Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an ...in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.
Mechanisms of therapeutic resistance and vulnerability evolve in metastatic cancers as tumor cells and extrinsic microenvironmental influences change during treatment. To support the development of ...methods for identifying these mechanisms in individual people, here we present an omic and multidimensional spatial (OMS) atlas generated from four serial biopsies of an individual with metastatic breast cancer during 3.5 years of therapy. This resource links detailed, longitudinal clinical metadata that includes treatment times and doses, anatomic imaging, and blood-based response measurements to clinical and exploratory analyses, which includes comprehensive DNA, RNA, and protein profiles; images of multiplexed immunostaining; and 2- and 3-dimensional scanning electron micrographs. These data report aspects of heterogeneity and evolution of the cancer genome, signaling pathways, immune microenvironment, cellular composition and organization, and ultrastructure. We present illustrative examples of how integrative analyses of these data reveal potential mechanisms of response and resistance and suggest novel therapeutic vulnerabilities.
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•Safe and reliable workflows for multiplatform measurements from single biopsies•Clinical metadata with 11 omic and imaging assays from serial biopsy and blood•Omic, cellular, and structural evolution of metastatic cancer in a single individual•Integrative analyses reveal new potential mechanisms of response and resistance
Identifying mechanisms of response and resistance to treatment in individual cancer patients is challenging but critical for improvement of precision medicine outcomes. Johnson et al. report a comprehensive atlas from a single individual with breast cancer and demonstrate how longitudinal, integrative analyses can provide new insights.
Aims
The aim of this study was to determine whether the CHA2DS2‐VASc score can predict adverse outcomes such as death, ischaemic stroke, and major haemorrhage, in patients with systolic heart failure ...in sinus rhythm.
Methods and results
CHA2DS2‐VASc scores were calculated for 1101 patients randomized to warfarin and 1123 patients randomized to aspirin. Adverse outcomes were defined as death or ischaemic stroke, death alone, ischaemic stroke alone, and major haemorrhage. Using proportional hazards models, we found that each 1‐point increase in the CHA2DS2‐VASc score was associated with increased hazard of death or ischaemic stroke events hazard ratio (HR) for the warfarin arm = 1.21, 95% confidence interval (CI) 1.13–1.30, P < 0.001; for aspirin, HR = 1.20, 95% CI 1.11–1.29, P < 0.001. Similar increased hazards for higher CHA2DS2‐VASc scores were observed for death alone, ischaemic stroke alone, and major haemorrhage. Overall performance of the CHA2DS2‐VASc score was assessed using c‐statistics for full models containing the risk score, treatment assignment, and score–treatment interaction, with the c‐statistics for the full models ranging from 0.57 for death to 0.68 for major haemorrhage.
Conclusions
The CHA2DS2‐VASc score predicted adverse outcomes in patients with systolic heart failure in sinus rhythm, with modest prediction accuracy.
Antimicrobial resistance (AMR) is continuing to grow across the world. Though often thought of as a mostly public health issue, AMR is also a major agricultural and environmental problem. As such, ...many researchers refer to it as the preeminent One Health issue. Aerial transport of antimicrobial-resistant bacteria via bioaerosols is still poorly understood. Recent work has highlighted the presence of antibiotic resistance genes in bioaerosols. Emissions of AMR bacteria and genes have been detected from various sources, including wastewater treatment plants, hospitals, and agricultural practices; however, their impacts on the broader environment are poorly understood. Contextualizing the roles of bioaerosols in the dissemination of AMR necessitates a multidisciplinary approach. Environmental factors, industrial and medical practices, as well as ecological principles influence the aerial dissemination of resistant bacteria. This article introduces an ongoing project assessing the presence and fate of AMR in bioaerosols across Canada. Its various sub-studies include the assessment of the emissions of antibiotic resistance genes from many agricultural practices, their long-distance transport, new integrative methods of assessment, and the creation of dissemination models over short and long distances. Results from sub-studies are beginning to be published. Consequently, this paper explains the background behind the development of the various sub-studies and highlight their shared aspects.
