Evolution Of Disease Research Articles

Environment, Lifestyles, and Climate Change: The Many Nongenetic Contributors to The Long and Winding Road to Autoimmune Diseases.

A critical unanswered question is what is causing the increase in the prevalence of autoimmunity and autoimmune diseases around the world. Given the rapidity of change, this is likely the result of major recent alterations in our exposures to environmental risk factors for these diseases. More evidence is becoming available that the evolution of autoimmune disease, years or even decades in the making, results from multiple exposures that alter susceptible genomes and immune systems over time. Exposures during sensitive phases in key developmental or hormonal periods may set the stage for the effects of later exposures. It is likely that synergistic and additive impacts of exposure mixtures result in chronic low-level inflammation. This inflammation may eventually pass thresholds that lead to immune system activation and autoimmunity, and with further molecular and pathologic changes, the complete clinical syndrome emerges. Much work remains to be done to define the mechanisms and risk and protective factors for autoimmune conditions. However, evidence points to a variety of pollutants, xenobiotics, infections, occupational exposures, medications, smoking, psychosocial stressors, changes in diet, obesity, exercise, and sleep patterns, as well as climate change impacts of increased heat, storms, floods, wildfires, droughts, UV radiation, malnutrition, and changing infections, as possible contributors. Substantial investments in defining the role of causal factors, in whom and when their effects are most important, the necessary and sufficient gene-environment interactions, improved diagnostics and therapies, and preventive strategies are needed now to limit the many negative personal, societal, and financial impacts that will otherwise occur.

Agonists, Antagonists and Receptors of Somatostatin: Pathophysiological and Therapeutical Implications in Neoplasias.

Somatostatin is a peptide that plays a variety of roles such as neurotransmitter and endocrine regulator; its actions as a cell regulator in various tissues of the human body are represented mainly by inhibitory effects, and it shows potent activity despite its physiological low concentrations. Somatostatin binds to specific receptors, called somatostatin receptors (SSTRs), which have different tissue distributions and associated signaling pathways. The expression of SSTRs can be altered in various conditions, including tumors; therefore, they can be used as biomarkers for cancer cell susceptibility to certain pharmacological agents and can provide prognostic information regarding disease evolution. Moreover, based on the affinity of somatostatin analogs for the different types of SSTRs, the therapeutic range includes conditions such as tumors, acromegaly, post-prandial hypotension, hyperinsulinism, and many more. On the other hand, a number of somatostatin antagonists may prove useful in certain medical settings, based on their differential affinity for SSTRs. The aim of this review is to present in detail the principal characteristics of all five SSTRs and to provide an overview of the associated therapeutic potential in neoplasias.

Enteric pathogens relationship with small bowel histologic features of environmental enteric dysfunction in a multicountry cohort study

BackgroundEnvironmental Enteric Dysfunction (EED) is an acquired disorder of asymptomatic altered gut function, the etiology of which is unknown. EED is postulated to be a major contributor to growth faltering in early childhood in regions where early-life enteropathogenic carriage is prevalent. Few studies have examined the critical organ (the upper small bowel) with enteropathogens in the evolution of small bowel disease. ObjectivesThe objective of this study was to determine if fecal enteropathogenic detection predicts subsequent EED histology. MethodsFecal samples were obtained from undernourished children aged <2 y without diarrhea enrolled in 3 cohort studies, who failed nutritional intervention and subsequently underwent endoscopy. Duodenal biopsies from 245 (Bangladesh n = 120, Pakistan n = 57, and Zambia n = 68) children were scored using a semiquantitative histologic grading protocol. Thirteen enteropathogens were sought in common across the 3 centers using TaqMan array cards (TAC) (Bangladesh and Pakistan) and the Luminex platform (Zambia). An additional 18 pathogens and 32 virulence loci were sought by TAC and included in sensitivity analyses restricted to TAC data. ResultsMultivariable linear regressions adjusting for study center, age at stool collection, and stool-to-biopsy interval demonstrated the following: 1) an association of norovirus and Shigella detection with subsequent enterocyte injury [β 0.2 (95% CI: 0.1, 0.3); P = 0.002 and β 0.2 (95% CI: 0.0, 0.3); P = 0.008, respectively], 2) association of Campylobacter with intraepithelial lymphocytes [β 0.2 (95% CI: 0.0, 0.4); P = 0.046], and 3) association of Campylobacter and enterotoxigenic Escherichia coli with a summative EED histopathology index score [β 4.2 (95% CI: 0.8, 7.7); P = 0.017 and β 3.9 (95% CI: 0.5, 7.3); P = 0.027, respectively]. All but 2 of these associations (Shigella-enterocyte injury and Campylobacter-index score) were also demonstrated in TAC-only sensitivity analyses, which identified additional associations between other pathogens, pathogen burden, or virulence loci primarily with the same histologic parameters. ConclusionsThe detection of some enteropathogens in asymptomatic infections is associated with subsequent EED histopathology. These novel findings offer a basis for future EED etiology and pathogenesis studies.

