming unit (PFU) (1.33 to 0.38 in 95% confidence limits) of the pathogen is enough to seroconvert 50% of the exposed population on average. For the BALB/c mouse time post inoculation model, an average dose of 0.28 plaque-forming units (PFU) (0.75 to 0.11 in 95% confidence limits) will seroconvert 50% of the exposed mice.</p

An efficient record linkage scheme using graphical analysis for identifier error detection

Integration of information on individuals (record linkage) is a key problem in healthcare delivery, epidemiology, and "business intelligence" applications. It is now common to be required to link very large numbers of records, often containing various combinations of theoretically unique identifiers, such as NHS numbers, which are both incomplete and error-prone