Several predictive biomarkers are currently approved or are under investigation for the selection of patients for checkpoint blockade. Tumor PD-L1 expression is used for stratification of non-small ...cell lung (NSCLC) patients, with tumor mutational burden (TMB) also being explored with promising results, and mismatch-repair deficiency is approved for tumor site-agnostic disease. While tumors with high PD-L1 expression, high TMB, or mismatch repair deficiency respond well to checkpoint blockade, tumors with lower PD-L1 expression, lower mutational burdens, or mismatch repair proficiency respond much less frequently.
We studied two patients with unexpected responses to checkpoint blockade monotherapy: a patient with PD-L1-negative and low mutational burden NSCLC and one with mismatch repair proficient colorectal cancer (CRC), both of whom lack the biomarkers associated with response to checkpoint blockade, yet achieved durable clinical benefit. Both maintained T-cell responses in peripheral blood to oncogenic driver mutations - BRAF-N581I in the NSCLC and AKT1-E17K in the CRC - years after treatment initiation. Mutation-specific T cells were also found in the primary tumor and underwent dynamic perturbations in the periphery upon treatment.
These findings suggest that T cell responses to oncogenic driver mutations may be more prevalent than previously appreciated and could be harnessed in immunotherapeutic treatment, particularly for patients who lack the traditional biomarkers associated with response. Comprehensive studies are warranted to further delineate additional predictive biomarkers and populations of patients who may benefit from checkpoint blockade.
Noroviruses are important agents of human gastroenteritis characterized by extensive sequence variation in the major capsid structural protein that likely encodes critical antigenic determinants of ...protective immunity. The lack of an infection model has limited detailed characterizations of viral antigenic relationships and identification of the essential components for protective immunity. This information would contribute to efficacious vaccine design against a broad array of norovirus strains. To understand the extent of heterotypic norovirus antibody specificity to inter- and intra-genogroup strains and its applicability to vaccine design, we collected sera from humans infected with different norovirus strains and from mice inoculated with alphavirus vectors expressing strain-specific recombinant norovirus-like particles (VLPs). We used VLPs that were assembled from Norwalk virus (NV), Hawaii virus (HV), Snow Mountain virus (SM) and Lordsdale virus (LV) as antigens to define and compare heterotypic antibody responses in humans and mice. We also examined if these heterotypic antibodies could block specific binding of ABH histo-blood group antigens, putative receptors for norovirus binding and entry, to norovirus VLPs. Furthermore, we examined the effect of multivalent inocula on the specificity, titer, and ligand blockade properties of systemic and mucosal norovirus-specific antibodies in mice. Our studies suggest that infection with one of several different genogroup I (GI) strains in humans induces heterotypic antibodies that block NV binding to ABH antigens, although comparable findings were not evident following infection with genogroup (GII) strains. Additionally, inoculating mice with vaccine cocktails encoding multiple norovirus VLPs enhances heterotypic and ligand attachment-blocking antibody responses against the LV strain not included in the cocktail. These data suggest that multivalent vaccination may provide better protection from a broader range of noroviruses than monovalent vaccination.
GM2 gangliosidosis is a group of neurodegenerative diseases caused by β-hexosaminidase A (HexA) enzyme deficiency. There is currently no cure. HexA is composed of two similar, nonidentical subunits, ...α and β, which must interact with the GM2 activator protein (GM2AP), a substrate-specific cofactor, to hydrolyze GM2 ganglioside. Mutations in either subunit or the activator can result in the accumulation of GM2 ganglioside within neurons throughout the central nervous system. The resulting neuronal cell death induces the primary symptoms of the disease: motor impairment, seizures, and sensory impairments. This study assesses the long-term effects of gene transfer in a Sandhoff (β-subunit knockout) mouse model. The study utilized a modified human β-hexosaminidase α-subunit (μ-subunit) that contains critical sequences from the β-subunit that enables formation of a stable homodimer (HexM) and interaction with GM2AP to hydrolyze GM2 ganglioside. We investigated a self-complementary adeno-associated viral (scAAV) vector expressing HexM, through intravenous injections of the neonatal mice. We monitored one cohort for 8 weeks and another cohort long-term for survival benefit, behavioral, biochemical, and molecular analyses. Untreated Sandhoff disease (SD) control mice reached a humane endpoint at approximately 15 weeks, whereas treated mice had a median survival age of 40 weeks, an approximate 2.5-fold survival advantage. On behavioral tests, the treated mice outperformed their knockout age-matched controls and perform similarly to the heterozygous controls. Through the enzymatic and GM2 ganglioside analyses, we observed a significant decrease in the GM2 ganglioside level, even though the enzyme levels were not significantly increased. Molecular analyses revealed a global distribution of the vector between brain and spinal cord regions. In conclusion, the neonatal delivery of a novel viral vector expressing the human HexM enzyme is effective in ameliorating the SD mouse phenotype for long-term. Our data could have implications not only for treatment of SD but also for Tay-Sachs disease (α-subunit deficiency) and similar brain disorders.