Understanding MDS stem cells: Advances and limitations

In work spanning several decades, extensive studies have focused on the properties of malignant stem cells that drive the pathogenesis of acute myeloid leukemia (AML). However, relatively little attention has been devoted to several serious myeloid malignancies that occur prior to the onset of frank leukemia, including myelodysplastic syndrome (MDS). Like leukemia, MDS is hypothesized to arise from a pool of immature malignant stem and progenitor cells (MDS-SCs) that serve as a reservoir for disease evolution and progression1. While multiple studies have sought to identify and characterize the biology and vulnerabilities of MDS-SCs, yet translation of scientific concepts to therapeutically impactful regimens has been limited. Here, we evaluate the currently known properties of MDS-SCs as well as the post-transcriptional mechanisms that drive MDS pathogenesis at a stem and progenitor level. We highlight limits and gaps in our characterization and understanding of MDS-SCs and address the extent to which the properties of MDS-SC are (and can be) inferred from the characterization of LSCs.

Host and antibiotic jointly select for greater virulence in Staphylococcus aureus.

Widespread antibiotic usage has resulted in the rapid evolution of drug-resistant bacterial pathogens and poses significant threats to public health. Resolving how pathogens respond to antibiotics under different contexts is critical for understanding disease emergence and evolution going forward. The impact of antibiotics has been demonstrated most directly through in vitro pathogen passaging experiments. Independent from antibiotic selection, interactions with hosts have also altered the evolutionary trajectories and fitness landscapes of pathogens, shaping infectious disease outcomes. However, it is unclear how interactions between hosts and antibiotics impact the evolution of pathogen virulence. Here, we evolved and re-sequenced Staphylococcus aureus , a major bacterial pathogen, varying exposure to host and antibiotics to tease apart the contributions of these selective pressures on pathogen adaptation. After 12 passages, S. aureus evolving in Caenorhabditis elegans nematodes exposed to a sub-minimum inhibitory concentration of antibiotic (oxacillin) became highly virulent, regardless of whether the ancestral pathogen was methicillin-resistant (MRSA) or methicillin-sensitive (MSSA). Host and antibiotic exposure selected for reduced drug susceptibility in MSSA lineages while increasing MRSA total growth outside hosts. We identified mutations in genes involved in complex regulatory networks linking virulence and metabolism, including codY , agr , and gdpP , suggesting that rapid adaptation to infect hosts may have pleiotropic effects. In particular, MSSA populations under selection from host and antibiotic accumulated mutations in the global regulator gene codY , which controls biofilm formation in S. aureus. These populations had indeed evolved more robust biofilms-a trait linked to both virulence and antibiotic resistance-suggesting evolution of one trait can confer multiple adaptive benefits. Despite evolving in similar environments, MRSA and MSSA populations proceeded on divergent evolutionary paths, with MSSA populations exhibiting more similarities across replicate populations. Our results underscore the importance of considering multiple and concurrent selective pressures as drivers of pervasive pathogen traits.

Ecology and Evolution of Infectious Diseases (NSF)

Ecology and Evolution of Infectious Diseases (NSF)

Convergent alterations in the tumor microenvironment of MYC-driven human and murine prostate cancer

How prostate cancer cells and their precursors mediate changes in the tumor microenvironment (TME) to drive prostate cancer progression is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we perform extensive single-cell RNA-sequencing (scRNA-seq) and molecular pathology of the comparative biology between human prostate cancer and key stages in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues reveal that cancer cell-intrinsic activation of MYC signaling is a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Cell communication network and pathway analyses in GEMMs show that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogram the TME during carcinogenesis, leading to a convergence of cell state alterations in neighboring epithelial, immune, and fibroblast cell types that parallel key findings in human prostate cancer.

Quantitative ultrashort echo time MR imaging of knee osteochondral junction: An ex vivo feasibility study.

Compositional changes can occur in the osteochondral junction (OCJ) during the early stages and progressive disease evolution of knee osteoarthritis (OA). However, conventional magnetic resonance imaging (MRI) sequences are not able to image these regions efficiently because of the OCJ region's rapid signal decay. The development of new sequences able to image and quantify OCJ region is therefore highly desirable. We developed a comprehensive ultrashort echo time (UTE) MRI protocol for quantitative assessment of OCJ region in the knee joint, including UTE variable flip angle technique for T1 mapping, UTE magnetization transfer (UTE-MT) modeling for macromolecular proton fraction (MMF) mapping, UTE adiabatic T1ρ (UTE-AdiabT1ρ) sequence for T1ρ mapping, and multi-echo UTE sequence for T2* mapping. B1 mapping based on the UTE actual flip angle technique was utilized for B1 correction in T1, MMF, and T1ρ measurements. Ten normal and one abnormal cadaveric human knee joints were scanned on a 3T clinical MRI scanner to investigate the feasibility of OCJ imaging using the proposed protocol. Volumetric T1, MMF, T1ρ, and T2* maps of the OCJ, as well as the superficial and full-thickness cartilage regions, were successfully produced using the quantitative UTE imaging protocol. Significantly lower T1, T1ρ, and T2* relaxation times were observed in the OCJ region compared with those observed in both the superficial and full-thickness cartilage regions, whereas MMF showed significantly higher values in the OCJ region. In addition, all four UTE biomarkers showed substantial differences in the OCJ region between normal and abnormal knees. These results indicate that the newly developed 3D quantitative UTE imaging techniques are feasible for T1, MMF, T1ρ, and T2* mapping of knee OCJ, representative of a promising approach for the evaluation of compositional changes in early knee OA.

Plasma proteomics and lipidomics facilitate elucidation of the link between Alzheimer's disease development and vessel wall fragility

Proximity Extension Assay (PEA) and mass spectrometry (MS) methodologies were utilized for the proteomic and lipidomic characterization of plasma specimens from patients who developed Alzheimer's disease. Proteomics was performed by both PEA and Liquid Chromatography (LC)/MS in this study, but all the more because LC/MS generally tends to be biased towards proteins with high expression and high variability, generating hypotheses proved challenging. Consequently, attempt was made to interpret the results from the PEA data. There were 150 significantly variable proteins and 68 lipids among 1000 proteins and 400 lipids. Pathway analysis was performed for both total and variable proteins measured to reduce bias, and it appeared that vascular fragility was related to AD. Furthermore, a multitude of lipid-associated proteins exhibited statistical changes. In certain instances, the function of individual proteins affected the factors associated with them, whereas others demonstrated trends contrary to anticipated outcomes. These trends seem indicative of diverse feedback mechanisms that provide homeostatic equilibrium. The degree of unsaturation of fatty acids, correlated with cardiovascular risk, warrants specific attention. Certain bile acids exhibited the potential to cause vascular endothelial damage. Contemplating these discoveries in tandem with previously documented phenomena, subtle shifts in homeostatic functions seem to be linked to the fragility of vascular endothelial cells. This is evidenced by the slow and chronic evolution of Alzheimer's disease from preclinical stages to its manifestation.