Practice patterns and durability of parallel stent graft techniques in complex endovascular aneurysm repair (EVAR) remain poorly defined. We aimed to quantify and compare the impact of renal chimney ...intra-aortic stent length (IASL) on geometric deformations of renal arteries in complex EVAR.
Thirty-eight nonconsecutive patients underwent EVAR utilizing parallel stent graft techniques (chimney EVAR chEVAR,
= 28; chimney endovascular aneurysm sealing chEVAS,
= 10) between 2010 and 2016. A total of 59 renal chimney stent grafts were used. Geometric quantification was derived from three-dimensional model-based centerline extraction. Renal chimney intra-aortic stent length (IASL) was defined as the length of chimney stent that extended from the proximal edge of the chimney stent to the ostium of the corresponding renal artery.
Mean IASL for both left and right renal arteries in the cohort was 35.7 mm. Renal arteries containing chimney IASL <30 mm trended toward a greater branch angle (135.4 vs. 127.8°,
= .06). Left renal arteries showed significantly greater branch angle among those with IASL <40 mm (135.5 vs. 121.7°,
= .045). Mean IASL for renal arteries in chEVAR was significantly longer compared to chEVAS (39.2 vs. 26.3 mm,
= .003). No difference was noted in overall branch angle or end-stent angle based on procedure type. ChEVAR with IASL <30 mm had significantly greater end-stent angle (48.2 vs. 33.5°,
= .03). In contrast, chEVAS patients showed no difference in end-stent angle based on IASL thresholds, but did have significantly greater branch angle among those with IASL <30 mm when grouped by both all renal arteries (133.5 vs. 113.5°,
= .004) and right renal arteries (134.3 vs. 111.6°,
= .02).
Renal chimney stents with longer IASL appear to exhibit less renal artery deformation, suggesting a more gradual and perpendicular transition of the chimney stent across the renal ostium.
Every year, billions of birds undertake extensive migrations between breeding and non-breeding areas, facing challenges that require behavioural adjustments, particularly to flight timing and ...duration. Such adjustments in daily activity patterns and the influence of extrinsic factors (e.g., environmental conditions, moonlight) have received much more research attention in terrestrial than marine migrants. Taking advantage of the widespread deployment in recent decades of combined light-level geolocator-immersion loggers, we investigated diel organisation and influence of the moon on flight activities during the non-breeding season of 21 migrant seabird species from a wide taxonomic range (6 families, 3 orders). Migrant seabirds regularly stopped (to either feed or rest) during migration, unlike some terrestrial and wetland birds which fly non-stop. We found an overall increase for most seabird species in time in flight and, for several species, also in flight bout duration, during migration compared to when resident at the non-breeding grounds. Additionally, several nocturnal species spent more of the day in flight during migration than at non-breeding areas, and vice versa for diurnal species. Nocturnal time in flight tended to increase during full moon, both during migration and at the non-breeding grounds, depending on species. Our study provides an extensive overview of activity patterns of migrant seabirds, paving the way for further research on the underlying mechanisms and drivers.
Correction: Echo Research & Practice 9:5 (2022) https://doi.org/10.1186/s44156-022-00003-8 The authors wish to clarify that the original title of this article 1 was incorrect, and the revised title ...(above) does not include reference to collaboration with the British Heart Valve Society. Confirmation of the position regarding level I, ‘abridged’ and focussed-repeat echocardiography protocols by adding in the following statement (page 5 line 7): ‘The BSE strive to ensure that patients receive the correct test at the correct time by the most appropriately skilled and qualified staff. Clinical indications and triaging for adult transthoracic echocardiography: a consensus statement by the British Society of Echocardiography in collaboration with British Heart Valve Society.
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