Imaging Pulmonary Fibrosis and Treatment Efficacy In Vivo with Autotaxin-Specific PET Ligand [18F]ATX-1905.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by unpredictable progression and limited therapeutic options. Current diagnosis relies on high resolution computed tomography (HRCT), which may not adequately capture early signs of deterioration. The enzyme autotaxin (ATX) emerges as a prominently expressed extracellular secretory enzyme in the lungs of IPF patients. The objective of this study was to evaluate the effectiveness of 18F-labeled ATX-targeted tracer [18F]ATX-1905, in comparison with [18F]FDG, for early fibrosis diagnosis, disease evolution monitoring, and treatment efficacy assessment in bleomycin-induced pulmonary fibrosis (BPF) models. To assess treatment efficacy, mice were treated with two commonly used drugs for IPF, pirfenidone or nintedanib, from Day 9 to Day 23 postbleomycin administration. Lung tissue assessments encompassed inflammation severity via H&E staining, and Ashcroft scoring via Masson staining, alongside quantification of ATX expression through ELISA. Positron emission tomography (PET) imaging employing [18F]FDG and [18F]ATX-1905 tracked disease progression pre- and post-treatment. The extent of pulmonary fibrosis corresponded to changes in ATX expression levels in the BPF mouse model. Notably, [18F]ATX-1905 exhibited elevated uptake in BPF lungs during the progression of the disease, particularly evident at the early stage (Day 9). This uptake was inhibited by an ATX inhibitor, PF-8380, underscoring the specificity of the radiotracer. Conversely, [18F]FDG uptake, peaking at Day 15, decreased subsequently, likely reflective of diminished inflammation. A 2-week treatment regimen using either pirfenidone or nintedanib resulted in notable reductions of ATX expression levels and fibrosis degrees within lung tissues, based on ELISA and Masson staining, as evidenced by PET imaging with [18F]ATX-1905. [18F]FDG uptake also decreased following the treatment period. Additionally, PET/CT imaging extended to a nonhuman primate (NHP) BPF model. The uptake of [18F]ATX-1905 (SUVmax = 2.2) was significantly higher than that of [18F]FDG (SUVmax = 0.7) in fibrotic lung tissue. Using our novel ATX-specific radiotracer [18F]ATX-1905 and PET/CT imaging, we demonstrated excellent ability in early fibrosis detection, disease monitoring, and treatment assessment within lungs of the BPF mouse models. [18F]ATX-1905 displayed remarkable specificity for ATX expression and high sensitivity for ATX alterations, suggesting its potential for monitoring varying ATX expression in lungs of IPF patients.

Pathogen shape: Implication on pathogenicity via respiratory deposition

The shape of environmental aerosols contributes to the discrepancy in their dynamic behavior compared to spherical particles, which have received inadequate consideration. We reported deposition patterns of aerosols and aerosol-transmissible pathogens in real human respiratory systems, taking into account their actual shape, using a validated computational-based model. We found that the shape of the aerosols significantly influenced its deposits and accessibility within the respiratory system, significantly in the tracheobronchial region. As an example, we estimated that over 180 % of differences in deposits in the trachea and bronchi were attributable to pathogens shape, inferring the underlying pathogenicity difference of these regions. These findings, capturing the spatial heterogeneity of pathogens and aerosols deposition in human respiratory system, have major implication for understanding the evolution of aerosol-related disease.

The Possible Associations between Tauopathies and Atherosclerosis, Diabetes Mellitus, Dyslipidemias, Metabolic Syndrome and Niemann-Pick Disease.

Clinical evaluation and treatment of tauopathic syndromes remain a challenge. There is a growing interest in theories concerning their possible associations with metabolic diseases. The possible connection between those diseases might be linked with cerebrovascular dysfunction. The endothelial cell damage and impairment of the blood-brain barrier observed in atherosclerosis or diabetes may play a role in contributing to tauopathic syndrome development. Additionally, the inflammation evoked by pathological metabolic changes may also be involved in this process. Multiple cases indicate the coexistence of metabolic disorders and tauopathic syndromes. These findings suggest that modifying the evolution of metabolic and cerebrovascular diseases may impact the course of neurodegenerative diseases. Obtained data could indicate the possible benefits of introducing routine carotid artery sonography, revascularization operation or antihypertensive medications among patients at high risk for tauopathies. This review has identified this understudied area, which is currently associated with several diseases for which there is no treatment. Due to the pathomechanisms linking metabolic diseases and tauopathies, further investigation of this area of research, including cohort studies, is recommended and may provide new pharmacological perspectives for treatment.

The Emerging Roles of Hydrogen Sulfide in Ferroptosis.

Significance: Ferroptosis, a form of regulated cell death characterized by a large amount of lipid peroxidation-mediated membrane damage, joins the evolution of multisystem diseases, for instance, neurodegenerative diseases, chronic obstructive pulmonary disease, acute respiratory distress syndrome, osteoporosis, osteoarthritis, and so forth. Since being identified as the third gasotransmitter in living organisms, the intricate role of hydrogen sulfide (H2S) in ferroptosis has emerged at the forefront of research. Recent Advances: Novel targets in the relevant metabolic pathways have been found, including transferrin receptor 1, cystine/glutamate antiporter, and others, coupled with the exploration of new signaling pathways, particularly the p53 signaling pathway, the nitric oxide/nuclear factor erythroid 2-related factor 2 signaling pathway, and so on. Many diseases such as emphysema and airway inflammation, myocardial diseases, endothelial dysfunction in aging arteries, and traumatic brain injury have recently been found to be alleviated directly by H2S inhibition of ferroptosis. Safe, effective, and tolerable novel H2S donors have been developed and have shown promising results in phase I clinical trials. Critical Issues: Complicated cross talk between the ferroptosis signaling pathway and oncogenicfactors results in the risk of cancer when inhibiting ferroptosis. Notably, targeted delivery of H2S is still a challenging task. Future Directions: Discovering more reliable and stable novel H2S donors and achieving their targeted delivery will enable further clinical trials for diseases associated with ferroptosis inhibition by H2S, determining their safety, efficacy, and tolerance.

Renal arterial resistance index before and after vericiguat administration: Should it be considered the fantastic five?

BackgroundHeart failure (HF) is a chronic-progressive disease. Once established, it is almost impossible to obtain a restitutio ad integrum of the cardiac function, but current strategies aim at slowing down the progression towards the terminal stages of the disease, which inevitably lead to the exitus. On the basis of these considerations, it appears clear that pharmacological interventions applied in this clinical condition should prevent first the development of the disease, by controlling the risk factors for HF thus reducing the onset of the disease, second slowing the disease evolution towards the terminal phases thus containing clinical symptoms and reducing the number of hospitalizations. In this scenario, the add-on therapy with vericiguat seems promising as reported in the VICTORIA study without affecting renal function. Several evidence indicates that renal arterial resistance index (RRI) seems to better reflect cardiovascular damage also in HF patients, thus affecting patients prognosis MethodsIn the present study we have analyzed the effect of vericiguat administration in 27 HF patients specifically evaluating RRI. ResultsVericiguat signicantly reduces RRI. ConclusionsThe findings of the present study seems to indicate that vericiguat, beyond its primary mechanism of action, might offer an additional advantage in HF patients.

Astrocytic centrin-2 expression in entorhinal cortex correlates with Alzheimer's disease severity.

Astrogliosis is a condition shared by acute and chronic neurological diseases and includes morphological, proteomic, and functional rearrangements of astroglia. In Alzheimer's disease (AD), reactive astrocytes frame amyloid deposits and exhibit structural changes associated with the overexpression of specific proteins, mostly belonging to intermediate filaments. At a functional level, amyloid beta triggers dysfunctional calcium signaling in astrocytes, which contributes to the maintenance of chronic neuroinflammation. Therefore, the identification of intracellular players that participate in astrocyte calcium signaling can help unveil the mechanisms underlying astrocyte reactivity and loss of function in AD. We have recently identified the calcium-binding protein centrin-2 (CETN2) as a novel astrocyte marker in the human brain and, in order to determine whether astrocytic CETN2 expression and distribution could be affected by neurodegenerative conditions, we examined its pattern in control and sporadic AD patients. By immunoblot, immunohistochemistry, and targeted-mass spectrometry, we report a positive correlation between entorhinal CETN2 immunoreactivity and neurocognitive impairment, along with the abundance of amyloid depositions and neurofibrillary tangles, thus highlighting a linear relationship between CETN2 expression and AD progression. CETN2-positive astrocytes were dispersed in the entorhinal cortex with a clustered pattern and colocalized with reactive glia markers STAT3, NFATc3, and YKL-40, indicating a human-specific role in AD-induced astrogliosis. Collectively, our data provide the first evidence that CETN2 is part of the astrocytic calcium toolkit undergoing rearrangements in AD and adds CETN2 to the list of proteins that could play a role in disease evolution.

Autoantibodies against beta cells to predict early insulin requirements in pediatric patients with clinically diagnosed type 2 diabetes.

Autoimmunity has emerged as a probable disease modifier in patients with clinically diagnosed type 2 diabetes mellitus (T2DM), that is, patients who have insulin resistance, obesity, and other cardiovascular risk factors, suggesting that the presence of glutamic acid decarboxylase (anti-GAD65), islet antigen 2 (anti-IA2), and zinc transporter 8 (anti-Zn8T) antibodies could have deleterious effects on beta cell function, causing failure and earlier requirement for insulin treatment. To evaluate anti-GAD65, anti-IA2 and anti-Zn8T as predictors of early insulin requirement in adolescents with a clinical diagnosis of T2DM. This was a case-control study in patients with clinically diagnosed with T2DM (68 cases and 64 controls with and without early insulin dependence respectively), male and female, aged 12-18 years. Somatometry, blood pressure, glucose, insulin, C-peptide, glycated hemoglobin A1c, and lipid profiles were assessed. ELISA was used to measure anti-GAD65, anti-IA2, and anti-Zn8T antibodies. Descriptive statistics, Pearson's χ 2 test, Student's t test, and logistic regression was performed. P < 0.05 was considered statistically significant. There were 132 patients (53.8% female), with a mean age was 15.9 ± 1.3 years, and there was a disease evolution time of 4.49 ± 0.88 years. The presence of anti-GAD65, anti-IA2, and anti-Zn8T positivity was found in 29.5%, 18.2%, and 15.9%, respectively. Dividing the groups by early or no insulin dependence showed that the group with insulin had a higher frequency of antibody positivity: anti-GAD65 odds ratio (OR): 2.42 (1.112-5.303, P = 0.026); anti-IA2: OR: 1.55 (0.859-2.818, P = 0.105); and anti-Zn8T: OR: 7.32 (2.039-26.279, P = 0.002). Anti-GAD65 positivity was high in our study. Anti-GAD65 and anti-Zn8T positivity showed a significantly depleted beta cell reserve phenotype, leading to an increased risk of early insulin dependence.

Albuminuria in patients with Systemic Lupus Erythematous

&lt;p&gt;Renal involvement is one of the main causes of morbidity and mortality in patients with Systemic Lupus Erythematous. Lupus Nephropathy should be detected early. Albuminuria may be the only finding in the early stage of kidney disease. An observational, descriptive and retrospective study was carried out to determine the presence of Albuminuria (&amp;gt; 30 mg/24 h) in 60 patients with SLE who were admitted to the Rheumatology Service of the “10 de Octubre” Surgical Clinical Hospital, between October 2013 and September 2014. Albuminuria was observed to increase with increasingly pronounced drops in Glomerular Filtration (predicted according to the equation used in the MDRD Study). A significant statistical association was also obtained between albuminuria and disease evolution time: the longer the disease evolution time, the greater the albuminuria observed. Albuminuria is frequent in patients with SLE, its values being directly proportional to the time of evolution of the disease. This did not occur with the Glomerular Filtration, which remained relatively constant for any time of disease evolution.&lt;/p&gt;

Anorexia nervosa: Disease process, challenges and hope

Anorexia nervosa, as a psychiatric disorder with a progressively high prevalence, is characterized by the following features: high mortality rate, serious harm, long-lasting effects, difficult to cure and easy to relapse. In recent years, Awareness of anorexia nervosa is different than in the past, going deeper: it is a complex disorder involving multiple systems. Many disciplines are also actively exploring it. However, there are still problems such as Pathologic mechanism unclear, no clear indicators of disease, no targeted drugs, and insufficient public awareness. This article analyses research in the fields of social environment, immunology and brain science in the order of disease onset, evolution and treatment (including difficulties in the treatment process, such as in Refeeding syndrome), and puts forward some recommendations for earlier intervention, comprehensive treatment, and optimization and maintenance of therapeutic efficacy in anorexia nervosa. It is also hoped that public awareness and attention will be raised. There are still many gaps in the road to overcoming anorexia nervosa, which has a large research space and is also not less challenging. Future research could focus on finding objective indicators for diagnosing anorexia nervosa or suggesting recovery, and finding targeted drugs from the perspective of multi-system interactions.

MRI-Derived Modeling of Disease Progression Patterns in Patients With Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is assumed to follow a steady course that is similar across patients. To date, phenotypic and temporal diversities of TLE evolution remain unknown. In this study, we aimed at simultaneously characterizing these sources of variability based on cross-sectional data. We studied consecutive patients with TLE referred for evaluation by neurologists to the Montreal Neurological Institute epilepsy clinic, who underwent in-patient video EEG monitoring and multimodal imaging at 3 Tesla, comprising 3D T1 and fluid-attenuated inversion recovery and 2D diffusion-weighted MRI. The cohort included patients with drug-resistant epilepsy and patients with drug-responsive epilepsy. The neuropsychological evaluation included Wechsler Adult Intelligence Scale-III and Leonard tapping task. The control group consisted of participants without TLE recruited through advertisement and who underwent the same MRI acquisition as patients. Based on surface-based analysis of key MRI markers of pathology (gray matter morphology and white matter microstructure), the Subtype and Stage Inference algorithm estimated subtypes and stages of brain pathology to which individual patients were assigned. The number of subtypes was determined by running the algorithm 100 times and estimating mean and SD of disease trajectories and the consistency of patients' assignments based on 1,000 bootstrap samples. Effect of normal aging was subtracted from patients. We examined associations with clinical and cognitive parameters and utility for individualized predictions. We studied 82 patients with TLE (52 female, mean age 35 ± 10 years; 11 drug-responsive) and 41 control participants (23 male, mean age 32 ± 8 years). Among 57 operated, 43/37/20 had Engel-I outcome/hippocampal sclerosis/hippocampal isolated gliosis, respectively. We identified 3 trajectory subtypes: S1 (n = 35), led by ipsilateral hippocampal atrophy and gliosis, followed by white-matter damage; S2 (n = 27), characterized by bilateral neocortical atrophy, followed by ipsilateral hippocampal atrophy and gliosis; and S3 (n = 20), typified by bilateral limbic white-matter damage, followed by bilateral hippocampal gliosis. Patients showed high assignability to their subtypes and stages (>90% bootstrap agreement). S1 had the highest proportions of patients with early disease onset (effect size d = 0.27 vs S2, d = 0.73 vs S3), febrile convulsions (χ2 = 3.70), drug resistance (χ2 = 2.94), a positive MRI (χ2 = 8.42), hippocampal sclerosis (χ2 = 7.57), and Engel-I outcome (χ2 = 1.51), pFDR < 0.05 across all comparisons. S2 and S3 exhibited the intermediate and lowest proportions, respectively. Verbal IQ and digit span were lower in S1 (d = 0.65 and d = 0.50, pFDR < 0.05) and S2 (d = 0.76 and d = 1.09, pFDR < 0.05), compared with S3. We observed progressive decline in sequential motor tapping in S1 and S3 (T = -3.38 and T = -4.94, pFDR = 0.027), compared with S2 (T = 2.14, pFDR = 0.035). S3 showed progressive decline in digit span (T = -5.83, p = 0.021). Supervised classifiers trained on subtype and stage outperformed subtype-only and stage-only models predicting drug response in 73% ± 1.0% (vs 70% ± 1.4% and 63% ± 1.3%) and 76% ± 1.6% for Engel-I outcome (vs 71% ± 0.8% and 72% ± 1.1%), pFDR < 0.05 across all comparisons. Cross-sectional MRI-derived models provide reliable prognostic markers of TLE disease evolution, which follows distinct trajectories, each associated with divergent patterns of hippocampal and whole-brain structural alterations, as well as cognitive and clinical profiles.

How is diagnostic uncertainty communicated and managed in real world primary care settings?

BackgroundManaging diagnostic uncertainty is a major challenge in primary care due to factors such as the absence of definitive tests, variable symptom presentations and disease evolution. Maintaining patient trust during a period of investigative uncertainty, whilst minimising scope for diagnostic error is a challenge. Mismanagement can lead to diagnostic errors, treatment delays, and suboptimal patient outcomes.ObjectiveOur aim was to explore how UK primary care physicians (GPs) address and communicate diagnostic uncertainty in practice.DesignThis qualitative study used video and audio-recordings. Verbatim transcripts were coded with a modified, validated tool to capture GPs’ actions and communication in primary care consultations that included diagnostic uncertainty. The tool includes items relating to advice regarding new symptoms or symptom deterioration (sometimes called ‘safety netting’). Video data was analysed to identify GP and patient body postures during and after the delivery of the management plan.ParticipantsAll patient participants had a consultation with a GP, were over the age of 50 and had (1) at least one new presenting problem or (2) one persistent problem that was undiagnosed.ApproachData collection occurred in GP-patient consultations during 2017–2018 across 7 practices in UK during 2017–2018.Key resultsGPs used various management strategies to address diagnostic uncertainty, including (1) symptom monitoring without treatment, (2) prescribed treatment with symptom monitoring, and (3) addressing risks that could arise from administrative tasks. GPs did not make management plans for potential treatment side effects. Specificity of uncertainty management plans varied among GPs, with only some offering detailed actions and timescales. The transfer of responsibility for the management plan to patients was usually delivered rather than negotiated, with most patients confirming acceptance before concluding the discussion.ConclusionsWe offer guidance to healthcare professionals, improving awareness of using and communicating management plans for diagnostic uncertainty.